bims-meract 2025-10-26 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–10–26
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Lipid metabolism in cancer cells: Its role in hepatocellular carcinoma progression and therapeutic resistance.
SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.
ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.
Inhibition of glutamine synthetase enhances hepatocellular carcinoma radiosensitivity through ROS-induced excessive mitophagy.
Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.
TM9SF1 drives the lipophagic flux via AMPK-ULK1 signaling to sustain metabolic fitness in HER2-positive breast cancer.
Chemotherapy-Treated Breast Cancer Cells Activate the WNT Signaling Pathway to Enter a Diapause-Like Early Persister State.
Organellar pH as an emerging vulnerability to exploit in cancer.
EZH2 confers lenvatinib resistance in hepatocellular carcinoma by suppressing ACSL1-Mediated ferroptosis.
PreTA-mediated metabolism of 5-fluorouracil by intratumoral Citrobacter freundii drives chemoresistance in pancreatic cancer.
The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.
PFKFB3 as a multifaceted driver and therapeutic target in castration-resistant prostate cancer.
SIRT6 promotes intrahepatic cholangiocarcinoma development by reprogramming glutamine metabolism via enhanced GLUL.
The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα.
CAV1 Stabilizes EPAS1 via VHL in Colon Cancer to Promote Autophagy-Dependent Ferroptosis, Inhibits Stemness and Improves Anti-PD-1 Efficacy.
Cancer Dormancy and Metabolism: From Molecular Insights to Translational Opportunities.
FKBP38 expression level dictates paclitaxel resistance via interacting with Bcl-2 in endometrial cancer.
Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.
Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.
Discovery of KMT5A repressed miR-99b cluster with potential to restore chemotherapy sensitivity in gastric cancer by regulating mitochondrial complex II and affecting OXPHOS.
p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.
On-genetic inactivation of caspase-3 and P53 increases cancer cell fitness by PDIA4 redistribution.
Histone deacetylase inhibitors sensitize glioblastoma models to temozolomide and reprogram immunosuppressive myeloid cells.
Amino acid metabolism-related LncRNAs as prognostic biomarkers and predictors of immunotherapy response in hepatocellular carcinoma.
The Emerging Role of Metabolic Interventions in Uveal Melanoma.

Hepatol Commun. 2025 Nov 01. pii: e0837. [Epub ahead of print]9(11):

Lipid metabolism in cancer cells: Its role in hepatocellular carcinoma progression and therapeutic resistance.

Tin Lok Wong, Yanshu Kong, Stephanie Ma.

  Liver cancer, with hepatocellular carcinoma (HCC) as its predominant form, remains among the deadliest malignancies worldwide. Despite the expanding array of treatment options, current therapies benefit only a limited subset of patients. Metabolic reprogramming is a hallmark of cancer, with lipid metabolism playing a pivotal role in tumor progression, metastasis, and therapy resistance. HCC is profoundly influenced by alterations in lipid metabolic pathways, notably those involved in steatotic liver disease, a major risk factor. Key aspects such as de novo lipogenesis, lipid uptake, fatty acid oxidation, lipid peroxidation, biosynthesis of bioactive lipids, and cholesterol biosynthesis are all reprogrammed in liver cancer cells. These metabolic shifts modify the cancer cell lipidome-altering fatty acid unsaturation levels and other lipid profiles-to promote survival and resistance during therapy. Recent technological advances have deepened our understanding of dysregulated lipid metabolism in HCC. In this review, we examine how various facets of lipid metabolism contribute to HCC disease progression and resistance to standard treatments, including tyrosine kinase inhibitors, immune checkpoint inhibitors, and radiotherapy. We also explore the potential of targeting lipid metabolic pathways to enhance therapeutic efficacy and overcome resistance, highlighting dietary interventions as a promising, low-cost, low-side-effect strategy to resensitize resistant HCC cells.

Keywords:  chemotherapy; hepatocellular carcinoma; immunotherapy; lipid metabolism; radiotherapy; targeted therapy; therapeutic resistance

DOI:  https://doi.org/10.1097/HC9.0000000000000837
Commun Biol. 2025 Oct 20. 8(1): 1485

SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.

Zhang Xianhong, Gao Yue, Zhang Yu, Zhang Yichen, Chen Yufei, Pei Xinke, Zhang Jinhui, Wang Yiqi, Du Yitian, Hao Shuailin, Ni Ting.

Protein lysine succinylation is a crucial post-translational modification that regulates nearly all aspects of eukaryotic and prokaryotic cell, including gene transcription, cell metabolism and redox homeostasis. Among them, metabolic disorders caused by dysfunctional post-translational modifications induce aging and aged-related diseases, including cancer. This study quantified the dynamic changes in protein succinylation in response to DNA damage stress induced by etoposide (ETOP) in tumor cells. A total of 4354 lysine succinylation sites on 1259 proteins were identified, many of which have not been previously reported. Bioinformatics analysis revealed that many proteins are involved in the metabolism of nicotinamide adenine dinucleotide phosphate (NADPH) in mitochondria (including MTHFD2). We further found that low activity or depletion of MTHFD2 enhances the degree of TIS in breast cancer cells and decreases their resistance to chemotherapeutic agents. Interestingly, we also found that SIRT5-mediated desuccinylation of MTHFD2 was able to reduce the senescence of breast cancer cells, thereby enhancing their resistance to chemotherapeutic drugs. This effect may explain the poorer prognosis observed in breast cancer patients with high expression levels of SIRT5 or MTHFD2. These systematic analyses provide new insights into targeting succinylation-modified metabolic proteins to enhance TIS, and their combination with senolytics for breast cancer therapy.

