Re: 암세포 굶기기 . 베타 하이드로뷰티레이트를 에너지로 사용하는 암의 유연성 2026!!

[문형철]

BHB(베타-하이드록시부티레이트)는

대장암(CRC)에서 이중 역할(dual role)을 한다.

일부 암세포에서는 종양 성장을 억제하지만,

다른 암세포(특히 특정 유전자 변이 보유 세포)에서는

대체 연료로 작용해 성장할 수 있다.

주요 내용 요약

1. BHB의 촉진 효과 (Pro-tumor effect)
   • 대장암 세포는 대사 유연성(metabolic plasticity)이 뛰어나서, 저포도당 환경에서 BHB를 MCT 수송체를 통해 들여와 BDH1 효소로 분해 → 아세틸-CoA → TCA 회로 → ATP 생산에 사용한다.
   • 특히 APC, KRAS, TP53 변이가 있는 세포(HCT116, SW480 등)에서 이 현상이 강하게 나타난다.
   • BHB가 ACAT1을 활성화 → IDH1 아세틸화 → HIF1α-SRC 축 활성화 → 증식, 이동, 줄기세포 특성 증가.
   • 예: 5-FU 처리 후 SW480 세포 일부에서 BHB가 생존율, 산화적 인산화(OCR), 이동력을 높임.
2. BHB의 억제 효과 (Anti-tumor effect)
   • HCAR2 수용체를 통해 Hopx 유전자를 활성화 → 세포 증식 억제.
   • HIF-1α/VEGFA 억제를 통해 혈관신생(angiogenesis) 감소.
   • 일부 상황에서는 옥살리플라틴(oxaliplatin) 저항성을 줄여 항암 효과를 높임.
3. 왜 이런 차이가 생기나?
   • 암세포의 대사 아형(metabolic subtype) 차이:
     • 순수 당분해형(glycolytic) → BHB에 취약
     • 케톤 분해형(ketolytic)으로 전환된 세포(p53 변이 등) → BHB를 잘 이용해 저혈당/케토 환경에서도 잘 살아남음
   • 종양 미세환경(TME)과의 상호작용도 중요 (면역세포, 혈관 등에 미치는 영향).

결론 및 시사점 (논문에서 강조하는 부분)

• 케토제닉 다이어트나 BHB 보충은 모든 대장암 환자에게 좋지 않을 수 있다.
• 개인화(personalized) 접근이 필수: 종양의 유전자 프로파일(APC/KRAS/TP53 변이 여부)와 대사 특성(케톤 이용 능력)을 미리 평가해야 한다.
• 향후 연구 방향: BHB를 활용하거나 차단하는 표적 치료 개발 (예: OXCT1, ACAT1 억제제 등).

이 논문은 이전에 말씀드린 “같은 BHB라도 어떤 암세포는 죽이고, 어떤 암세포는 오히려 키울 수 있다”는 내용을 가장 최근(2026년)에 체계적으로 정리한 리뷰

β-Hydroxybutyrate, a primary metabolite of ketogenic diets and its dual role in modulating colorectal cancer: from molecular mechanisms to therapeutic insights

• Review
• Open access
• Published: 24 February 2026

• Volume 26, article number 168, (2026)
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Clinical and Experimental MedicineAims and scopeSubmit manuscript

β-Hydroxybutyrate, a primary metabolite of ketogenic diets and its dual role in modulating colorectal cancer: from molecular mechanisms to therapeutic insights

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• Parisa Rashidi, 
• Zahra Bagheri, 
• Zahra Khodayar, 
• Saba Tarkashvand, 
• Negin Elahirad, 
• Reihaneh Akhoondi, 
• Sepehr Hoseinzadeh Moghaddam, 
• Masoud Sanati, 
• Roya Haghighatjou, 
• Reza Yekani, 
• Mahtab Mehboodi, 
• Armita Banimahdidehkordi, 
• Saman Rabiei, 
• Houra Dinvari & 
• Mohammad Hasan Maleki 

• 776 Accesses

• 6 Altmetric

• Explore all metrics 

Abstract

Colorectal cancer (CRC) is a genetically varied malignancy noted for its metabolic flexibility, which enables cancer cells to adapt to different energy sources. Beta-hydroxybutyrate (BHB), a significant ketone body that is elevated during ketogenic diets, has attracted considerable attention for its potential therapeutic benefits. ​However, recent evidence indicates that BHB may paradoxically facilitate the advancement of CRC by acting as an alternative energy source, especially in cancer cells with mutations in critical genes such as APC, KRAS, and TP53. This review investigates the mechanisms through which CRC cells utilize BHB for their survival, focusing on enhanced metabolic plasticity, resistance to apoptosis, and modified responses to chemotherapy and immunotherapy. It also explores the interaction between BHB and the tumor microenvironment (TME), emphasizing how BHB can influence immune responses and tumor progression. Given the complexity of BHB’s role in CRC, the review underscores the necessity for personalized approaches that consider the tumor’s genetic and metabolic characteristics. Understanding the dual role of BHB in CRC is essential for devising more effective therapeutic strategies that can either harness or counteract its effects, thereby guiding the application of ketogenic diets and other metabolic interventions in the treatment of CRC.

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Introduction

Colorectal cancer (CRC) is one of the most preval‎ent malignancies worldwide, with substantial implications for public health due to its high morbidity and mortality rates [1, 2]. The traditional understanding of cancer metabolism has been dominated by the Warburg effect, which describes how cancer cells preferentially utilize glycolysis for energy production, even in the presence of oxygen [3]. This metabolic shift is thought to support the rapid growth and survival of cancer cells by providing both energy and biosynthetic precursors. However, recent research has revealed that cancer cells, including those in colorectal cancer, may exhibit metabolic flexibility, allowing them to exploit alternative energy sources, including ketone bodies like beta-hydroxybutyrate (BHB) [4].

BHB is a ketone body produced by the liver during periods of low glucose availability, such as fasting or ketogenic diets [5,6,7,8,9]. While BHB has been investigated for its potential therapeutic benefits, particularly in brain cancers [10,11,12] and other conditions [8], its role in colorectal cancer is more complex. T Mao study revealed that CRC cells may have the capacity to utilize BHB as an alternative energy source, potentially aiding in their survival and progression, especially under metabolic stress conditions [13].

This review aims to explore the various mechanisms by which BHB levels can be increased in colorectal cancer and discuss how BHB, paradoxically, might contribute to cancer progression rather than suppression. The review will also cover the genetic factors involved in CRC progression and their interactions with BHB, providing a comprehensive understanding of why ketogenic diets may fail as a therapeutic strategy in CRC.

Beta-hydroxybutyrate: metabolism and function

Synthesis of beta-hydroxybutyrate

BHB is primarily synthesized in the liver from acetyl-CoA, a product of fatty acid oxidation [8, 14]. This process is typically upregulated during periods of carbohydrate restriction, fasting, or ketogenic diets, conditions under which the body switches from glucose to fat as its primary energy source [15]. The key steps in BHB synthesis involve the following enzymes: 3-Hydroxy-3-Methylglutaryl-CoA Synthase (HMGCS2) which catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA, the precursor of ketone bodies, HMG-CoA Lyase (HMGCL) which converts HMG-CoA to acetoacetate, the first ketone body formed in the pathway, and finally Beta-Hydroxybutyrate Dehydrogenase (BDH1) which acts as the key enzyme in the reduction of Acetoacetate to beta-hydroxybutyrate in the presence of NADH [16, 17] (Fig. 1).

Fig. 1

Full size image

Schematic illustration of hepatic beta-hydroxybutyrate (BHB) synthesis. Under conditions of glucose restriction, such as during a ketogenic diet, free fatty acids undergo mitochondrial beta-oxidation in the liver, generating acetyl-CoA. Two acetyl-CoA molecules are condensed by thiolase to form acetoacetyl-CoA, which is then converted to HMG-CoA by mitochondrial HMG-CoA synthase (HMGCS2). HMG-CoA lyase (HMGCL) cleaves HMG-CoA to acetoacetate, which is subsequently reduced to BHB by beta-hydroxybutyrate dehydrogenase in an NADH-dependent reaction. BHB is released into systemic circulation and transported to peripheral tissues, where it is oxidized back to acetoacetate in the mitochondria to serve as an alternative energy substrate

Once synthesized, BHB is released into the bloodstream, where it can be taken up by various tissues and converted back into acetyl-CoA, fueling the tricarboxylic acid (TCA) cycle for ATP production [18]. This process allows cells to continue producing energy in the absence of sufficient glucose [14, 19].

Role of beta-hydroxybutyrate in cellular metabolism

BHB has multiple roles in cellular metabolism beyond serving as an energy source. It is also involved in signaling pathways and can influence gene expression‎ by acting as an inhibitor of histone deacetylases (HDACs) [11]. This inhibition can lead to changes in the expression‎ of genes involved in metabolism, inflammation, and cell survival.

In the context of cancer, BHB’s role is dual-faceted. While it can induce apoptosis and reduce oxidative stress in some cancer models [9, 20, 21], it may also provide a survival advantage to cancer cells that can utilize it as an alternative fuel [13, 22]. The capacity of cancer cells to metabolically adapt and exploit BHB for energy is particularly relevant in the case of CRC, where tumor cells may exhibit significant metabolic plasticity [23].

Mechanisms of increasing beta-hydroxybutyrate levels in the body

Various strategies can elevate BHB levels in the body, including dietary interventions, pharmacological agents, and lifestyle modifications.

