Metabolic Treatment Research Articles

Metabolic reprogramming of glucose: the metabolic basis for the occurrence and development of hepatocellular carcinoma

Primary liver cancer is a common malignant tumor of the digestive system, with hepatocellular carcinoma (HCC) being the most prevalent type. It is characterized by high malignancy, insidious onset, and a lack of specific early diagnostic and therapeutic markers, posing a serious threat to human health. The occurrence and development of HCC are closely related to its metabolic processes. Similar to other malignant tumors, metabolic reprogramming occurs extensively in tumor cells, with glucose metabolism reprogramming being particularly prominent. This is characterized by abnormal activation of glycolysis and inhibition of oxidative phosphorylation and gluconeogenesis, among other changes. Glucose metabolism reprogramming provides intermediates and energy for HCC to meet its demands for rapid growth, proliferation, and metastasis. Additionally, various enzymes and signaling molecules involved in glucose metabolism reprogramming play irreplaceable roles. Therefore, regulating key metabolic enzymes and pathways in these processes is considered an important target for the diagnosis and treatment of HCC. This paper reviews the current status and progress of glucose metabolism reprogramming in HCC, aiming to provide new insights for the diagnosis, detection, and comprehensive treatment strategies of HCC involving combined glucose metabolism intervention in clinical settings.

PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.

Differentiation arrest and dependence on oxidative metabolism are features shared among genetically diverse acute myeloid leukemias (AML). A phenotypic CRISPR-Cas9 screen in AML identified dependence on phosphoseryl-tRNA kinase (PSTK), an atypical kinase required for the biosynthesis of all selenoproteins. In vivo, PSTK inhibition (PSTKi) impaired AML cell growth and leukemic stem cell self-renewal. Notably, timed pharmacologic PSTKi effectively targeted chemo-resistant AML in murine and patient-derived xenograft models, showing selectivity for malignant cells over normal hematopoietic cells. Mechanistically, PSTKi-induced reactive oxygen species (ROS) triggering mitochondrial DNA release into the cytosol and activated cGAS-STING. This activation in turn disrupted iron metabolism augmenting ROS generation and amplifying ferroptosis. Together, these findings reveal a self-reinforcing PSTK-cGAS-STING-ROS loop culminating in an oxidative crisis and ferroptotic cell death of leukemic stem cells. The data highlight the potential for augmenting standard cancer chemotherapies using timed metabolic intervention to eliminate chemopersisting cells and thereby impede disease relapse.

EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma

BackgroundHeterogeneous clinical features and prognosis in neuroblastoma (NB) children are frequently dominated by immune elements. Dysfunction and apoptosis in immune cells result from the exposure to continuous tumor-related antigen stimulation and coinhibitory signals. To date, key factors pointing to the restriction of NB-specific CD8+ T cells remain elusive.MethodsWe performed bulk-RNA sequencing and lipidomic analyses of children with mediastinal NB. Bioinformatics analysis and biological validation were applied to uncover the underlying mechanism.ResultsThree subtypes were identified using nonnegative matrix factorization (NMF), among which we highlighted an apoptotic status of infiltrated CD8+ T cells, along with the highest CD52 and EDF1 expression in Cluster3 (C3) subtypes. It was verified that high EDF1 expression in NB cells led to Lactosylceramide (LacCer) accumulation, as well as downstream ganglioside-GD3, which subsequently increased the expression of CD52 and immune checkpoint genes, chemotaxis, and apoptosis-related events in activated CD8+T cells. Mechanistically, EDF1 was recruited as a coactivator to form the NF-κB/RelA/EDF1 complex, which further prevented the promoter region methylation of ST8SIA1, to elevate its transcription.ConclusionThese findings characterize abundant GD3 in NB cells, which regulated by the EDF1/RelA/ST8SIA1 axis, is responsible for CD8+ T cell dysfunction. Inhibition of EDF1 may reduce suppressive factors and prevent immune escape of NB cells. Modulating NB-associated GD3 levels through metabolic intervention is beneficial for tuning the depth and duration of responses to current NB therapies. The integration of transcriptomic and lipidomic data offers a more comprehensive understanding of the interaction between LacCer metabolites and the immune status in NB.Graphical

Metal Ion and Antibiotic Co-loaded Nanoparticles for Combating Methicillin-Rresistant Staphylococcus aureus-Induced Osteomyelitis.