DOI: https://doi.org/10.1038/s42003-025-08878-z
Adv Sci (Weinh). 2025 Oct 23. e14077

ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.

Shuai Shao, Wei Li, Yulong Hong, Ruijiang Zeng, Liang Zhu, Lu Yi, Yuan Li, Yinhuai Wang, Haojie Huang, Xuewen Jiang, Xin Jin.

  Ferroptosis represents a promising vulnerability to overcome therapeutic resistance in castration-resistant prostate cancer (CRPC). While S-palmitoylation of lipid peroxide-scavenging proteins such as GPX4 and SLC7A11 has been shown to suppress ferroptosis, whether palmitoylation modulates the lipid peroxidation generation remains unclear. Here, we identified the palmitoyltransferase ZDHHC2 as a critical driver of enzalutamide resistance through destabilizing ACSL4. ZDHHC2 is transcriptionally upregulated by a FOXA1/CXXC5/TET2 complex and promotes S-palmitoylation of the deubiquitinase USP19, which impairs its interaction with ACSL4. This disrupts USP19-mediated ACSL4 stabilization, promoting its ubiquitin-proteasome degradation and consequently suppressing lipid peroxidation and ferroptosis. We developed a small-molecule ZDHHC2 inhibitor, TTZ1, which restores ACSL4 protein, reactivates ferroptosis, and reverses enzalutamide resistance in CRPC cell lines and patient-derived xenograft models. This study uncovers a previously unrecognized mechanism by which palmitoylation regulates ferroptosis through modulating ACSL4 stability, and highlights the ZDHHC2-USP19-ACSL4 axis as a druggable target for overcoming resistance in advanced prostate cancer.

Keywords:  ACSL4; CRPC; ZDHHC2; ferroptosis; lipid peroxide production

DOI:  https://doi.org/10.1002/advs.202514077
Mol Biol Rep. 2025 Oct 23. 53(1): 5

Inhibition of glutamine synthetase enhances hepatocellular carcinoma radiosensitivity through ROS-induced excessive mitophagy.

Rao Liu, Guangyu Ju, Yijun Lu, Xiao Liu, Qi Ding, Kaiwei Wang, Hongcang Gu, Junchao Qian.

   BACKGROUND: Glutamine' synthetase (GS) plays a central role in glutamine metabolism and has been implicated in the progression and treatment resistance of hepatocellular carcinoma (HCC). Although previous studies have explored GS in tumor metabolism, its role in modulating mitophagy and radiosensitivity in HCC cells remains unclear.
METHODS: We analyzed GS expression in HCC using data from the TCGA database, followed by treatment of HepG2, Hep3B and Huh7 cells with the GS inhibitor L-methionine sulfoximine (MSO) and exposure to ionizing radiation. Cellular responses were evaluated through CCK-8 assays, Western blotting, immunofluorescence, flow cytometry, colony formation assays, and mitochondrial membrane potential measurements.
RESULTS: Correlation analysis revealed a positive association between GS expression and mitophagy-related genes in HCC. MSO treatment enhanced the effects of radiotherapy, leading to increased ROS production, reduced antioxidant capacity, and aggravated mitochondrial damage. Mitophagy activation was confirmed by LC3-II accumulation and upregulation of the PINK1/Parkin pathway. Notably, the radiosensitizing effect of MSO was partially reversed by Mdivi-1, indicating that mitophagy contributes to MSO-mediated radiosensitization.
CONCLUSION: These findings indicate that inhibition of GS enzyme activity enhances oxidative stress and mitophagy, thereby promoting radiosensitivity in HCC cells. This study provides new insights into the role of GS in overcoming radiotherapy resistance and highlights its potential as a therapeutic target to improve radiotherapeutic outcomes in HCC.

Keywords:  Glutamine synthetase; Hepatocellular carcinoma; Mitophagy; Radiosensitizing

DOI:  https://doi.org/10.1007/s11033-025-11172-0
Sci Rep. 2025 Oct 23. 15(1): 37028

Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.

Martina Spada, Cristina Piras, Vera Piera Leoni, Mattia Casula, Gabriella Simbula, Antonio Noto, Katia Lilliu, Karolina Krystyna Kopeć, Gabriele Serreli, Federica Murgia, Federica Etzi, Tinuccia Dettori, Luigi Atzori, Paola Caria.

  Colorectal cancer (CRC) cells are 'addicted' to glutamine to satisfy energy and biosynthetic needs. Inhibiting glutamine metabolism enzymes, like glutaminase, is a potential cancer therapy strategy. Although the GLS inhibitor CB-839 is being evaluated in clinical trials, a comprehensive assessment of its antitumor activity in CRC cells is crucial. The present study aimed to evaluate the impact of CB-839 treatment on different CRC cell lines in terms of survival and proliferation. Furthermore, metabolic adaptations resulting from CB-839 treatment, particularly in energetic pathways, were investigated. Three CRC cell lines (HCT116, HT29, and SW480) were treated with different CB-839 concentrations. Cytotoxicity was assessed via MTT assay, proliferation capacity by flow cytometry, and ATP production rates by Seahorse XF analysis. Moreover, metabolomic profile was explored with untargeted GC-MS and 1H-NMR, and targeted analysis of the Krebs cycle was conducted using GC-MS/MS. HT29 cells exhibited the highest sensitivity to CB-839. Subsequent experiments focused on HT29 and SW480 cells. CB-839 treatment altered cell cycle progression and increased glycolytic ATP production in HT29 cells. Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels. This study highlighted glutamine's key role in CRC cells and provided a foundation for elucidating the mechanisms of response and resistance to CB-839.