Ketogenic diets

A ketogenic diet is a high-fat, low-carbohydrate diet that forces the body to enter a state of ketosis, where ketone bodies, including BHB, are produced because of increased fatty acid oxidation [24]. The ketogenic diet has gained attention as a potential therapeutic strategy for various cancers, including CRC, due to its ability to reduce glucose availability, thereby starving cancer cells of their primary energy source [25].

However, emerging evidence suggests that the ketogenic diet might not be entirely effective in CRC. Some colorectal cancer cells have shown the ability to adapt to low-glucose environments by utilizing alternative energy sources like BHB [26, 27]. This metabolic flexibility undermines the therapeutic potential of ketogenic diets, as CRC cells may continue to proliferate despite the reduced glucose levels.

Exogenous ketones

Exogenous ketones, available primarily as ketone salts or esters, offer a direct source of BHB that circumvents the necessity for endogenous ketogenesis [28]. This unique capability allows for a rapid elevation of blood BHB levels, thus providing a convenient method to induce ketosis without the need for strict dietary compliance [29, 30].

The administration of exogenous ketones leads to a swift increase in circulating BHB concentrations. By supplying this ketone directly, individuals can enter a state of ketosis more conveniently than through traditional methods, which often require significant dietary restrictions such as high-fat and low-carbohydrate intake [31]. Exogenous ketone supplementation allows for increased BHB levels while avoiding the challenges linked to strict ketogenic diets. Users can expect to achieve increased BHB levels shortly after intake, thus quickly experiencing the benefits of ketosis, which can include improved energy levels and enhanced cognitive function. There is emerging evidence suggesting that exogenous ketones may play a role in various therapeutic applications, such as weight management, cognitive enhancement, and potentially in managing conditions characterized by high oxidative stress [32,33,34].

​.

Fasting and caloric restriction

Fasting and caloric restriction are well-established methods for increasing endogenous BHB production [35, 36]. These dietary interventions induce a metabolic switch from glucose metabolism to fat oxidation, a process that significantly enhances the body’s production of ketone bodies, particularly BHB [37, 38].

When an individual fasts or restricts caloric intake, the body initially utilizes stored glycogen as its primary energy source. As glycogen stores deplete, typically within 24 h, the body begins to adapt by increasing the oxidation of fatty acids. This transition is crucial as it leads to the liver converting fatty acids into ketone bodies, including acetoacetate, acetone, and beta-hydroxybutyrate [36, 39,40,41].

​Fasting has been shown to possess anti-cancer properties, primarily by altering the metabolic landscape that supports tumor growth [42]. One mechanism by which fasting exerts its anti-cancer effects is through the reduction of insulin levels. Insulin is a potent growth factor that can stimulate the proliferation of cancer cells. Lower insulin levels, resulting from fasting, diminish the anabolic signaling that fuels cancer cell growth and survival [43].

Moreover, fasting reduces the availability of glucose and other nutrients that are essential for cancer cell metabolism [44,45,46]. Many cancers are characterized by a high dependence on glycolysis for energy production, known as the Warburg effect, where cancer cells preferentially metabolize glucose even in the presence of oxygen. By depriving cancer cells of glucose and nutrients through fasting, these interventions can induce metabolic stress in tumors, potentially leading to reduced growth rates and increased apoptosis (programmed cell death) [47, 48].

Research has indicated that various forms of fasting, including intermittent fasting or prolonged fasting, may inhibit tumor growth in several types of cancer models. For instance, studies involving animal models have demonstrated that fasting inhibits the progression of tumors in breast, prostate, and colon cancer, suggesting a broad spectrum of potential applications [49].

Furthermore, fasting may enhance the effectiveness of certain cancer therapies such as chemotherapy and radiation. The rationale behind this approach lies in the ability of fasting to condition normal cells to become more resistant to the cytotoxic effects of cancer treatments while simultaneously sensitizing cancer cells to these therapies [50, 51].

In summary, fasting and caloric restriction are potent strategies to increase endogenous BHB production through a metabolic shift from glucose to fat oxidation. The implications of these dietary interventions extend beyond metabolic health, influencing cancer dynamics by reducing insulin levels and nutrient availability for tumors. As research continues to unfold, fasting may become a significant adjunctive treatment strategy in cancer care, offering a low-cost, accessible means to enhance therapeutic outcomes and improve patient prognosis.

Pharmacological agents

Numerous pharmacological agents can influence the concentrations of BHB by either promoting ketogenesis or imitating the effects of BHB. For example, medications that activate peroxisome proliferator-activated receptor alpha (PPARα), such as fenofibrate [52] commonly prescribed to decrease triglyceride levels can enhance fatty acid oxidation, leading to an increase in BHB synthesis. Additionally, compounds that inhibit glycolysis, such as 2-deoxyglucose (2-DG) [53], may create a state of metabolic stress that promotes the utilization of ketone bodies, including BHB. While these pharmacological agents offer a targeted approach to modulating metabolism, their role in CRC is still under investigation [54, 55]. ​There might be a significant concern regarding the potential for these agents to stimulate tumor growth by providing cancer cells with alternative energy substrates [56]. This underscores the necessity for further research into the complex interactions among these pharmacological agents, BHB, and tumor metabolism.

Metabolic flexibility in colorectal cancer cells

The ability of cancer cells to alter their metabolic processes in response to changing environmental conditions, particularly the presence of various energy substrates, is essential for their survival and advancement [57]. This metabolic adaptability permits these cells to switch between different energy sources, such as glucose, fatty acids, and ketone bodies, in accordance with availability [58]. There is evidence that BHB can be used as a fuel in other cancers like breast and chondrosarcoma cancer cells [22, 59]. ​Such flexibility might facilitate the survival of colorectal cancer cells as well in a wide range of environments, enhancing their resilience and promoting tumor development. The HCT-119 cell line exhibits an increased tendency for metabolic reprogramming owing to genetic mutations, including those in the KRAS gene [60,61,62,63,64,65]. This cell line has the ability to utilize various alternative energy substrates, such as ketones, in contrast to other lines, such as SW480 and HT-29, which demonstrate a stronger dependence on the glycolytic pathway and a diminished capability for ketone oxidation [66,67,68]. This distinction signifies significant differences in the metabolic adaptability between these cell lines. By effectively leveraging available substrates, these cells can meet their energy requirements, even under conditions of metabolic stress or nutrient competition (unpublished).

The Warburg effect and beyond

The Warburg effect refers to a phenomenon found in cancer cells wherein they preferentially depend on glycolysis to produce adenosine triphosphate (ATP), even when there is an adequate supply of oxygen that would typically support oxidative phosphorylation [69]. This shift highlights a fundamental change in the way cancer cells source their energy compared to normal cells, which predominantly engage in oxidative metabolism under oxygen-rich conditions. Glycolysis is a metabolic pathway that transforms glucose into pyruvate while generating ATP. In the context of the Warburg effect, cancer cells continue to favor this pathway in the presence of oxygen, which would otherwise allow for more efficient ATP production through mitochondrial oxidative processes [3, 70].

The reliance on glycolysis enables rapid ATP generation, which is crucial for the swift division and growth of cancer cells. In addition to energy production, glycolysis yields important intermediates that act as precursors for essential biomolecules like amino acids, nucleotides, and lipids .These compounds are vital for synthesizing new cellular components necessary for growth and proliferation [71]. Moreover, the tumor microenvironment frequently experiences low oxygen levels. The term “hypoxia” denotes a deficiency of oxygen within tumor tissues or surrounding areas. ​This phenomenon frequently occurs because of the accelerated proliferation of cancer cells, which imposes strain on the vascular system primarily due to heightened energy requirements and rapid cell division [72]. Additionally, the irregularity of the vascular architecture within tumors and the compression of blood vessels by tumor cells contribute to the development of hypoxic conditions [73, 74]. In response, cancer cells increasingly rely on glycolysis, where the conversion of pyruvate to lactate allows for continued ATP production without the need for oxygen [75, 76].

Recent research underscores that while the Warburg effect is important, it is not the sole metabolic strategy utilized by cancer cells. CRC cells demonstrate metabolic flexibility, which enables them to switch to alternative energy sources when glucose is scarce. In conditions of limited glucose availability, cancer cells can adapt by metabolizing fatty acids or amino acids [77, 78].

Cancer cells can oxidize fatty acids to produce ATP through a process known as beta-oxidation. This metabolic pathway is particularly effective in supplying energy when glycolysis is compromised. Additionally, during periods of low glucose, such as fasting or following ketogenic diets, cancer cells can convert ketone bodies into usable energy. Ketone bodies are synthesized in the liver from fatty acids during extended low carbohydrate intake [44, 79,80,81].

The ability of cancer cells to utilize these alternative substrates holds significant implications for developing therapeutic strategies aimed at targeting cancer metabolism (Fig. 2). Ketogenic diets, for example, intentionally lower glucose consumption while increasing fat intake, leading to heightened ketone levels in the body [82]. This deliberate shift in metabolic substrates could potentially impede the growth of glucose-dependent tumors by depriving them of their primary energy source. A comprehensive understanding of the metabolic adaptations in cancer cells aids in designing therapeutic interventions that leverage these pathways. By inhibiting glucose metabolism while promoting the use of fatty acids or ketones, it may be possible to slow tumor growth or enhance the effectiveness of existing cancer treatments [83]. To summarize, the Warburg effect is pivotal in understanding cancer cell metabolism, emphasizing the preference for glycolysis. ​However, the observed metabolic flexibility allows cancer cells to adapt to diverse nutrient conditions, which is critical for developing effective strategies to target cancer metabolism.