Methicillin-resistant Staphylococcus aureus (MRSA) causes osteomyelitis (OM), which seriously threatens public health due to its antimicrobial resistance. To increase the sensitivity of antibiotics and eradicate intracellular bacteria, a Zn2+ and vancomycin (Van) codelivered nanotherapeutic (named Man-Zn2+/Van NPs) was fabricated and characterized via mannose (Man) modification. Man-Zn2+/Van NPs exhibit significant inhibitory activity against extra- and intracellular MRSA and obviously decrease the minimum inhibitory concentration of Van. Man-Zn2+/Van NPs can be easily internalized by MRSA-infected macrophages and significantly accumulated in infected bone via Man-mediated targeting. In vivo experiments in a mouse OM model verified that Man-Zn2+/Van NPs significantly reduce the extra- and intracellular MRSA burden, improve gait patterns, increase bone mass, and decrease inflammatory cytokine expression. The antibacterial mechanism of Man-Zn2+/Van NPs includes destruction of the MRSA membrane, degeneration of intracellular proteins and DNA, inhibition of MRSA glycolysis, and intervention in the energy metabolism of bacteria. Overall, this metal-antibiotic nanotherapeutics strategy provides new insight for combating extra- and intracellular infections caused by MRSA-induced OM.

The measurement, regulation and biological activity of FAHFAs.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are bioactive lipids that are positively correlated with metabolic health in humans and mice. Since their discovery, understanding the role and regulation of FAHFAs has been a prime focus of research into these lipids. In this Review, we describe how FAHFAs are quantitatively measured from biological samples. We then highlight advances in elucidating the genes responsible for the regulation of endogenous FAHFA levels through the degradation, biosynthesis and storage of FAHFAs. We conclude by presenting several examples of antidiabetic and immunomodulatory effects of FAHFAs in cells and in vivo, including their ability to protect against type 1 diabetes. These FAHFA topics are interconnected by their reliance on chemistry and chemical biology to enlighten this frontier of lipid biology, offering new perspectives on metabolic health and potential therapeutic interventions.

Photoredox-Mediated Immunotherapy Utilizing Rhenium(I) Photocatalysts with Electron Donor-Acceptor-Donor Configuration.

The hypoxic environment of solid tumors significantly diminishes the therapeutic efficacy of oxygen-dependent photodynamic therapy. Developing efficient photosensitizers that operate via photoredox catalysis presents a promising strategy to overcome this challenge. Herein, we report the rational design of two rhenium(I) tricarbonyl complexes (Re-TPO and Re-TP) with electron donor-acceptor-donor configuration. Notably, Re-TP exhibits aggregation-induced emission properties and enhanced spin-orbit coupling compared to Re-TPO, thus exhibiting promoted photosensitizing capability. In addition to generating type I and II reactive oxygen species, the excited Re-TP facilitates the photocatalytic oxidation of NADH to NAD+ and the photoreduction of pyruvic acid to lactic acid. This metabolic intervention triggers PD-L1-linked immune responses and disrupts tumor redox balance, leading to ferroptosis and immunogenic cell death. The combined ferroptosis and immunotherapy effects significantly suppress both primary and distant B16 tumors. This investigation provides a compelling model for designing efficient metal-based PSs for photoredox-mediated photoimmunotherapy against hypoxic tumors.

Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions.

Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.

Cellular Signaling of Amino Acid Metabolism in Prostate Cancer.