Keywords:  CB-839; Colorectal cancer; Energetic metabolism; Glutaminase-1 inhibition; Glutamine metabolism; Glutaminolysis

DOI:  https://doi.org/10.1038/s41598-025-20528-2
Cell Death Dis. 2025 Oct 24. 16(1): 755

TM9SF1 drives the lipophagic flux via AMPK-ULK1 signaling to sustain metabolic fitness in HER2-positive breast cancer.

Xiaofen Li, Xiaoqin Yu, Kaiyan Huang, Xin Yu, Shiping Luo, Xiewei Huang, Chuangui Song.

Therapeutic resistance and recurrence in human epidermal growth factor receptor 2-positive breast cancer (HER2 + BC) remain critical challenges that portend poor patient outcomes. Dysregulated autophagy and lipid metabolism contribute to tumor progression, yet the crosstalk between these pathways is poorly understood. This study investigates the role of transmembrane 9 superfamily member 1 (TM9SF1) in lipophagy and lipid metabolic reprogramming in HER2 + BC under metabolic stress. Clinically, TM9SF1 was significantly upregulated in HER2 + BC tissues and correlated with poor prognosis. Functionally, its expression correlated with markers of enhanced autophagy and lysosomal lipid catabolism, and it promoted tumor cell proliferation in vitro and in vivo. Conversely, TM9SF1 knockdown suppressed lipophagy under both basal and starvation conditions, inhibiting lipid droplet (LD) hydrolysis and the conversion of triglycerides to free fatty acids. This suppression was phenotypically characterized by LD accumulation, reduced autophagosomes and lipophagosomes, and altered enzymatic and lipidomic profiles. Mechanistically, TM9SF1 sustained lipophagy by promoting the phosphorylation of AMP-activated protein kinase at Thr172 and UNC-51-like kinase 1 at Ser555. Consequently, TM9SF1 was pivotal for lipid metabolic reprogramming, maintaining energy homeostasis and enhancing adaptation to nutrient deprivation through lipophagy. Overall, our findings identify TM9SF1 as a key HER2 + BC-associated regulator that drives lipophagy via the AMP-activated protein kinase-UNC-51-like kinase 1 pathway, facilitating LD turnover and free fatty acids utilization to sustain energy homeostasis in HER2 + BC. This work establishes a critical link between malignant phenotypes and metabolic resilience. Targeting this regulatory network represents a promising strategy to dismantle the metabolic scaffolds underlying HER2 + BC aggressiveness and therapeutic resistance.

DOI: https://doi.org/10.1038/s41419-025-08093-y
Cancer Res. 2025 Oct 21.

Chemotherapy-Treated Breast Cancer Cells Activate the WNT Signaling Pathway to Enter a Diapause-Like Early Persister State.

Youssef El Laithy, Willy Antoni Abreu De Oliveira, Anirudh Pabba, Alessandra Qualizza, Gwenny Cosemans, Paula Garcia-Diaz, François Richard, Paraskevi Athanasouli, Carla Rios Luci, Wout De Wispelaere, Larissa Mourao, Siân Hamer, Stijn Moens, Anchel De Jaime-Soguero, Maria Francesca Baietti, Stefan J Hutten, Jos Jonkers, Stephen-John Sammut, Stefaan Soenen, Colinda Lgj Scheele, Alejandra Bruna, Christine Desmedt, Daniela Annibali, Frederic Lluis.

Cancer cells can acquire a reversible, dormant drug-tolerant persister state mimicking embryonic diapause to evade therapy pressure. Deciphering the precise mechanisms driving cancer cells into or out of a diapause-like persister cell-state could provide strategies to overcome resistance. Here, we showed that following chemotherapy, diverse therapeutic agents converge on WNT pathway activation to induce a de novo diapause-like cell state across various triple-negative breast cancer (TNBC) cell line, xenograft, and patient-derived organoid models. Among early persister cells, only transcriptionally WNT-active persisters exhibited the transcriptional and functional characteristics typical of diapause-like cells, including a negative correlation with MYC transcriptional activity and reversible restricted proliferation. The WNT signaling pathway functioned as both an inducer and biomarker of the diapause-like early persister cell state in both parental (chemo-naïve) and chemotherapy-treated cells. Entry into and exit from the diapause-like early persister cell state was triggered by the transcriptional upregulation of components essential for canonical WNT ligand secretion. A combinatorial treatment strategy inhibiting WNT ligand secretion alongside chemotherapy effectively targeted the early mechanisms underlying the acquisition and enrichment of a diapause-like cell phenotype. These findings reveal WNT pathway activation as an early event that leads to a reversible diapause-like persister state and highlight the potential of targeting this axis to prevent the development of drug-resistant populations before they are firmly established.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4165
Trends Cancer. 2025 Oct 23. pii: S2405-8033(25)00234-1. [Epub ahead of print]

Organellar pH as an emerging vulnerability to exploit in cancer.

Cheska Marie Galapate, Cosimo Commisso.

  Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pHi). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pHi provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.

Keywords:  cancer metabolism; organelle acidification; pH homeostasis

DOI:  https://doi.org/10.1016/j.trecan.2025.09.006
BMC Cancer. 2025 Oct 24. 25(1): 1638

EZH2 confers lenvatinib resistance in hepatocellular carcinoma by suppressing ACSL1-Mediated ferroptosis.