Fig. 2

Full size image

Glucose and beta-hydroxybutyrate (BHB) metabolism in colorectal cancer (CRC) cells. Glucose, transported via GLUT1, undergoes glycolysis to produce pyruvate, which is primarily converted to lactate. A smaller fraction of pyruvate is converted to acetyl-CoA by PDH, fueling the TCA cycle. BHB, imported through MCT1, is metabolized to acetoacetate (AcAc) and subsequently acetoacetyl-CoA (AcAc-CoA), which enters the TCA cycle, supporting ATP production for energy demand. BHB, beta-hydroxybutyrate; CRC, colorectal cancer; GLUT1, glucose transporter 1; MCT1, monocarboxylate transporter 1; PDH, pyruvate dehydrogenase; AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; TCA, tricarboxylic acid; ATP, adenosine triphosphate

Utilization of beta-hydroxybutyrate by colorectal cancer cells

CRC cells have been observed to express various enzymes that aid in the uptake and utilization of BHB as an alternative energy source. A key group of proteins involved in this process are the monocarboxylate transporters (MCTs). These transporters are crucial for facilitating the transport of ketone bodies, including BHB, across cellular membranes. Research has shown that MCTs are often upregulated in cancer cells, enabling them to effectively absorb BHB from their external environment [84, 85].

Once BHB is taken up by the cancer cell, it is converted back into acetyl-CoA by the enzyme 3-hydroxybutyrate dehydrogenase 1 (BDH1) [86]. This conversion is important because acetyl-CoA is a vital metabolite that feeds into the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or citric acid cycle. The TCA cycle is a fundamental metabolic pathway essential for cellular respiration, allowing to produce ATP, which serves as the primary energy source for the cell. By converting BHB into acetyl-CoA, CRC cells can meet their energy and biosynthetic demands even in conditions where glucose is limited [59]. Alpha-ketoglutarate (α-KG) is an organic acid that serves as a key intermediary metabolite within the Krebs cycle, also referred to as the citric acid cycle. This compound is essential for cellular energy production and the metabolism of various substances in the organism. More specifically, α-KG is vital to metabolic pathways associated with proteins, lipids, and carbohydrates. Research indicates that α-ketoglutarate may impede tumor proliferation by regulating the citric acid cycle and mitigating abnormal metabolic processes under normoxic conditions. Numerous studies have demonstrated that α-KG supplementation can result in a reduction of tumor growth in experimental models of CRC.

Nevertheless, the anticancer effects of α-KG and BHB might be negated in certain cancer contexts due to specific metabolic pathways or mutations, such as isocitrate dehydrogenase (IDH) mutations [87,88,89,90,91].

This ability poses a challenge for therapeutic strategies designed to combat CRC by restricting glucose availability, such as ketogenic diets and other dietary interventions. The capacity of CRC cells to efficiently utilize BHB reduces the effectiveness of these dietary strategies and highlights the metabolic flexibility of cancer cells. Particularly during periods of metabolic stress induced by ketogenic diets or fasting, the presence of BHB in the bloodstream may enhance the survival and proliferation of CRC cells [26] (unpublished). In this situation, where the intention is to deprive cancer cells of glucose, BHB functions as an alternative energy source, enabling these cells to sustain their growth and viability. This metabolic adaptability can strengthen the resilience of CRC cells, making them more resistant to therapies that aim to lower glucose levels. Moreover, the metabolic diversity exhibited by CRC cells emphasizes the intricate nature of cancer metabolism and suggests that energy metabolism-targeting strategies should be more complex.

The expression‎ of acetyl-coenzyme A acetyltransferase 1 (ACAT1) is found to be elevated in paired human CRC tissues. β-hydroxybutyrate may promote tumorigenesis by modulating ACAT1, which in turn leads to the acetylation of downstream isocitrate dehydrogenase 1 (IDH1). The genetic silencing of ACAT1 significantly inhibits CRC progression and inhibits the effects of β-hydroxybutyrate, both in vitro and in vivo [26]. ​ The acetylation of IDH1 K224, a key enzyme in the TCA cycle, has been linked to decreased α-KG production and activation of the HIF1α-SRC axis, ultimately promoting CRC proliferation and metastasis [13].

Another study showed that Beta-Hydroxybutyrate enhances growth, movement, and Stem Cell Characteristics in a Subset of 5FU-Treated SW480 Cells focusing on metabolic adaptability in colon cancer. BHB elevated the viability of both SW480 cells and those treated with 5FU. The findings indicated a notable reduction in extracellular acidification rate (ECAR) and an increase in oxygen consumption rate (OCR) in both groups after BHB administration, highlighting a preference for oxidative phosphorylation over glycolysis. Moreover, BHB treatment led to an upregulation of genes associated with stem cell traits and mitochondrial development while downregulating genes linked to the glycolytic pathway and cellular differentiation in 5FU-exposed cells. ​The capacity for self-renewal and migratory ability in cells treated with BHB showed a significant enhancement [23].

Future therapeutic approaches may need to focus not only on glucose deprivation but also on a thorough understanding of the metabolic pathways that cancer cells exploit. Gaining this understanding could facilitate the development of more effective strategies to inhibit CRC growth and enhance treatment outcomes, potentially by targeting multiple metabolic pathways simultaneously rather than relying on a single dietary intervention. ​Therefore, the implications of CRC cells’ utilization of BHB are significant, indicating a need for innovative treatment approaches for colorectal cancer that take these metabolic adaptations into account.

A recent study has identified two metabolism-based molecular subtypes linked to the ketogenic treatment of colon cancer including the glycolytic subtype (glycolysis+/ketolysis-) and the ketolytic subtype (glycolysis+/ketolysis+). These subtypes exhibit distinct metabolic enzyme profiles and mitochondrial dysfunctions, as well as varying responses to ketone-based interventions in both in vitro and in vivo settings.

This study showed that the glycolytic subtype can be converted into the ketolytic subtype in tumors with p53 mutations when glucose is restricted, leading to resistance against ketogenic therapy. This resistance is associated with the upregulation of ketolytic enzymes, such as 3-oxoacid CoA-transferase 1 (OXCT1), driven by mutant p53. An allosteric activator of mutant p53 successfully inhibits the altered molecular expression‎ and the reprogrammed metabolism, which in turn suppresses tumor growth (Fig. 3).

Fig. 3

Full size image

BHB shows detrimental effects on CRC by modulating CRC metabolism, thus enhancing energy production and supporting tumor growth. BHB upregulates the expression‎ of ACAT1, which catalyzes the conversion of AcAc to Ac-CoA. ACAT1 directly acetylates and activates IDH1, thereby enhancing its enzymatic activity. Activated IDH1 accelerates the TCA cycle, leading to increased ATP production. This enhanced metabolic activity meets the energetic and biosynthetic demands of CRC cells, promoting tumor proliferation and survival. ACAT1, acetyl-CoA acetyltransferase 1; AcAc, acetoacetate; Ac-CoA, acetyl-CoA; IDH1, isocitrate dehydrogenase 1; TCA, tricarboxylic acid cycle; ATP, adenosine triphosphate

The results underscore the importance of metabolic subtyping in optimizing ketogenic therapy for colon cancer and reveal mutant p53 as a potential target for enhancing the effectiveness of cotreatments through synthetic lethality strategies [92].

CRC suppression by BHB

There are also several studies proposing that BHB might suppress CRC progression. The dietary screening conducted in autochthonous animal models of CRC reveals that ketogenic diets confer a significant tumor-inhibitory effect [80, 81, 93,94,95,96]. This effect is paralleled by the ketone body BHB, which demonstrates the capability to reduce the proliferation of colonic crypt cells and effectively suppress intestinal tumor growth. The mechanism through which BHB exerts its effects involves interaction with the surface receptor Hcar2, leading to the induction of the transcriptional regulator Hopx. This interaction results in alterations in gene expression‎, subsequently inhibiting cell proliferation within the colonic environment [97]. The anti-cancer properties of BHB were explored within the context of an Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced colitis-associated colorectal cancer (CAC) model and associated tumor organoid derivative. Exogenous supplementation with BHB was found to alleviate tumor burden and reduce angiogenesis in the CAC model. Furthermore, transcriptomic assessment indicated that BHB significantly downregulated vascular endothelial growth factor A (VEGFA), expression‎ within the CAC tumor mucosa. In vitro studies demonstrated that BHB diminished VEGFA levels in hypoxia-treated CT26 cells by targeting the transcription factor hypoxia-inducible factor 1-alpha (HIF-1α). The removal of HIF-1α was observed to largely negate the inhibitory effects of BHB on CAC tumor formation. Additionally, a correlation was noted between lower levels of ketogenesis-related enzymes in tumor tissues and poorer survival outcomes in colon cancer patients [98]. ​.

The potential of BHB to counteract resistance to oxaliplatin (Oxa) in CRC and its underlying mechanisms was investigated in another study. The effects of BHB on CRC-Oxa cells were eval‎uated in vitro, focusing on cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT). Additionally, mouse models were employed to study BHB’s impact on tumor growth and metastasis. The study included eight Oxa responders and seven nonresponders, measuring serum BHB and levels of specific histone modifications (H3K79me, H3K27ac, H3K14ac) in tissues. Investigations included DOT1L gene knockdown and GNE-049 treatment to determine BHB’s role in reversing CRC-Oxa resistance via H3K79 demethylation and H3K27 deacetylation. The findings indicated that BHB treatment reduced CRC-Oxa cell proliferation, migration, invasion, and EMT, while also suppressing tumor growth and metastasis in mice. Clinical analysis linked decreased serum BHB levels to drug resistance in patients. Furthermore, negative correlations were observed between BHB levels and histone modifications, suggesting that H3K79me inhibition may disrupt BHB’s functional targets, reducing its efficacy [99]. ​.