Prostate cancer is one of the most common malignancies affecting men worldwide and a leading cause of cancer-related mortality, necessitating a deeper understanding of its underlying biochemical pathways. Similar to other cancer types, prostate cancer is also characterised by aberrantly activated metabolic pathways that support tumour development, such as amino acid metabolism, which is involved in modulating key physiological and pathological cellular processes during the progression of this disease. The metabolism of several amino acids, such as glutamine and methionine, crucial for tumorigenesis, is dysregulated and commonly discussed in prostate cancer. And the roles of some less studied amino acids, such as histidine and glycine, have also been covered in prostate cancer studies. Aberrant regulation of two major signalling pathways, mechanistic target of rapamycin (mTOR) and general amino acid control non-depressible 2 (GCN2), is a key driver of reshaping the amino acid metabolism landscape in prostate cancer. By summarising our current understanding of how amino acid metabolism is modulated in prostate cancer, here, we provide further insights into certain potential therapeutic targets for managing prostate cancer through metabolic interventions.

Dark microglia: a therapeutic target to prevent synaptic loss and neurodegeneration?

Dark microglia is a distinct state of microglia progressively increasing with aging and present in high numbers in neurodegenerative diseases. Dark microglia are characterised by various ultrastructural markers of cellular stress, including a condensed, electron-dense cytoplasm and nucleoplasm, giving them a dark appearance in electron microscopy. Expression of classical homeostatic microglia markers such as like IBA1, P2RY12 and TMEM119 is significantly down-regulated in dark microglia. Dark microglial cells are also hyper-ramified and make extensive interactions, phagocytic and non-phagocytic, with synapses, myelinated axons, amyloid plaques and the vasculature, suggesting a role in brain remodelling in aging and disease. Emergence of dark microglia is linked to the activation of integrated stress response. It is suggested that metabolic interventions such as ketogenic diets and supplements could be effective at targeting and normalizing dark microglia, with positive outcomes on brain resilience and healthy cognitive aging. Keywords: microglia; synaptic loss; neurodegeneration; Alzheimer’s disease; integrated stress response; metabolism; magnetic resonance imaging

Metabolic Reprogramming in Prostate Cancer: The Roles of HOXB13 and FASN in Tumor Progression and Therapy

Metabolic reprogramming, particularly lipid metabolism, is a hallmark of cancer progression and a critical vulnerability in prostate cancer (PCa). Two pivotal studies, one by Lu et al. and the other by Dairo et al., have illuminated the roles of HOXB13, a transcriptional regulator, and fatty acid synthase (FASN), a key enzyme in lipid biosynthesis, in the metabolic dysregulation of PCa. The Lu et al. study highlights HOXB13’s role in androgen receptor (AR)-independent PCa, where it regulates lipid metabolism via epigenetic mechanisms involving histone deacetylase HDAC3. A G84E mutation in HOXB13 disrupts this regulation, leading to increased lipid synthesis and a pro-metastatic phenotype. The Dairo et al. study demonstrates that FASN hypomethylation, coupled with increased expression, drives lipid biosynthesis critical for tumor growth. Both studies establish a link between HOXB13 mutations and FASN dysregulation, underscoring their interplay in PCa biology. Therapeutically, pharmacological inhibition of FASN mitigates the aggressive features of HOXB13-deficient or mutant PCa, highlighting lipid metabolism as a promising target. Despite their strengths, including robust methodologies, limitations include reliance on preclinical models and the need for broader patient diversity. These studies collectively emphasize the potential of metabolic and epigenetic interventions for precision medicine in PCa, paving the way for novel therapies targeting lipid metabolism in patients with specific genetic and epigenetic profiles.

Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.

Metabolic reprogramming in both immune and cancer cells plays a crucial role in the antitumor immune response. Recent studies indicate that cancer metabolism not only sustains carcinogenesis and survival via altered signaling but also modulates immune cell function. Metabolic crosstalk within the tumor microenvironment results in nutrient competition and acidosis, thereby hindering immune cell functionality. Interestingly, immune cells also undergo metabolic reprogramming that enables their proliferation, differentiation, and effector functions. This review highlights the regulation of antitumor immune responses through metabolic reprogramming in cancer and immune cells and explores therapeutic strategies that target these metabolic pathways in cancer immunotherapy, including using chimeric antigen receptor (CAR)-T cells. We discuss innovative combinations of immunotherapy, cellular therapies, and metabolic interventions that could optimize the efficacy of existing treatment protocols.