Yibin Zhang, Yucong Lin, Huitang Cai, Tongchong Zhou.

   BACKGROUND: Lenvatinib resistance significantly limits treatment efficacy in hepatocellular carcinoma (HCC), yet the underlying mechanisms remain poorly understood. This study investigates the role of EZH2 in mediating lenvatinib resistance through ferroptosis regulation, aiming to identify novel therapeutic targets for overcoming drug resistance in HCC.
METHODS: EZH2 expression patterns were analyzed using TCGA datasets and validated in clinical HCC samples through RT-qPCR. Lenvatinib-resistant HCC cell lines were established to examine EZH2's functional role. The impact of EZH2 on ferroptosis was evaluated by measuring cell proliferation, reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) levels. Mechanistic investigations were performed using EZH2 knockdown, ACSL1 expression analysis, and H3K27me3 modification assays. The therapeutic potential of EZH2 inhibition was further assessed in xenograft models.
RESULTS: EZH2 was significantly overexpressed in HCC tissues and correlated with poor patient survival. Resistant cell models demonstrated EZH2-mediated suppression of ferroptosis through ACSL1 downregulation via H3K27me3, evidenced by altered ROS, MDA and GSH levels. Genetic inhibition of EZH2 restored lenvatinib sensitivity by upregulating ACSL1 and promoting ferroptosis. In vivo studies confirmed that EZH2 targeting enhanced lenvatinib's antitumor effects in resistant HCC models.
CONCLUSIONS: Our findings establish EZH2 as a critical regulator of lenvatinib resistance in HCC through ACSL1-mediated ferroptosis suppression. The EZH2-H3K27me3-ACSL1 axis represents a promising therapeutic target for overcoming drug resistance, offering new strategies to improve HCC treatment outcomes.

Keywords:  ACSL1; EZH2; Ferroptosis; Hepatocellular carcinoma; Lenvatinib resistance

DOI:  https://doi.org/10.1186/s12885-025-15086-9
Cell Rep. 2025 Oct 22. pii: S2211-1247(25)01244-6. [Epub ahead of print]44(11): 116473

PreTA-mediated metabolism of 5-fluorouracil by intratumoral Citrobacter freundii drives chemoresistance in pancreatic cancer.

Weiben Xu, Ying Zhou, Haiying Ding, Mengqian Ye, Shujing Li, Linwei Xu, Xiangyu Jin, Zhajun Zhan, Lulu Song, Yuhua Zhang, Canming Wang, Zhengqin Zhu, Liefeng Ma, Libin Pan, Luo Fang.

  Pancreatic cancer is highly malignant, and while fluoropyrimidines (5-fluorouracil [5-FU] and capecitabine) are critical first-line treatments for metastatic cases, drug resistance remains a major challenge. In this study, we identified an association between Citrobacter enrichment in pancreatic tumors and poor overall survival in patients with pancreatic cancer, particularly in patients receiving fluoropyrimidine-based treatment. Co-culture of 5-FU with the Citrobacter freundii strain isolated from pancreatic cancer and intratumoral injection of this strain in xenograft models significantly reduce the antitumor efficacy of 5-FU. Subsequent analyses using mass spectrometry, bioinformatics, and gene knockout experiments revealed that C. freundii strain inactivates 5-FU via the PreTA, which is homologous to human dihydropyrimidine dehydrogenase (DPD). Gimeracil, a DPD inhibitor, preserves the efficacy of 5-FU by blocking PreTA activity. Other preTA-harboring bacteria also metabolized 5-FU, indicating broader bacteria-mediated 5-FU resistance. These findings reveal a potential microbiome-driven mechanism of chemotherapy failure and identify PreTA as a druggable target.

Keywords:  5-fluorouracil; CP: Cancer; CP: Microbiology; Citrobacter freundii strain; drug resistance; intratumoral microbiome; pancreatic cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.116473
Cell Death Dis. 2025 Oct 21. 16(1): 750

The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.

Shin-Ichiro Kawaguchi, Kazuya Sato, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Kaoru Tominaga, Hitoshi Endo, Tom Kouki, Nobuhiko Ohno, Yoshinobu Kanda.

Leukemia cells are consistently subjected to higher oxidative stress than normal cells. To mitigate reactive oxygen species (ROS) overload, which can trigger various forms of cell death, leukemia cells employ a robust antioxidant defense system and maintain redox homeostasis. Recent evidence suggests that dimethyl fumarate (DMF), a derivative of fumarate, inactivates the antioxidant glutathione (GSH), thereby inducing oxidative stress and metabolic dysfunction, eventually leading to cell death in cancer cells. In this study, we observed that DMF decreases the GSH/oxidated GSH ratio and increases intracellular ROS levels, the extent of which is closely correlated with cell death, in acute myeloid leukemia (AML) cell lines. DMF reduced the mitochondrial membrane potential and oxidative phosphorylation (OXPHOS), effects that were almost fully restored by the antioxidant N-acetylcysteine, suggesting that these responses are ROS-dependent. Electron microscopy and inhibition assays revealed that apoptosis, rather than necroptosis or ferroptosis, is the predominant form of cell death of AML cells following DMF treatment. Notably, the combination of DMF and the BCL-2 selective BH3-mimetic venetoclax induced marked cell death in AML cells, including venetoclax-refractory　BCL-2 low expressing U937 and acquired venetoclax-resistant MOLM-14 cells. This combination also caused greater mitochondrial depolarization and a more profound reduction in OXPHOS activity than either agent alone. Collectively, our findings indicate that DMF exerts potent anti-leukemia activity in AML cells and sensitizes cells to venetoclax treatment by synergistically disrupting mitochondrial integrity through ROS accumulation.