It has been reported that the administration of exogenous BHB could significantly mitigate the severity of acute experimental colitis. This attenuation was evidenced by lower disease activity indices, shortened colon length, and improved histological scores. Additionally, there was a notable decrease in crypt loss and epithelial damage. BHB treatment led to a marked increase in the colonic expression‎ of genes associated with M2 macrophages, such as IL-4Ra, IL-10, arginase 1 (Arg-1), and chitinase-like protein 3, following dextran sulfate sodium (DSS) exposure. This observation indicates a pronounced skewing towards M2 macrophage polarization in vivo. Furthermore, in vitro studies demonstrated that BHB directly facilitated the phosphorylation of STAT6 and upregulated M2 macrophage-specific gene expression‎ in macrophages stimulated with IL-4 [100] (Fig. 4).

Fig. 4

Full size image

BHB exerts anti-tumor effects by targeting key pathways involved in CRC progression through metabolic remodeling of the tumor microenvironment and intrinsic cellular pathways to restrain tumor growth. Angiogenesis Inhibition: BHB binds to the HCAR2 receptor, leading to a reduction in HIF-1α levels. This decrease in HIF-1α downregulates VEGFA expression‎, inhibiting the formation of new blood vessels essential for tumor vascularization. Suppression of Cell Proliferation: Concurrently, BHB inhibits histone deacetylase (HDAC) activity, resulting in increased acetylation and transcription of the tumor suppressor gene Hopx. Elevated Hopx levels impede cancer cell proliferation. HCAR2, hydroxycarboxylic acid receptor 2; HIF-1α, hypoxia-inducible factor 1-alpha; VEGFA, vascular endothelial growth factor A; HDAC, histone deacetylase; Hopx, homeodomain-only protein X

Genetic factors in colorectal cancer progression and inhibition and their interaction with beta-hydroxybutyrate

The advancement of colorectal cancer is influenced by a complex interaction of genetic mutations and epigenetic changes that impact essential signaling pathways related to cell growth, survival, and metabolism. The genetic profile of CRC is vital in determining how tumor cells respond to metabolic approaches like the ketogenic diet. As previously highlighted, mutations in genes such as APC (adenomatous polyposis coli), KRAS, and TP53 can significantly affect the metabolic characteristics of CRC cells and their capacity to utilize BHB. Gaining insight into the genetic framework of CRC and how it interacts with metabolic components such as BHB is vital for creating effective therapeutic approaches (Table 1).

Table 1 Genetic factors in colorectal cancer progression and Inhibition and their interaction with β-hydroxybutyrate

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APC gene and Wnt signaling

The Wnt signaling pathway is crucial for the development and maintenance of colorectal tissues. Mutations in the APC gene, which are frequently observed in colorectal cancer, lead to the accumulation of β-catenin in the nucleus, where it activates Wnt target genes that are involved in cell proliferation [101]. ​This abnormal activation of the Wnt pathway plays a significant role in the initiation and progression of colorectal cancer by promoting uncontrolled cell division and growth [102].

BHB may affect the Wnt signaling pathway through its impact on histone acetylation and gene expression‎. Specifically, BHB functions as a HDAC inhibitor, resulting in the hyperacetylation of histones and changes in the expression‎ of Wnt target genes [103]. In some situations, the HDAC-inhibitory properties of BHB have been linked to tumor-suppressive outcomes, such as promoting differentiation and apoptosis in cancer cells [23]. However, the interaction between BHB and Wnt signaling in colorectal cancer is intricate and can vary depending on the tumor’s specific genetic background. In colorectal cancer cells carrying APC mutations, the influence of BHB on Wnt signaling may depend on the context. In certain instances, the HDAC-inhibitory effects of BHB could potentially amplify Wnt signaling by further increasing the expression‎ of oncogenic Wnt target genes, thereby accelerating tumor progression [104, 105]. On the other hand, BHB might also promote the expression‎ of genes that encourage differentiation and apoptosis, counteracting the consequences of APC mutations. Ultimately, the overall effect likely relies on the specific epigenetic landscape of the tumor and the presence of additional genetic alterations [23].

KRAS and MAPK/ERK signaling

The KRAS gene encodes a small GTPase that serves as a crucial regulator of the MAPK/ERK signaling pathway, which plays a significant role in regulating cell growth, proliferation, and survival [106]. Approximately 30–40% of colorectal cancers exhibit mutations in KRAS, which are linked to a poor prognosis and resistance to certain targeted therapies, such as EGFR inhibitors [107].

Colorectal cancer cells with KRAS mutations display altered metabolic profiles, including enhanced glycolysis and a greater dependence on alternative energy sources. Research indicates that KRAS mutations may provide a metabolic advantage, allowing cancer cells to utilize ketone bodies like BHB more effectively. This metabolic adaptability could enable KRAS-mutant CRC cells to thrive in low-glucose environments, such as those induced by ketogenic diets or fasting [108,109,110].

BHB may interact with the MAPK/ERK pathway by modulating oxidative stress and mitochondrial function [111]. For instance, BHB has been demonstrated to decrease the production of reactive oxygen species (ROS) and enhance mitochondrial efficiency, potentially promoting the survival of KRAS-mutant cells under metabolic stress. Additionally, BHB-mediated inhibition of HDACs could change the expression‎ of genes associated with the MAPK/ERK pathway, further affecting tumor behavior [112, 113]. Therefore, it is essential to comprehend the specific effects of BHB on KRAS-mutant CRC cells to eval‎uate the potential risks and benefits of ketogenic diets and other methods that increase BHB levels.

TP53 and apoptosis

The TP53 gene encodes the p53 protein, a critical tumor suppressor that plays a vital role in regulating the cell cycle, DNA repair, and apoptosis. Mutations in TP53 are found in about 50% of colorectal cancers and are linked to increased genomic instability and resistance to programmed cell death [114].

BHB has been shown to affect apoptotic pathways in cancer cells, with its effects potentially differing based on the p53 status. In colorectal cancer cells lacking functional p53, BHB may inhibit apoptosis by serving as an alternative energy source, thus promoting cell survival during metabolic stress. This could enable these p53-deficient CRC cells to avoid cell death, ultimately contributing to tumor growth [92].

Conversely, BHB’s ability to inhibit HDACs might alter the expression‎ of p53 target genes, possibly restoring certain functions of p53 or activating alternative apoptotic pathways. For instance, the hyperacetylation of histones induced by BHB may enhance the expression‎ of pro-apoptotic genes, leading to cell death in some colorectal cancer cells [97]. ​However, in the presence of p53 mutations or loss, these effects may not be sufficient to overcome the overall survival advantage that BHB provides to cancer cells.

Interaction of β-hydroxybutyrate with the tumor microenvironment

The tumor microenvironment (TME) is crucial in shaping the response of CRC cells to metabolic therapies. It consists of diverse cell types, including immune cells, fibroblasts, and endothelial cells, in addition to extracellular matrix components and various signaling molecules. The interactions among these components significantly influence tumor growth, metastasis, and therapeutic responses [13, 98]. BHB has emerged as a significant metabolic regulator in the tumor microenvironment, potentially suppressing colorectal cancer through various mechanisms [115]. Here, we discuss how BHB influences the tumor microenvironment in the context of colorectal cancer, focusing on angiogenesis inhibition, modulation of tumor-associated neutrophils, and promotion of M2 macrophage polarization.

BHB plays a crucial role in restraining colitis-associated tumorigenesis by inhibiting angiogenesis driven by hypoxia-inducible factor 1-alpha (HIF-1α). HIF-1α is a transcription factor that, when activated, promotes the expression‎ of vascular endothelial growth factor A (VEGFA), which drives blood vessel formation to supply nutrients to tumors. BHB reduces HIF-1α expression‎ in colorectal cancer cells, subsequently downregulating VEGFA levels. This action limits the tumor’s ability to develop a blood supply, restricting its growth and progression [98].

The ketogenic diet, which leads to elevated levels of BHB, has been shown to modulate the polarization of tumor-associated neutrophils (TANs) via the AMOT-YAP/TAZ signaling pathway. Neutrophils in the tumor microenvironment can exhibit both pro-tumoral and anti-tumoral functions, depending on their polarization state. BHB derived from the ketogenic diet promotes a shift in TANs towards a phenotype that inhibits tumor progression. By orchestrating this polarization, BHB reduces the recruitment and activation of neutrophils that could otherwise support tumor growth and metastasis, creating a less favorable environment for cancer development [116]. Another significant effect of BHB is its ability to promote M2 macrophage polarization through the STAT6-dependent signaling pathway. M2 macrophages are typically associated with tissue repair and resolution of inflammation, contrasting with the pro-inflammatory M1 macrophages. The shift toward M2 polarization induced by BHB not only promotes tissue repair but also helps to suppress inflammation that can facilitate tumor growth. The increased presence of M2 macrophages within the tumor microenvironment is correlated with improved outcomes in colorectal cancer, as these cells can foster an anti-tumor immune response and inhibit pro-tumoral inflammation [100].

BHB may impact the TME in other ways, potentially leading to the ineffectiveness of the ketogenic diet in CRC. For instance, BHB can modulate immune cell functions within the TME, which might alter the body’s anti-tumor immune response. Additionally, BHB’s role in inhibiting HDAC and its effects on gene expression‎ can affect stromal cell behaviors, resulting in changes to the TME that may promote tumor progression [13, 117]. Moreover, the presence of BHB in the TME could serve as an alternative energy source not just for cancer cells but also for other stromal cells [117, 118]. This availability could foster a supportive environment for tumor growth and survival, which would counteract the therapeutic goals of the ketogenic diet.