Exploring the Therapeutic Role of Flavonoids Through AMPK Activation in Metabolic Syndrome: A Narrative Review.

Metabolic syndrome (MetS) is a cluster of interrelated metabolic abnormalities that significantly elevate the risk of cardiovascular disease, obesity, and diabetes. Flavonoids, a diverse class of bioactive polyphenolic compounds found in plant-derived foods and beverages, have garnered increasing attention as potential therapeutic agents for improving metabolic health. This review provides a comprehensive analysis of the therapeutic effects of flavonoids in the context of the MetS, with a particular focus on their modulation of the AMP-activated protein kinase (AMPK) pathway. AMPK serves as a central regulator of cellular energy balance, glucose metabolism, and lipid homeostasis, making it a critical target for metabolic intervention. Through a systematic review of the literature up to April 2024, preclinical studies across various flavonoid subclasses, including flavonols, and flavan-3-ols, were analysed to elucidate their mechanistic roles in metabolic regulation. Many studies suggests that flavonoids enhance glycolipid metabolism by facilitating glucose transporter 4 (GLUT4) translocation and activating the AMPK pathway, thereby improving glycemic control in diabetes models. In obesity-related studies, flavonoids demonstrated significant inhibitory effects on lipid synthesis, reduced adipogenesis, and attenuated proinflammatory cytokine secretion via AMPK activation. These findings show the broad therapeutic potential of flavonoids in addressing the MetS and its associated disorders. While these preclinical insights highlight flavonoids as promising natural agents for metabolic health improvement, it is important to note that their excessive concentrations may disrupt these pathways, potentially leading to metabolic imbalance and cytotoxicity. Further studies and clinical trials are essential to determine optimal dosing regimens, formulations, and the long-term safety and efficacy of flavonoids. This review highlights the importance of flavonoids for natural interventions targeting MetS and its comorbidities, offering a foundation for future translational research.

Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers.

Pancreatic and hepatobiliary cancers are increasing in prevalence and contribute significantly to cancer-related mortality worldwide. Emerging therapeutic approaches, particularly immunotherapy, are gaining attention for their potential to harness the patient's immune system to combat these tumors. Understanding the role of immune cells in the tumor microenvironment (TME) and their metabolic reprogramming is key to developing more effective treatment strategies. This review aims to explore the relationship between immune cell function and glucose metabolism in the TME of pancreatic and hepatobiliary cancers. This review synthesizes current research on the metabolic adaptations of immune cells, specifically focusing on glucose metabolism within the TME of pancreatic and hepatobiliary cancers. We examine the mechanisms by which immune cells influence tumor progression through metabolic reprogramming and how these interactions can be targeted for therapeutic purposes. Immune cells in the TME undergo significant metabolic changes, with glucose metabolism playing a central role in modulating immune responses. These metabolic shifts not only affect immune cell function but also influence tumor behavior and progression. The unique metabolic features of immune cells in pancreatic and hepatobiliary cancers provide new opportunities for targeting immune responses to combat these malignancies more effectively. Understanding the complex relationship between immune cell glucose metabolism and tumor progression in the TME of pancreatic and hepatobiliary cancers offers promising therapeutic strategies. By modulating immune responses through targeted metabolic interventions, it may be possible to improve the efficacy of immunotherapies and better combat these aggressive cancers.

SCARB1 links cholesterol metabolism-mediated ferroptosis inhibition to radioresistance in tumor cells.