DOI: https://doi.org/10.1038/s41419-025-08040-x
Cell Death Dis. 2025 Oct 24. 16(1): 760

PFKFB3 as a multifaceted driver and therapeutic target in castration-resistant prostate cancer.

Lin Chen, Yu-Xin Xu, Ying-Ying Ren, Zhi-Da Wang, Xue-Man Dong, Yi-Min Chen, Pu Wu, Tong Wu, Fei Xiang, Tian Xie, Qi Zhang, Jian-Liang Zhou.

Castration-resistant prostate cancer (CRPC) is the advanced stage of prostate cancer (PCa) progression, characterized by limited therapeutic options and significant challenges from drug resistance development. We show that PFKFB3, an essential regulator of glycolytic metabolism, is significantly upregulated in PCa tissues and CRPC cell lines, where it plays a pivotal role in driving CRPC progression. Knockdown of PFKFB3 or inhibition by a small molecule inhibitor significantly inhibits the growth and invasion of CRPC cells, whereas overexpression promotes malignant behaviors. Mechanistically, PFKFB3 modulates the PI3K/Akt-Wnt/β-catenin pathway, resulting in enhanced tumor cell proliferation. Additionally, combining a PFKFB3 inhibitor with docetaxel produces synergistic anti-CRPC effects and reduces toxicity. Therefore, PFKFB3-mediated metabolic reprogramming underlies CRPC progression, highlighting its potential as a therapeutic target and emphasizing the need for further exploration in the development of safe and effective PFKFB3 inhibitors for precise targeted therapy in CRPC.

DOI: https://doi.org/10.1038/s41419-025-08089-8
Gut. 2025 Oct 23. pii: gutjnl-2025-335729. [Epub ahead of print]

SIRT6 promotes intrahepatic cholangiocarcinoma development by reprogramming glutamine metabolism via enhanced GLUL.

Mi Zhang, Chanyuan Chen, Haifeng Zhang, Tanqing Long, Tingjie Wang, Nanjin Ding, Ruitao Long, Hua Wu, Zhilu Ma, Zhongyu Cheng, Junyan Tao, Dong Kuang, Lei Li, Chuanrui Xu.

   BACKGROUND: SIRT6 acts as a tumour suppressor in multiple cancers by regulating glucose and lipid metabolism, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear.
OBJECTIVE: We investigated the role and molecular mechanisms of SIRT6 in ICC development and progression.
DESIGN: Spatial transcriptome and single-cell sequencing data from public ICC cohorts and clinical specimens were used to establish the clinical relevance of SIRT6 overexpression. B/R cell-established allografts and AKT/YAP-induced primary ICC mouse models were used to investigate the oncogenic role of SIRT6. The function of SIRT6 in metabolic regulation was assessed using seahorse analysis, metabolomics and isotope tracing. The transcriptional targets of SIRT6 were screened by RNA sequencing and confirmed by dual-luciferase assay and chromatin immunoprecipitation, and the molecular interactions and deacetylation activity of SIRT6 were analysed via co-immunoprecipitation.
RESULTS: SIRT6 was highly expressed in both human and mouse ICC tissues and cell lines. SIRT6 knockdown significantly inhibited ICC cell growth in vitro and ICC development in mouse models. Hydrodynamic co-injection of SIRT6 and AKT resulted in ICC formation in mice. SIRT6 promoted glutamine synthesis by enhancing GLUL transcription and stabilising GLUL protein degradation. SIRT6 silencing decreased glutamine levels, subsequently reducing the levels of nucleotides and amino acids in ICC cells. Thus, SIRT6 or GLUL inhibitors can suppress ICC progression and significantly enhance the sensitivity to chemotherapy.
CONCLUSIONS: Our findings establish SIRT6 as an oncogenic driver in ICC by orchestrating glutamine metabolic reprogramming and highlight the SIRT6-GLUL axis as a potential therapeutic target for ICC.

Keywords:  CELL GROWTH; HEPATOBILIARY CANCER; LIVER METABOLISM; MOLECULAR ONCOLOGY

DOI:  https://doi.org/10.1136/gutjnl-2025-335729
Cell Metab. 2025 Oct 22. pii: S1550-4131(25)00396-1. [Epub ahead of print]

The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα.

Zhifu Xie, Long Cheng, Yue Hu, Gaolei Song, Fan Wang, Mei Zhang, Yangming Zhang, Xinwen Zhang, Chendong Zhou, Xiaoxue Zhu, Xinyu Sun, Honghong Xu, Qian Song, Yulin Yang, Jie Zheng, Shaohui Ji, Jiming Ye, Chen Zhou, Xiaoying Lai, Wei Li, Yifan Zhang, Xiaoyan Chen, Junqi Niu, Yanhua Ding, Fajun Nan, Jingya Li.

  The rise in the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is attributed significantly to dysregulated lipid metabolism. This study discovered that the enedioic acid ATP-citrate lyase (ACLY) inhibitor 326E, an investigational new drug in a phase 2a study for hypercholesterolemia, markedly reduces hepatic lipid accumulation and alleviates MASH in mouse models of MASH. Mechanistic studies demonstrated that 326E exerts these effects not only by inhibiting ACLY to reduce de novo lipogenesis (DNL) but also as a peroxisome proliferator-activated receptor α (PPARα) allosteric regulator to increase hepatic fatty acid oxidation (FAO). The efficacy of activated PPARα for MASH is enhanced by suppressed recycling of FAO products to lipid accumulation as a result of ACLY inhibition. Subsequent studies in cynomolgus monkeys (Macaca fascicularis) confirmed the effectiveness of 326E for MASH in primate species. In a randomized phase 1b/2a clinical trial in patients with MASH (NCT06491576), 326E was well tolerated and reduced circulating gamma-glutamyl transferase (γ-GGT). Taken together, our results indicate the therapeutic potential of 326E for MASH via distinctive dual mechanisms of inhibiting ACLY while activating PPARα.