Conclusions

BHB is a double-edged sword in the realm of colorectal cancer. Although it may offer certain therapeutic advantages in some cancer types, its role in colorectal cancer is more multifaceted due to the metabolic adaptability of CRC cells and their capacity to utilize BHB as an alternative energy source. The ineffectiveness of ketogenic diets in certain CRC cases underscores the importance of gaining a deeper insight into how BHB interacts with tumor metabolism and genetic factors.

CRC is marked by a wide variety of genetic mutations and epigenetic changes that promote tumor progression and shape the metabolic behavior of cancer cells. Understanding how these genetic elements interact with BHB is vital for formulating more effective treatment strategies. By stratifying patients according to their genetic profiles and metabolic traits, it may be possible to identify those most likely to benefit from ketogenic diets or other interventions that elevate BHB levels.

Moreover, the relationship between BHB and the TME adds further complexity to the task of applying metabolic therapies in colorectal cancer. Future studies should concentrate on dissecting the intricate connections between BHB, tumor metabolism, the TME, and the genetic framework of CRC. This understanding could facilitate the development of personalized and effective therapeutic approaches that consider the specific metabolic and genetic profile of each patient’s tumor.

​In conclusion, while BHB presents potential as a therapeutic instrument in certain contexts, its function in colorectal cancer necessitates careful eval‎uation and further research. By synthesizing knowledge from genetics, metabolism, and TME, we can enhance our understanding of the potential benefits and drawbacks of BHB in colorectal cancer treatment and devise more targeted and effective therapeutic strategies.

Data availability

No datasets were generated or analysed during the current study.

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    β-Hydroxybutyrate, a primary metabolite of ketogenic diets and its dual role in modulating colorectal cancer: from molecular mechanisms to therapeutic insights

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    • Published: 24 February 2026
    • Volume 26, article number 168, (2026)
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    β-Hydroxybutyrate, a primary metabolite of ketogenic diets and its dual role in modulating colorectal cancer: from molecular mechanisms to therapeutic insights

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    • Parisa Rashidi, 
    • Zahra Bagheri, 
    • Zahra Khodayar, 
    • Saba Tarkashvand, 
    • Negin Elahirad, 
    • Reihaneh Akhoondi, 
    • Sepehr Hoseinzadeh Moghaddam, 
    • Masoud Sanati, 
    • Roya Haghighatjou, 
    • Reza Yekani, 
    • Mahtab Mehboodi, 
    • Armita Banimahdidehkordi, 
    • Saman Rabiei, 
    • Houra Dinvari & 
    • Mohammad Hasan Maleki 

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    Abstract

    Colorectal cancer (CRC) is a genetically varied malignancy noted for its metabolic flexibility, which enables cancer cells to adapt to different energy sources. Beta-hydroxybutyrate (BHB), a significant ketone body that is elevated during ketogenic diets, has attracted considerable attention for its potential therapeutic benefits. ​However, recent evidence indicates that BHB may paradoxically facilitate the advancement of CRC by acting as an alternative energy source, especially in cancer cells with mutations in critical genes such as APC, KRAS, and TP53. This review investigates the mechanisms through which CRC cells utilize BHB for their survival, focusing on enhanced metabolic plasticity, resistance to apoptosis, and modified responses to chemotherapy and immunotherapy. It also explores the interaction between BHB and the tumor microenvironment (TME), emphasizing how BHB can influence immune responses and tumor progression. Given the complexity of BHB’s role in CRC, the review underscores the necessity for personalized approaches that consider the tumor’s genetic and metabolic characteristics. Understanding the dual role of BHB in CRC is essential for devising more effective therapeutic strategies that can either harness or counteract its effects, thereby guiding the application of ketogenic diets and other metabolic interventions in the treatment of CRC.

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    Introduction

    Colorectal cancer (CRC) is one of the most preval‎ent malignancies worldwide, with substantial implications for public health due to its high morbidity and mortality rates [1, 2]. The traditional understanding of cancer metabolism has been dominated by the Warburg effect, which describes how cancer cells preferentially utilize glycolysis for energy production, even in the presence of oxygen [3]. This metabolic shift is thought to support the rapid growth and survival of cancer cells by providing both energy and biosynthetic precursors. However, recent research has revealed that cancer cells, including those in colorectal cancer, may exhibit metabolic flexibility, allowing them to exploit alternative energy sources, including ketone bodies like beta-hydroxybutyrate (BHB) [4].

    BHB is a ketone body produced by the liver during periods of low glucose availability, such as fasting or ketogenic diets [5,6,7,8,9]. While BHB has been investigated for its potential therapeutic benefits, particularly in brain cancers [10,11,12] and other conditions [8], its role in colorectal cancer is more complex. T Mao study revealed that CRC cells may have the capacity to utilize BHB as an alternative energy source, potentially aiding in their survival and progression, especially under metabolic stress conditions [13].

    This review aims to explore the various mechanisms by which BHB levels can be increased in colorectal cancer and discuss how BHB, paradoxically, might contribute to cancer progression rather than suppression. The review will also cover the genetic factors involved in CRC progression and their interactions with BHB, providing a comprehensive understanding of why ketogenic diets may fail as a therapeutic strategy in CRC.

    Beta-hydroxybutyrate: metabolism and function

    Synthesis of beta-hydroxybutyrate

    BHB is primarily synthesized in the liver from acetyl-CoA, a product of fatty acid oxidation [8, 14]. This process is typically upregulated during periods of carbohydrate restriction, fasting, or ketogenic diets, conditions under which the body switches from glucose to fat as its primary energy source [15]. The key steps in BHB synthesis involve the following enzymes: 3-Hydroxy-3-Methylglutaryl-CoA Synthase (HMGCS2) which catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA, the precursor of ketone bodies, HMG-CoA Lyase (HMGCL) which converts HMG-CoA to acetoacetate, the first ketone body formed in the pathway, and finally Beta-Hydroxybutyrate Dehydrogenase (BDH1) which acts as the key enzyme in the reduction of Acetoacetate to beta-hydroxybutyrate in the presence of NADH [16, 17] (Fig. 1).

    Fig. 1

    

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    Schematic illustration of hepatic beta-hydroxybutyrate (BHB) synthesis. Under conditions of glucose restriction, such as during a ketogenic diet, free fatty acids undergo mitochondrial beta-oxidation in the liver, generating acetyl-CoA. Two acetyl-CoA molecules are condensed by thiolase to form acetoacetyl-CoA, which is then converted to HMG-CoA by mitochondrial HMG-CoA synthase (HMGCS2). HMG-CoA lyase (HMGCL) cleaves HMG-CoA to acetoacetate, which is subsequently reduced to BHB by beta-hydroxybutyrate dehydrogenase in an NADH-dependent reaction. BHB is released into systemic circulation and transported to peripheral tissues, where it is oxidized back to acetoacetate in the mitochondria to serve as an alternative energy substrate

    Once synthesized, BHB is released into the bloodstream, where it can be taken up by various tissues and converted back into acetyl-CoA, fueling the tricarboxylic acid (TCA) cycle for ATP production [18]. This process allows cells to continue producing energy in the absence of sufficient glucose [14, 19].

    Role of beta-hydroxybutyrate in cellular metabolism

    BHB has multiple roles in cellular metabolism beyond serving as an energy source. It is also involved in signaling pathways and can influence gene expression‎ by acting as an inhibitor of histone deacetylases (HDACs) [11]. This inhibition can lead to changes in the expression‎ of genes involved in metabolism, inflammation, and cell survival.

    In the context of cancer, BHB’s role is dual-faceted. While it can induce apoptosis and reduce oxidative stress in some cancer models [9, 20, 21], it may also provide a survival advantage to cancer cells that can utilize it as an alternative fuel [13, 22]. The capacity of cancer cells to metabolically adapt and exploit BHB for energy is particularly relevant in the case of CRC, where tumor cells may exhibit significant metabolic plasticity [23].

    Mechanisms of increasing beta-hydroxybutyrate levels in the body

    Various strategies can elevate BHB levels in the body, including dietary interventions, pharmacological agents, and lifestyle modifications.

    Ketogenic diets

    A ketogenic diet is a high-fat, low-carbohydrate diet that forces the body to enter a state of ketosis, where ketone bodies, including BHB, are produced because of increased fatty acid oxidation [24]. The ketogenic diet has gained attention as a potential therapeutic strategy for various cancers, including CRC, due to its ability to reduce glucose availability, thereby starving cancer cells of their primary energy source [25].

    However, emerging evidence suggests that the ketogenic diet might not be entirely effective in CRC. Some colorectal cancer cells have shown the ability to adapt to low-glucose environments by utilizing alternative energy sources like BHB [26, 27]. This metabolic flexibility undermines the therapeutic potential of ketogenic diets, as CRC cells may continue to proliferate despite the reduced glucose levels.

    Exogenous ketones

    Exogenous ketones, available primarily as ketone salts or esters, offer a direct source of BHB that circumvents the necessity for endogenous ketogenesis [28]. This unique capability allows for a rapid elevation of blood BHB levels, thus providing a convenient method to induce ketosis without the need for strict dietary compliance [29, 30].

    The administration of exogenous ketones leads to a swift increase in circulating BHB concentrations. By supplying this ketone directly, individuals can enter a state of ketosis more conveniently than through traditional methods, which often require significant dietary restrictions such as high-fat and low-carbohydrate intake [31]. Exogenous ketone supplementation allows for increased BHB levels while avoiding the challenges linked to strict ketogenic diets. Users can expect to achieve increased BHB levels shortly after intake, thus quickly experiencing the benefits of ketosis, which can include improved energy levels and enhanced cognitive function. There is emerging evidence suggesting that exogenous ketones may play a role in various therapeutic applications, such as weight management, cognitive enhancement, and potentially in managing conditions characterized by high oxidative stress [32,33,34].

    ​.