Ferroptosis is an iron-dependent form of cell death triggered by the excessive accumulation of lipid peroxides. Understanding the regulatory mechanisms of ferroptosis and developing strategies to target this process hold significant clinical applications in tumor therapy. Our study aims to search for novel candidate genes involved in the regulation of ferroptosis and to investigate their mechanism of action in ferroptosis and tumor therapy. We employed a CRISPR-Cas9 library to perform a genome-wide screen under ferroptosis inducer treatment conditions, revealing Scavenger Receptor Class B Member 1(SCARB1) as a novel candidate gene involved in ferroptosis regulation. Subsequently, lipidomic analyses, metabolic interventions, and relevant cellular experimental analyses were performed to elucidate the role of SCARB1 in ferroptosis, lipid peroxidation, and tumor therapy. Our study confirmed that SCARB1 significantly inhibits ferroptosis and lipid peroxidation induced by ferroptosis inducers. Mechanistically, SCARB1 inhibits ferroptosis through the regulation of cholesterol metabolism, and the upregulation of CoQ10 level is demonstrated to mediate the suppression of ferroptosis by SCARB1 after lipidomic analysis and metabolic intervention. Interestingly, SCARB1 exerts a tumor suppressive effect regarding tumor growth, migration and invasion, which is possibly independent of ferroptosis regulation. However, SCARB1 promotes radioresistance through the upregulation of cholesterol metabolism and inhibition of ferroptosis, while the combination of ferroptosis inducers can overcome radioresistance in tumor cells with high SCARB1 expression. This study establishes a theoretical foundation for the regulation of ferroptosis by SCARB1 and highlights the potential of targeting lipid metabolism to overcome radioresistance in cancer therapy. The identification of SCARB1 as a key player in ferroptosis and its dual role in tumor suppression and radioresistance provides new avenues for therapeutic intervention in cancer treatment.

Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

Association of Low-Attenuation Plaque with Impaired Glucose Tolerance and Type 2 Diabetes Mellitus in Patients with Suspected Coronary Artery Disease.

The aim of this study was to evaluate the differences in plaque composition and burden between normal glycemic status (NGS) and dysglycemia expressed as impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). Clinically indicated coronary computed tomography angiography was used to evaluate patients with suspected coronary artery disease (CAD). An oral glucose tolerance test was performed to assess glycemic status. Patients were stratified as NGS, IGT, and T2DM. Plaque volumes were quantified using validated software, with further compositional measurements of low-attenuation, non-calcified, and calcified plaque burden. Of 355 patients with suspected CAD, 220 had NGS, 92 were diagnosed with IGT, and 43 with known T2DM. Low-attenuation plaque volume was significantly higher in IGT (209 mm3, p < 0.02) and T2DM (243 mm3, p = 0.005) compared with NGS (166 mm3). Total plaque burden was similar between all groups, but a significantly greater low-attenuation plaque burden was seen in IGT (p = 0.03) and T2DM (p = 0.02) compared with NGS. The multivariate linear regression model adjusted for clinical risk factors showed that patients with IGT had a greater low-attenuation plaque burden compared with those with NGS (p = 0.03). Interestingly, no significant differences in plaque burdens were observed between those with IGT and T2DM in both univariate and multivariate analyses. Dysglycemia, including impaired glucose tolerance and type 2 diabetes mellitus, was associated with increased low-attenuation plaque burden compared with normal glycemic status. Patients with IGT demonstrated plaque burden similar to patients with known T2DM, underscoring the need for early metabolic intervention.

Ketogenic Diet as a Nutritional Metabolic Intervention for Obsessive-Compulsive Disorder: A Narrative Review.

The substantial evidence supporting the ketogenic diet (KD) in epilepsy management has spurred research into its effects on other neurological and psychiatric conditions. Despite differences in characteristics, symptoms, and underlying mechanisms, these conditions share common pathways that the KD may influence. The KD reverses metabolic dysfunction. Moreover, it has been shown to support neuroprotection through mechanisms such as neuronal energy support, inflammation reduction, amelioration of oxidative stress, and reversing mitochondrial dysfunction. The adequate intake of dietary nutrients is essential for maintaining normal brain functions, and strong evidence supports the role of nutrition in the treatment and prevention of many psychiatric and neurological disorders. Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition marked by persistent, distressing thoughts or impulses (obsessions) and repetitive behaviors performed in response to these obsessions (compulsions). Recent studies have increasingly examined the role of nutrition and metabolic disorders in OCD. This narrative review examines current evidence on the potential role of the KD in the treatment of OCD. We explore research on the KD's effects on psychiatric disorders to assess its potential relevance for OCD treatment. Additionally, we identify key gaps in the preclinical and clinical research that warrant further study in applying the KD as a metabolic therapy for OCD.