Keywords:  326E; ACLY; PPARα; fatty acid β-oxidation; lipogenesis; metabolic dysfunction-associated steatohepatitis; phase 1b/2a clinical trial

DOI:  https://doi.org/10.1016/j.cmet.2025.09.011
FASEB J. 2025 Oct 31. 39(20): e71124

CAV1 Stabilizes EPAS1 via VHL in Colon Cancer to Promote Autophagy-Dependent Ferroptosis, Inhibits Stemness and Improves Anti-PD-1 Efficacy.

Lianghe Li, Rui Li, Wei Zhan, Zuyin Zhuo, Jiandong Zhang, Qing Li, Song Mu, Wen Chen, Lei Li, Siyao He.

  Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system. Immune checkpoint blockade (ICB) is a promising strategy for CRC treatment, but its limited efficacy poses a challenge. Bioinformatics methods were used to screen ferroptosis-related genes in CRC. Cellular biology methods investigated endothelial PAS domain protein 1 (EPAS1) impact on cellular characteristics, stemness, and ferroptosis. Finally, in vivo experiments validated EPAS1's influence on anti-PD-1 therapy efficacy. We have found that EPAS1 is a risk gene in CRC, which can inhibit the growth, invasion, and stemness of colon cancer cells both in vitro and in vivo, and promote ferroptosis. Mechanistically, caveolin 1 (CAV1) regulates the expression of von Hippel-Lindau tumor suppressor (VHL) to inhibit the ubiquitination of EPAS1, increase its stability, further enhance the expression of nuclear receptor coactivator 4 (NCOA4) and autophagy-lysosome formation, leading to cell iron overload and inducing ferroptosis. Our study confirms EPAS1 regulates ferroptosis, impacting epithelial-mesenchymal transition (EMT) and stemness in CRC cells, and highlights its role in ICB. These findings inform CRC treatment.

Keywords:  CAV1; EPAS1; colorectal cancer; ferroptosis; ubiquitylation

DOI:  https://doi.org/10.1096/fj.202501953R
Cancer Lett. 2025 Oct 22. pii: S0304-3835(25)00669-X. [Epub ahead of print] 218097

Cancer Dormancy and Metabolism: From Molecular Insights to Translational Opportunities.

Yashi Wang, Lingyue Liu, Xiaozhen Zhang, Tingbo Liang, Xueli Bai.

  Cancer dormancy refers to a reversible state where cancer cells enter a quiescent phase, allowing them to evade therapeutic interventions and remain undetected. This state can lead to potential reactivation years later, resulting in relapse and metastasis. This phenomenon presents a significant challenge in cancer treatment, as dormant cells often exhibit resistance to conventional therapies. Recent studies emphasize the crucial role of metabolic reprogramming in regulating cancer dormancy, closely interacting with the tumor microenvironment. Dormant cancer cells undergo metabolic adaptations that enable their survival in a hostile tumor microenvironment. These adaptations include a decreased reliance on glycolysis and an increased dependence on oxidative phosphorylation and fatty acid oxidation. Exosomes, extracellular matrix, and cancer-associated fibroblasts dynamically regulate these metabolic states by mediating intercellular communication and modulating the biochemical and mechanical properties of the tumor microenvironment. In parallel, epigenetic regulation fine-tunes metabolic gene expression, reinforcing the dormant phenotype and enabling plastic transitions between dormancy and proliferation. Additionally, these cells utilize autophagy to recover nutrients and manage microenvironmental stress. These metabolic changes help dormant cells maintain a low metabolic state while preserving their ability to reactivate when conditions become favorable. Understanding the relationship between dormancy and metabolism offers new therapeutic opportunities aimed at targeting metabolic pathways to prevent relapse and metastasis. This review explores the mechanisms of metabolic reprogramming in dormancy induction, maintenance, and escape, providing insights into potential therapeutic strategies.

Keywords:  Autophagy; Cancer dormancy; Fatty acid oxidation; Metabolic reprogramming; Oxidative phosphorylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218097
Biochem Pharmacol. 2025 Oct 21. pii: S0006-2952(25)00702-6. [Epub ahead of print] 117437

FKBP38 expression level dictates paclitaxel resistance via interacting with Bcl-2 in endometrial cancer.

Yunjing Yan, Yimei Lai, Minyi Tang, Shuai Wang, Gengmiao Xiao, Yunping Mu, Xiaoli Wu, Allan Z Zhao, Fanghong Li.