    Fasting and caloric restriction

    Fasting and caloric restriction are well-established methods for increasing endogenous BHB production [35, 36]. These dietary interventions induce a metabolic switch from glucose metabolism to fat oxidation, a process that significantly enhances the body’s production of ketone bodies, particularly BHB [37, 38].

    When an individual fasts or restricts caloric intake, the body initially utilizes stored glycogen as its primary energy source. As glycogen stores deplete, typically within 24 h, the body begins to adapt by increasing the oxidation of fatty acids. This transition is crucial as it leads to the liver converting fatty acids into ketone bodies, including acetoacetate, acetone, and beta-hydroxybutyrate [36, 39,40,41].

    ​Fasting has been shown to possess anti-cancer properties, primarily by altering the metabolic landscape that supports tumor growth [42]. One mechanism by which fasting exerts its anti-cancer effects is through the reduction of insulin levels. Insulin is a potent growth factor that can stimulate the proliferation of cancer cells. Lower insulin levels, resulting from fasting, diminish the anabolic signaling that fuels cancer cell growth and survival [43].

    Moreover, fasting reduces the availability of glucose and other nutrients that are essential for cancer cell metabolism [44,45,46]. Many cancers are characterized by a high dependence on glycolysis for energy production, known as the Warburg effect, where cancer cells preferentially metabolize glucose even in the presence of oxygen. By depriving cancer cells of glucose and nutrients through fasting, these interventions can induce metabolic stress in tumors, potentially leading to reduced growth rates and increased apoptosis (programmed cell death) [47, 48].

    Research has indicated that various forms of fasting, including intermittent fasting or prolonged fasting, may inhibit tumor growth in several types of cancer models. For instance, studies involving animal models have demonstrated that fasting inhibits the progression of tumors in breast, prostate, and colon cancer, suggesting a broad spectrum of potential applications [49].

    Furthermore, fasting may enhance the effectiveness of certain cancer therapies such as chemotherapy and radiation. The rationale behind this approach lies in the ability of fasting to condition normal cells to become more resistant to the cytotoxic effects of cancer treatments while simultaneously sensitizing cancer cells to these therapies [50, 51].

    In summary, fasting and caloric restriction are potent strategies to increase endogenous BHB production through a metabolic shift from glucose to fat oxidation. The implications of these dietary interventions extend beyond metabolic health, influencing cancer dynamics by reducing insulin levels and nutrient availability for tumors. As research continues to unfold, fasting may become a significant adjunctive treatment strategy in cancer care, offering a low-cost, accessible means to enhance therapeutic outcomes and improve patient prognosis.

    Pharmacological agents

    Numerous pharmacological agents can influence the concentrations of BHB by either promoting ketogenesis or imitating the effects of BHB. For example, medications that activate peroxisome proliferator-activated receptor alpha (PPARα), such as fenofibrate [52] commonly prescribed to decrease triglyceride levels can enhance fatty acid oxidation, leading to an increase in BHB synthesis. Additionally, compounds that inhibit glycolysis, such as 2-deoxyglucose (2-DG) [53], may create a state of metabolic stress that promotes the utilization of ketone bodies, including BHB. While these pharmacological agents offer a targeted approach to modulating metabolism, their role in CRC is still under investigation [54, 55]. ​There might be a significant concern regarding the potential for these agents to stimulate tumor growth by providing cancer cells with alternative energy substrates [56]. This underscores the necessity for further research into the complex interactions among these pharmacological agents, BHB, and tumor metabolism.

    Metabolic flexibility in colorectal cancer cells

    The ability of cancer cells to alter their metabolic processes in response to changing environmental conditions, particularly the presence of various energy substrates, is essential for their survival and advancement [57]. This metabolic adaptability permits these cells to switch between different energy sources, such as glucose, fatty acids, and ketone bodies, in accordance with availability [58]. There is evidence that BHB can be used as a fuel in other cancers like breast and chondrosarcoma cancer cells [22, 59]. ​Such flexibility might facilitate the survival of colorectal cancer cells as well in a wide range of environments, enhancing their resilience and promoting tumor development. The HCT-119 cell line exhibits an increased tendency for metabolic reprogramming owing to genetic mutations, including those in the KRAS gene [60,61,62,63,64,65]. This cell line has the ability to utilize various alternative energy substrates, such as ketones, in contrast to other lines, such as SW480 and HT-29, which demonstrate a stronger dependence on the glycolytic pathway and a diminished capability for ketone oxidation [66,67,68]. This distinction signifies significant differences in the metabolic adaptability between these cell lines. By effectively leveraging available substrates, these cells can meet their energy requirements, even under conditions of metabolic stress or nutrient competition (unpublished).

    The Warburg effect and beyond

    The Warburg effect refers to a phenomenon found in cancer cells wherein they preferentially depend on glycolysis to produce adenosine triphosphate (ATP), even when there is an adequate supply of oxygen that would typically support oxidative phosphorylation [69]. This shift highlights a fundamental change in the way cancer cells source their energy compared to normal cells, which predominantly engage in oxidative metabolism under oxygen-rich conditions. Glycolysis is a metabolic pathway that transforms glucose into pyruvate while generating ATP. In the context of the Warburg effect, cancer cells continue to favor this pathway in the presence of oxygen, which would otherwise allow for more efficient ATP production through mitochondrial oxidative processes [3, 70].

    The reliance on glycolysis enables rapid ATP generation, which is crucial for the swift division and growth of cancer cells. In addition to energy production, glycolysis yields important intermediates that act as precursors for essential biomolecules like amino acids, nucleotides, and lipids .These compounds are vital for synthesizing new cellular components necessary for growth and proliferation [71]. Moreover, the tumor microenvironment frequently experiences low oxygen levels. The term “hypoxia” denotes a deficiency of oxygen within tumor tissues or surrounding areas. ​This phenomenon frequently occurs because of the accelerated proliferation of cancer cells, which imposes strain on the vascular system primarily due to heightened energy requirements and rapid cell division [72]. Additionally, the irregularity of the vascular architecture within tumors and the compression of blood vessels by tumor cells contribute to the development of hypoxic conditions [73, 74]. In response, cancer cells increasingly rely on glycolysis, where the conversion of pyruvate to lactate allows for continued ATP production without the need for oxygen [75, 76].

    Recent research underscores that while the Warburg effect is important, it is not the sole metabolic strategy utilized by cancer cells. CRC cells demonstrate metabolic flexibility, which enables them to switch to alternative energy sources when glucose is scarce. In conditions of limited glucose availability, cancer cells can adapt by metabolizing fatty acids or amino acids [77, 78].

    Cancer cells can oxidize fatty acids to produce ATP through a process known as beta-oxidation. This metabolic pathway is particularly effective in supplying energy when glycolysis is compromised. Additionally, during periods of low glucose, such as fasting or following ketogenic diets, cancer cells can convert ketone bodies into usable energy. Ketone bodies are synthesized in the liver from fatty acids during extended low carbohydrate intake [44, 79,80,81].

    The ability of cancer cells to utilize these alternative substrates holds significant implications for developing therapeutic strategies aimed at targeting cancer metabolism (Fig. 2). Ketogenic diets, for example, intentionally lower glucose consumption while increasing fat intake, leading to heightened ketone levels in the body [82]. This deliberate shift in metabolic substrates could potentially impede the growth of glucose-dependent tumors by depriving them of their primary energy source. A comprehensive understanding of the metabolic adaptations in cancer cells aids in designing therapeutic interventions that leverage these pathways. By inhibiting glucose metabolism while promoting the use of fatty acids or ketones, it may be possible to slow tumor growth or enhance the effectiveness of existing cancer treatments [83]. To summarize, the Warburg effect is pivotal in understanding cancer cell metabolism, emphasizing the preference for glycolysis. ​However, the observed metabolic flexibility allows cancer cells to adapt to diverse nutrient conditions, which is critical for developing effective strategies to target cancer metabolism.

    Fig. 2

    

    Full size image

    Glucose and beta-hydroxybutyrate (BHB) metabolism in colorectal cancer (CRC) cells. Glucose, transported via GLUT1, undergoes glycolysis to produce pyruvate, which is primarily converted to lactate. A smaller fraction of pyruvate is converted to acetyl-CoA by PDH, fueling the TCA cycle. BHB, imported through MCT1, is metabolized to acetoacetate (AcAc) and subsequently acetoacetyl-CoA (AcAc-CoA), which enters the TCA cycle, supporting ATP production for energy demand. BHB, beta-hydroxybutyrate; CRC, colorectal cancer; GLUT1, glucose transporter 1; MCT1, monocarboxylate transporter 1; PDH, pyruvate dehydrogenase; AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; TCA, tricarboxylic acid; ATP, adenosine triphosphate

    Utilization of beta-hydroxybutyrate by colorectal cancer cells

    CRC cells have been observed to express various enzymes that aid in the uptake and utilization of BHB as an alternative energy source. A key group of proteins involved in this process are the monocarboxylate transporters (MCTs). These transporters are crucial for facilitating the transport of ketone bodies, including BHB, across cellular membranes. Research has shown that MCTs are often upregulated in cancer cells, enabling them to effectively absorb BHB from their external environment [84, 85].