The Fifth Annual Symposium of the Midwest Aging Consortium.

As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28-30, 2024, was hosted by The Ohio State University in Columbus, Ohio and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, while two keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research.

The Prognostic Value of Preoperative Total Cholesterol in Surgically Treated Oral Cavity Cancer.

With growing evidence linking lipid profile changes to tumor development and cancer prognosis, we investigated the prognostic significance of preoperative serum total cholesterol (TC) levels in patients with oral cavity squamous cell carcinoma (OSCC) undergoing surgical treatment. We conducted a retrospective observational study involving 310 patients with primary OSCC who received surgery at our hospital from January 2009 to December 2018. Receiver operating characteristic curve analysis was performed to determine the optimal preoperative TC cutoff value, with the Youden Index employed as the optimization criterion to maximize the sum of sensitivity and specificity. Variables with p < 0.1 in the univariable analysis were included in the multivariable Cox regression model, and stepwise selection was used to identify the optimal subset of prognostic factors for overall survival (OS) and disease-free survival (DFS). An optimal TC cutoff of 157 mg/dL was established. Patients with TC < 157 mg/dL exhibited significantly lower 5-year rates of OS and DFS (p < 0.001 and p = 0.006, respectively). Multivariable analysis confirmed that TC < 157 mg/dL represented an independent prognostic factor for reduced OS and DFS rates. Subgroup analyses reinforced the consistent prognostic significance of TC. We also constructed a nomogram (concordance index: 0.74) to provide personalized OS predictions, enhancing the clinical utility of TC. Preoperative TC appears to be a significant prognostic factor for OS and DFS after OSCC surgery. Routine TC assessment facilitates the development of nomograms for personalized survival predictions, supports clinicians in tailoring treatment strategies, and guides nutritional or metabolic interventions to enhance patient outcomes. Further multicenter prospective studies are needed to validate our findings.

Targeting the SIRT3/MnSOD and JNK/HMGB1/Beclin 1 Axes: Role of Apigenin in Multifaceted Metabolic Intervention in Colorectal Cancer.

Colorectal cancer (CRC) is the third most prevalent cancer worldwide. While chemotherapy remains the standard treatment approach, natural products have emerged as a promising alternative. Among these, apigenin, a natural flavonoid, has garnered significant attention due to its pro-oxidant and antioxidant properties in various types of cancer. This study aimed to assess the potential impact of apigenin in CRC treatment by targeting mitochondrial SIRT3, HMGB1, and beclin 1-mediated autophagy in a mouse model of CRC. We administered 20 mg/kg of dimethyl hydrazine (DMH) intraperitoneally once weekly for 20 weeks to induce CRC in C57BL/6 mice. After 6 weeks of initiating the study, apigenin was intragastrically co-administered by oral gavage at 25 and 50 mg/kg until the end of week 20. The results revealed significant weight loss, shortening of the colon, and diarrhea in DMH-induced CRC, which are considered the marks of CRC. In addition, histopathological examination revealed dysplastic changes in the DMH-treated group, while no dysplasia was found in the apigenin-treated CRC groups. Importantly, the administration of apigenin to DMH-treated animals has led to a significant reduction of SIRT3 and MnSOD expression levels with a significant increase in LC3-II at either dose and a significant dose-dependent increase in the levels of MDA, c-JNK, HMGB1, and beclin 1 compared to the DMH-treated group. In conclusion, apigenin may have a promising role in suppressing DMH-induced CRC. It elicits a pro-oxidant activity by suppressing the gene expression of SIRT3 and subsequently, its target MnSOD, resulting in increased reactive oxygen species (ROS) and lipid peroxidation. The released ROS, in turn, activates JNK-mediated autophagy by enhancing HMGB1, beclin 1, and LC3-II protein levels.