  Endometrial cancer (EC) is a gynecological malignancy that faces the serious challenge of chemotherapy resistance. Therefore, there is an urgent clinical need to investigate this issue. In this study, we focused on the potential role of FKBP38, a membrane-bound chaperone protein primarily located in the outer mitochondrial membrane. Previous studies have reported reduced FKBP38 expression in ovarian and breast cancer tissues. In this study, we found that FKBP38 expression was significantly decreased in human EC tissues and correlated with poor overall survival in patients receiving chemotherapy. Knockdown of FKBP38 expression in EC cells increased the half-maximal inhibitory concentration of paclitaxel and attenuated the therapeutic response in xenograft models. FKBP38 co-localized and interacted with Bcl-2, and reduced FKBP38 expression inhibited paclitaxel-induced apoptosis by stabilizing mitochondrial function. Importantly, under paclitaxel treatment, FKBP38 knockdown not only increased Bcl-2 expression but also prevented the binding of Bcl-2 to the pro-apoptotic protein, Bad. Collectively, these findings imply that FKBP38 inhibits paclitaxel resistance by interacting with Bcl-2, thereby preserving mitochondrial function. Thus, FKBP38 may serve as a suitable biomarker for targeted antimetabolite therapy in EC.

Keywords:  Bcl-2; Chemotherapy; Endometrial cancer; FKBP38; Mitochondrial function

DOI:  https://doi.org/10.1016/j.bcp.2025.117437
Nat Metab. 2025 Oct 20.

Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.

Li Shen, Shenghao Wang, Chao Gao, Qin Li, Shuya Feng, Weiyan Sun, Xu Liu, Yiyi Ba, Yihui Chu, Yu Zhou, Junjie Pan, Hao Xu, Xu Zhang, Wenwei Zhu, Lunxiu Qin, Ming Lu.

Increased acetyl-coenzyme A (acetyl-CoA) generation facilitates cancer metastasis and represents a critical metabolic characteristic of metastatic cancers. To maintain high acetyl-CoA levels, cancer cells often enhance the uptake of acetate for acetyl-CoA biosynthesis. However, the microenvironmental source of acetate remains largely unknown. Here we demonstrate that acetate is secreted by tumour-associated macrophages (TAMs) and taken up by hepatocellular carcinoma (HCC) cells to support acetate accumulation. Mechanistically, HCC cell-derived lactate activates the lipid peroxidation-aldehyde dehydrogenase 2 (ALDH2) pathway in TAMs, which promotes the TAMs' acetate production and secretion. Inhibition of ALDH2 or of lipid peroxidation in TAMs abrogates acetate-induced migration of HCC cells in vitro. In an orthotopic HCC model involving male mice, genetic ablation of ALDH2 in TAMs reduces HCC cell acetate levels and HCC lung metastases. Collectively, our findings reveal a metabolic interaction between HCC cells and TAMs-involving lactate, lipid peroxidation and acetate-and position TAMs as an acetate reservoir that drives HCC metastasis.

DOI: https://doi.org/10.1038/s42255-025-01393-9
PLoS Biol. 2025 Oct;23(10): e3003453

Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.

Wakiko Iwata, Nora Haggerty, Hiromi Sesaki, Miho Iijima.

Mitochondrial division and fusion are critical regulators of cancer cell metabolism, proliferation, survival, metastasis, and drug resistance. Division promotes tumor development by reprogramming energy metabolism, whereas its inhibition can suppress tumor growth and metastasis. The mechanochemical GTPase DRP1, a key mediator of mitochondrial division, has emerged as a promising therapeutic target. Mitochondrial cristae also contribute to cancer progression by modulating metabolic reprogramming and oncogenic signaling. Targeting these processes may stimulate anti-tumor innate immune responses through the release of mitochondrial DNA into the cytoplasm. A deeper understanding of tumor-specific mitochondrial membrane structures and dynamics could therefore reveal novel intervention strategies and guide precision cancer therapies.

DOI: https://doi.org/10.1371/journal.pbio.3003453
Pharmacol Res. 2025 Oct 17. pii: S1043-6618(25)00421-9. [Epub ahead of print]221 107996

Discovery of KMT5A repressed miR-99b cluster with potential to restore chemotherapy sensitivity in gastric cancer by regulating mitochondrial complex II and affecting OXPHOS.

Liaoran Niu, Xiaoyu Kang, Jianyong Zheng, Fei Wu, Shushang Liu, Liu Hong, Haiming Liu, Jiuping Wang, Daiming Fan, Yongzhan Nie, Zhangqian Chen.

  Gastric cancer remains a formidable global health challenge, with drug resistance being a primary contributor to its high mortality rates. Therefore, understanding the mechanisms driving drug resistance is crucial for developing more effective therapeutic interventions. Utilizing high content screening technology, we identified let-7e-5p and miR-125a-5p as the key regulators of drug resistance in GC, both being members of the miR-99b cluster. Findings from GC cells, organoids and PDX models demonstrated that overexpression of the miR-99b cluster sensitized GC to cisplatin, likely through its inhibitory effects on mitochondrial respiratory function, particularly OXPHOS. We further demonstrated that multiple components, especially SDHC subunit of respiratory complex II, were regulated by miR-99b cluster and played critical roles in GC chemoresistance. Then, through a comprehensive screen of epigenetic compounds, we identified KMT5A as a key upstream repressor of the miR-99b cluster in GC, which reinforces the H4K20me1 modification within the miR-99b cluster region. Moreover, elevated KMT5A expression and decreased miR-125a-5p expression indicated both poorer prognosis and chemo-resistance in patients with GC. This study highlights the multifaceted roles of the miR-99b cluster in GC and offers novel perspectives for the development of innovative therapeutics aimed at overcoming chemoresistance and enhancing treatment efficacy for GC patients.

Keywords:  Chemotherapy resistance; Epigenetic mechanisms; Gastric cancer; MicroRNA; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.phrs.2025.107996
Cancer Discov. 2025 Oct 21.

p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.