    Once BHB is taken up by the cancer cell, it is converted back into acetyl-CoA by the enzyme 3-hydroxybutyrate dehydrogenase 1 (BDH1) [86]. This conversion is important because acetyl-CoA is a vital metabolite that feeds into the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or citric acid cycle. The TCA cycle is a fundamental metabolic pathway essential for cellular respiration, allowing to produce ATP, which serves as the primary energy source for the cell. By converting BHB into acetyl-CoA, CRC cells can meet their energy and biosynthetic demands even in conditions where glucose is limited [59]. Alpha-ketoglutarate (α-KG) is an organic acid that serves as a key intermediary metabolite within the Krebs cycle, also referred to as the citric acid cycle. This compound is essential for cellular energy production and the metabolism of various substances in the organism. More specifically, α-KG is vital to metabolic pathways associated with proteins, lipids, and carbohydrates. Research indicates that α-ketoglutarate may impede tumor proliferation by regulating the citric acid cycle and mitigating abnormal metabolic processes under normoxic conditions. Numerous studies have demonstrated that α-KG supplementation can result in a reduction of tumor growth in experimental models of CRC.

    Nevertheless, the anticancer effects of α-KG and BHB might be negated in certain cancer contexts due to specific metabolic pathways or mutations, such as isocitrate dehydrogenase (IDH) mutations [87,88,89,90,91].

    This ability poses a challenge for therapeutic strategies designed to combat CRC by restricting glucose availability, such as ketogenic diets and other dietary interventions. The capacity of CRC cells to efficiently utilize BHB reduces the effectiveness of these dietary strategies and highlights the metabolic flexibility of cancer cells. Particularly during periods of metabolic stress induced by ketogenic diets or fasting, the presence of BHB in the bloodstream may enhance the survival and proliferation of CRC cells [26] (unpublished). In this situation, where the intention is to deprive cancer cells of glucose, BHB functions as an alternative energy source, enabling these cells to sustain their growth and viability. This metabolic adaptability can strengthen the resilience of CRC cells, making them more resistant to therapies that aim to lower glucose levels. Moreover, the metabolic diversity exhibited by CRC cells emphasizes the intricate nature of cancer metabolism and suggests that energy metabolism-targeting strategies should be more complex.

    The expression‎ of acetyl-coenzyme A acetyltransferase 1 (ACAT1) is found to be elevated in paired human CRC tissues. β-hydroxybutyrate may promote tumorigenesis by modulating ACAT1, which in turn leads to the acetylation of downstream isocitrate dehydrogenase 1 (IDH1). The genetic silencing of ACAT1 significantly inhibits CRC progression and inhibits the effects of β-hydroxybutyrate, both in vitro and in vivo [26]. ​ The acetylation of IDH1 K224, a key enzyme in the TCA cycle, has been linked to decreased α-KG production and activation of the HIF1α-SRC axis, ultimately promoting CRC proliferation and metastasis [13].

    Another study showed that Beta-Hydroxybutyrate enhances growth, movement, and Stem Cell Characteristics in a Subset of 5FU-Treated SW480 Cells focusing on metabolic adaptability in colon cancer. BHB elevated the viability of both SW480 cells and those treated with 5FU. The findings indicated a notable reduction in extracellular acidification rate (ECAR) and an increase in oxygen consumption rate (OCR) in both groups after BHB administration, highlighting a preference for oxidative phosphorylation over glycolysis. Moreover, BHB treatment led to an upregulation of genes associated with stem cell traits and mitochondrial development while downregulating genes linked to the glycolytic pathway and cellular differentiation in 5FU-exposed cells. ​The capacity for self-renewal and migratory ability in cells treated with BHB showed a significant enhancement [23].

    Future therapeutic approaches may need to focus not only on glucose deprivation but also on a thorough understanding of the metabolic pathways that cancer cells exploit. Gaining this understanding could facilitate the development of more effective strategies to inhibit CRC growth and enhance treatment outcomes, potentially by targeting multiple metabolic pathways simultaneously rather than relying on a single dietary intervention. ​Therefore, the implications of CRC cells’ utilization of BHB are significant, indicating a need for innovative treatment approaches for colorectal cancer that take these metabolic adaptations into account.

    A recent study has identified two metabolism-based molecular subtypes linked to the ketogenic treatment of colon cancer including the glycolytic subtype (glycolysis+/ketolysis-) and the ketolytic subtype (glycolysis+/ketolysis+). These subtypes exhibit distinct metabolic enzyme profiles and mitochondrial dysfunctions, as well as varying responses to ketone-based interventions in both in vitro and in vivo settings.

    This study showed that the glycolytic subtype can be converted into the ketolytic subtype in tumors with p53 mutations when glucose is restricted, leading to resistance against ketogenic therapy. This resistance is associated with the upregulation of ketolytic enzymes, such as 3-oxoacid CoA-transferase 1 (OXCT1), driven by mutant p53. An allosteric activator of mutant p53 successfully inhibits the altered molecular expression‎ and the reprogrammed metabolism, which in turn suppresses tumor growth (Fig. 3).

    Fig. 3

    

    Full size image

    BHB shows detrimental effects on CRC by modulating CRC metabolism, thus enhancing energy production and supporting tumor growth. BHB upregulates the expression‎ of ACAT1, which catalyzes the conversion of AcAc to Ac-CoA. ACAT1 directly acetylates and activates IDH1, thereby enhancing its enzymatic activity. Activated IDH1 accelerates the TCA cycle, leading to increased ATP production. This enhanced metabolic activity meets the energetic and biosynthetic demands of CRC cells, promoting tumor proliferation and survival. ACAT1, acetyl-CoA acetyltransferase 1; AcAc, acetoacetate; Ac-CoA, acetyl-CoA; IDH1, isocitrate dehydrogenase 1; TCA, tricarboxylic acid cycle; ATP, adenosine triphosphate

    The results underscore the importance of metabolic subtyping in optimizing ketogenic therapy for colon cancer and reveal mutant p53 as a potential target for enhancing the effectiveness of cotreatments through synthetic lethality strategies [92].

    CRC suppression by BHB

    There are also several studies proposing that BHB might suppress CRC progression. The dietary screening conducted in autochthonous animal models of CRC reveals that ketogenic diets confer a significant tumor-inhibitory effect [80, 81, 93,94,95,96]. This effect is paralleled by the ketone body BHB, which demonstrates the capability to reduce the proliferation of colonic crypt cells and effectively suppress intestinal tumor growth. The mechanism through which BHB exerts its effects involves interaction with the surface receptor Hcar2, leading to the induction of the transcriptional regulator Hopx. This interaction results in alterations in gene expression‎, subsequently inhibiting cell proliferation within the colonic environment [97]. The anti-cancer properties of BHB were explored within the context of an Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced colitis-associated colorectal cancer (CAC) model and associated tumor organoid derivative. Exogenous supplementation with BHB was found to alleviate tumor burden and reduce angiogenesis in the CAC model. Furthermore, transcriptomic assessment indicated that BHB significantly downregulated vascular endothelial growth factor A (VEGFA), expression‎ within the CAC tumor mucosa. In vitro studies demonstrated that BHB diminished VEGFA levels in hypoxia-treated CT26 cells by targeting the transcription factor hypoxia-inducible factor 1-alpha (HIF-1α). The removal of HIF-1α was observed to largely negate the inhibitory effects of BHB on CAC tumor formation. Additionally, a correlation was noted between lower levels of ketogenesis-related enzymes in tumor tissues and poorer survival outcomes in colon cancer patients [98]. ​.

    The potential of BHB to counteract resistance to oxaliplatin (Oxa) in CRC and its underlying mechanisms was investigated in another study. The effects of BHB on CRC-Oxa cells were eval‎uated in vitro, focusing on cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT). Additionally, mouse models were employed to study BHB’s impact on tumor growth and metastasis. The study included eight Oxa responders and seven nonresponders, measuring serum BHB and levels of specific histone modifications (H3K79me, H3K27ac, H3K14ac) in tissues. Investigations included DOT1L gene knockdown and GNE-049 treatment to determine BHB’s role in reversing CRC-Oxa resistance via H3K79 demethylation and H3K27 deacetylation. The findings indicated that BHB treatment reduced CRC-Oxa cell proliferation, migration, invasion, and EMT, while also suppressing tumor growth and metastasis in mice. Clinical analysis linked decreased serum BHB levels to drug resistance in patients. Furthermore, negative correlations were observed between BHB levels and histone modifications, suggesting that H3K79me inhibition may disrupt BHB’s functional targets, reducing its efficacy [99]. ​.

    It has been reported that the administration of exogenous BHB could significantly mitigate the severity of acute experimental colitis. This attenuation was evidenced by lower disease activity indices, shortened colon length, and improved histological scores. Additionally, there was a notable decrease in crypt loss and epithelial damage. BHB treatment led to a marked increase in the colonic expression‎ of genes associated with M2 macrophages, such as IL-4Ra, IL-10, arginase 1 (Arg-1), and chitinase-like protein 3, following dextran sulfate sodium (DSS) exposure. This observation indicates a pronounced skewing towards M2 macrophage polarization in vivo. Furthermore, in vitro studies demonstrated that BHB directly facilitated the phosphorylation of STAT6 and upregulated M2 macrophage-specific gene expression‎ in macrophages stimulated with IL-4 [100] (Fig. 4).

    Fig. 4

    

    Full size image

    BHB exerts anti-tumor effects by targeting key pathways involved in CRC progression through metabolic remodeling of the tumor microenvironment and intrinsic cellular pathways to restrain tumor growth. Angiogenesis Inhibition: BHB binds to the HCAR2 receptor, leading to a reduction in HIF-1α levels. This decrease in HIF-1α downregulates VEGFA expression‎, inhibiting the formation of new blood vessels essential for tumor vascularization. Suppression of Cell Proliferation: Concurrently, BHB inhibits histone deacetylase (HDAC) activity, resulting in increased acetylation and transcription of the tumor suppressor gene Hopx. Elevated Hopx levels impede cancer cell proliferation. HCAR2, hydroxycarboxylic acid receptor 2; HIF-1α, hypoxia-inducible factor 1-alpha; VEGFA, vascular endothelial growth factor A; HDAC, histone deacetylase; Hopx, homeodomain-only protein X

    Genetic factors in colorectal cancer progression and inhibition and their interaction with beta-hydroxybutyrate

    The advancement of colorectal cancer is influenced by a complex interaction of genetic mutations and epigenetic changes that impact essential signaling pathways related to cell growth, survival, and metabolism. The genetic profile of CRC is vital in determining how tumor cells respond to metabolic approaches like the ketogenic diet. As previously highlighted, mutations in genes such as APC (adenomatous polyposis coli), KRAS, and TP53 can significantly affect the metabolic characteristics of CRC cells and their capacity to utilize BHB. Gaining insight into the genetic framework of CRC and how it interacts with metabolic components such as BHB is vital for creating effective therapeutic approaches (Table 1).

    Table 1 Genetic factors in colorectal cancer progression and Inhibition and their interaction with β-hydroxybutyrate

    Full size table

    APC gene and Wnt signaling

    The Wnt signaling pathway is crucial for the development and maintenance of colorectal tissues. Mutations in the APC gene, which are frequently observed in colorectal cancer, lead to the accumulation of β-catenin in the nucleus, where it activates Wnt target genes that are involved in cell proliferation [101]. ​This abnormal activation of the Wnt pathway plays a significant role in the initiation and progression of colorectal cancer by promoting uncontrolled cell division and growth [102].

    BHB may affect the Wnt signaling pathway through its impact on histone acetylation and gene expression‎. Specifically, BHB functions as a HDAC inhibitor, resulting in the hyperacetylation of histones and changes in the expression‎ of Wnt target genes [103]. In some situations, the HDAC-inhibitory properties of BHB have been linked to tumor-suppressive outcomes, such as promoting differentiation and apoptosis in cancer cells [23]. However, the interaction between BHB and Wnt signaling in colorectal cancer is intricate and can vary depending on the tumor’s specific genetic background. In colorectal cancer cells carrying APC mutations, the influence of BHB on Wnt signaling may depend on the context. In certain instances, the HDAC-inhibitory effects of BHB could potentially amplify Wnt signaling by further increasing the expression‎ of oncogenic Wnt target genes, thereby accelerating tumor progression [104, 105]. On the other hand, BHB might also promote the expression‎ of genes that encourage differentiation and apoptosis, counteracting the consequences of APC mutations. Ultimately, the overall effect likely relies on the specific epigenetic landscape of the tumor and the presence of additional genetic alterations [23].

    KRAS and MAPK/ERK signaling

    The KRAS gene encodes a small GTPase that serves as a crucial regulator of the MAPK/ERK signaling pathway, which plays a significant role in regulating cell growth, proliferation, and survival [106]. Approximately 30–40% of colorectal cancers exhibit mutations in KRAS, which are linked to a poor prognosis and resistance to certain targeted therapies, such as EGFR inhibitors [107].

    Colorectal cancer cells with KRAS mutations display altered metabolic profiles, including enhanced glycolysis and a greater dependence on alternative energy sources. Research indicates that KRAS mutations may provide a metabolic advantage, allowing cancer cells to utilize ketone bodies like BHB more effectively. This metabolic adaptability could enable KRAS-mutant CRC cells to thrive in low-glucose environments, such as those induced by ketogenic diets or fasting [108,109,110].

    BHB may interact with the MAPK/ERK pathway by modulating oxidative stress and mitochondrial function [111]. For instance, BHB has been demonstrated to decrease the production of reactive oxygen species (ROS) and enhance mitochondrial efficiency, potentially promoting the survival of KRAS-mutant cells under metabolic stress. Additionally, BHB-mediated inhibition of HDACs could change the expression‎ of genes associated with the MAPK/ERK pathway, further affecting tumor behavior [112, 113]. Therefore, it is essential to comprehend the specific effects of BHB on KRAS-mutant CRC cells to eval‎uate the potential risks and benefits of ketogenic diets and other methods that increase BHB levels.

    TP53 and apoptosis

    The TP53 gene encodes the p53 protein, a critical tumor suppressor that plays a vital role in regulating the cell cycle, DNA repair, and apoptosis. Mutations in TP53 are found in about 50% of colorectal cancers and are linked to increased genomic instability and resistance to programmed cell death [114].

    BHB has been shown to affect apoptotic pathways in cancer cells, with its effects potentially differing based on the p53 status. In colorectal cancer cells lacking functional p53, BHB may inhibit apoptosis by serving as an alternative energy source, thus promoting cell survival during metabolic stress. This could enable these p53-deficient CRC cells to avoid cell death, ultimately contributing to tumor growth [92].

    Conversely, BHB’s ability to inhibit HDACs might alter the expression‎ of p53 target genes, possibly restoring certain functions of p53 or activating alternative apoptotic pathways. For instance, the hyperacetylation of histones induced by BHB may enhance the expression‎ of pro-apoptotic genes, leading to cell death in some colorectal cancer cells [97]. ​However, in the presence of p53 mutations or loss, these effects may not be sufficient to overcome the overall survival advantage that BHB provides to cancer cells.

    Interaction of β-hydroxybutyrate with the tumor microenvironment

    The tumor microenvironment (TME) is crucial in shaping the response of CRC cells to metabolic therapies. It consists of diverse cell types, including immune cells, fibroblasts, and endothelial cells, in addition to extracellular matrix components and various signaling molecules. The interactions among these components significantly influence tumor growth, metastasis, and therapeutic responses [13, 98]. BHB has emerged as a significant metabolic regulator in the tumor microenvironment, potentially suppressing colorectal cancer through various mechanisms [115]. Here, we discuss how BHB influences the tumor microenvironment in the context of colorectal cancer, focusing on angiogenesis inhibition, modulation of tumor-associated neutrophils, and promotion of M2 macrophage polarization.

    BHB plays a crucial role in restraining colitis-associated tumorigenesis by inhibiting angiogenesis driven by hypoxia-inducible factor 1-alpha (HIF-1α). HIF-1α is a transcription factor that, when activated, promotes the expression‎ of vascular endothelial growth factor A (VEGFA), which drives blood vessel formation to supply nutrients to tumors. BHB reduces HIF-1α expression‎ in colorectal cancer cells, subsequently downregulating VEGFA levels. This action limits the tumor’s ability to develop a blood supply, restricting its growth and progression [98].

    The ketogenic diet, which leads to elevated levels of BHB, has been shown to modulate the polarization of tumor-associated neutrophils (TANs) via the AMOT-YAP/TAZ signaling pathway. Neutrophils in the tumor microenvironment can exhibit both pro-tumoral and anti-tumoral functions, depending on their polarization state. BHB derived from the ketogenic diet promotes a shift in TANs towards a phenotype that inhibits tumor progression. By orchestrating this polarization, BHB reduces the recruitment and activation of neutrophils that could otherwise support tumor growth and metastasis, creating a less favorable environment for cancer development [116]. Another significant effect of BHB is its ability to promote M2 macrophage polarization through the STAT6-dependent signaling pathway. M2 macrophages are typically associated with tissue repair and resolution of inflammation, contrasting with the pro-inflammatory M1 macrophages. The shift toward M2 polarization induced by BHB not only promotes tissue repair but also helps to suppress inflammation that can facilitate tumor growth. The increased presence of M2 macrophages within the tumor microenvironment is correlated with improved outcomes in colorectal cancer, as these cells can foster an anti-tumor immune response and inhibit pro-tumoral inflammation [100].

    BHB may impact the TME in other ways, potentially leading to the ineffectiveness of the ketogenic diet in CRC. For instance, BHB can modulate immune cell functions within the TME, which might alter the body’s anti-tumor immune response. Additionally, BHB’s role in inhibiting HDAC and its effects on gene expression‎ can affect stromal cell behaviors, resulting in changes to the TME that may promote tumor progression [13, 117]. Moreover, the presence of BHB in the TME could serve as an alternative energy source not just for cancer cells but also for other stromal cells [117, 118]. This availability could foster a supportive environment for tumor growth and survival, which would counteract the therapeutic goals of the ketogenic diet.

    Conclusions

    BHB is a double-edged sword in the realm of colorectal cancer. Although it may offer certain therapeutic advantages in some cancer types, its role in colorectal cancer is more multifaceted due to the metabolic adaptability of CRC cells and their capacity to utilize BHB as an alternative energy source. The ineffectiveness of ketogenic diets in certain CRC cases underscores the importance of gaining a deeper insight into how BHB interacts with tumor metabolism and genetic factors.

    CRC is marked by a wide variety of genetic mutations and epigenetic changes that promote tumor progression and shape the metabolic behavior of cancer cells. Understanding how these genetic elements interact with BHB is vital for formulating more effective treatment strategies. By stratifying patients according to their genetic profiles and metabolic traits, it may be possible to identify those most likely to benefit from ketogenic diets or other interventions that elevate BHB levels.

    Moreover, the relationship between BHB and the TME adds further complexity to the task of applying metabolic therapies in colorectal cancer. Future studies should concentrate on dissecting the intricate connections between BHB, tumor metabolism, the TME, and the genetic framework of CRC. This understanding could facilitate the development of personalized and effective therapeutic approaches that consider the specific metabolic and genetic profile of each patient’s tumor.

    ​In conclusion, while BHB presents potential as a therapeutic instrument in certain contexts, its function in colorectal cancer necessitates careful eval‎uation and further research. By synthesizing knowledge from genetics, metabolism, and TME, we can enhance our understanding of the potential benefits and drawbacks of BHB in colorectal cancer treatment and devise more targeted and effective therapeutic strategies.

    Data availability

    No datasets were generated or analysed during the current study.

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