Mengxiong Wang, Kathryn T Bieging-Rolett, Alyssa M Kaiser, Colleen A Brady, John H Lockhart, Sofia Ferreira, Kha T Nguyen, Arati Rajeevan, Simone A Evans, Tianyu Zhao, Nitin Raj, Arielle Elkrief, Sam E Tischfield, Marc Ladanyi, Michael G Ozawa, Nam Q Bui, Christopher T Chen, Elsa R Flores, Laura D Attardi.

Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0525
Oncogene. 2025 Oct 21.

On-genetic inactivation of caspase-3 and P53 increases cancer cell fitness by PDIA4 redistribution.

Gal Twito, Faiza Amterat Abu Abayed, Ayelet Gilad, Suma Biadsy, Noa Gavriel, Suad Sheikh Suliman, Yarden Mizrahi, Hila Megged, Mor Tenenboim, Naim Abu-Freha, Aeid Igbaria.

Numerous cellular pathways are known to cause resistance in cancer cells. The unfolded protein response (UPR), a signaling pathway activated during proteostasis stress in the endoplasmic reticulum (ER), is an adaptive process to increase cancer cell fitness. However, the molecular mechanism between ER stress, UPR activation, and chemoresistance is insufficiently understood. Here, we report that ER stress induction and UPR activation are necessary for chemoresistance to cisplatin and doxorubicin. Mild ER stress is a sufficient precondition for cancer cells to evade cisplatin- and doxorubicin-associated cell death. Mechanistically, ER stress induction results in the redistribution of PDIA4 from the ER to the cytosol, facilitated by the c-tail-anchored proteins DNAJB12 and DNAJB14 and the cytosolic HSC70-cochaperone SGTA. In the cytosol, PDIA4 forms an inhibitory interaction with caspase-3 and wt-p53, leading to their attenuation and increased cancer cell proliferation. Furthermore, we show that PDIA4 must originate from the ER to inhibit caspase-3 and wt-p53 in the cytosol. Silencing PDIA4, DNAJB12/14, or SGTA rescues wt-p53 and caspase-3 activity. Finally, we found that in tumors isolated from colorectal cancer patients, PDIA4 and DNAJB12 are highly expressed compared to their healthy tissues; this expression is associated with the induction of the UPR. Our data show a novel non-genetic mechanism to inhibit apoptosis and suggest PDIA4, DNAJB12/14, and SGTA as novel therapeutic targets to rescue apoptosis and inhibit proliferation in cancer cells.

DOI: https://doi.org/10.1038/s41388-025-03606-7
Sci Rep. 2025 Oct 21. 15(1): 36804

Histone deacetylase inhibitors sensitize glioblastoma models to temozolomide and reprogram immunosuppressive myeloid cells.

Golnaz Asaadi Tehrani, Rebecca N Kubick, Maksym Zarodniuk, Meenal Datta.

  Histone deacetylase inhibitors (HDACis) are promising anti-cancer agents but remain underexplored in glioblastoma (GBM). This study evaluated the effects of three HDACis-CAY10603, vorinostat (SAHA), and valproic acid (VPA)-on human GBM cell lines (U87, MGG8) with immortalized human astrocytes (IHAs) as healthy controls. HDACis were tested alone or in combination with temozolomide (TMZ), the standard chemotherapy for GBM, in both 2D (monolayer) and 3D (neurosphere) cultures. Additionally, co-culture of GBM cells with macrophages (M0, biochemically differentiated from THP-1 human monocytes) was used to examine the impact of HDACis on cancer-immune interactions. Results demonstrated that all three HDACis significantly reduced cell viability and synergistically enhanced the effect of TMZ. CAY10603 and SAHA induced early apoptosis and upregulated caspase 3 (CASP3) expression, whereas VPA primarily induced late apoptosis and necrosis in GBM cultures. VPA induced both G0/G1 and G2/M cell cycle arrest, while SAHA and CAY10603 only induced G2/M arrest. mRNA expression analysis following HDACi treatment in U87 neurospheres revealed that HDACis inhibited expression of markers for epithelial-to-mesenchymal transition (EMT), proliferation, and stemness pathways. In U87-M0 co-cultures, we observed significant upregulation of stemness markers and the pro-inflammatory cytokine TNF-α following CAY10603 and VPA treatments. In contrast, TMZ monotherapy upregulated the expression of the immunosuppressive cytokine TGF-[Formula: see text]. These findings suggest that HDAC inhibition-including the novel small molecule CAY10603-sensitizes GBM to temozolomide and confers potent anti-tumor effects that combat GBM (e.g., reducing proliferation, EMT, stemness). Among the HDAC inhibitors tested, CAY10603 exhibited the most potent anti-tumor effect in 3D neurosphere and macrophage co-culture models, significantly enhancing apoptosis and disrupting pro-tumorigenic and anti-inflammatory signaling in GBM. Our in vitro findings -e.g., with 3D neurospheres that better mimic physiological tumor growth than 2D monolayers-warrant future in vivo testing of HDACis alone or in combination with chemotherapy.

Keywords:  Chemotherapy resistance; HDAC; Macrophages; Neurospheres; Suberoylanilide hydroamic acid; Valproic acid

DOI:  https://doi.org/10.1038/s41598-025-20749-5
Discov Oncol. 2025 Oct 22. 16(1): 1947

Amino acid metabolism-related LncRNAs as prognostic biomarkers and predictors of immunotherapy response in hepatocellular carcinoma.

Jiaxing Zhang, Xiaojing Zhu, Long Hu, Liyue Yu, Yan Xu.

   BACKGROUND: HCC has a high mortality rate among common malignancies. Finding the pathway that is involved with HCC is the main challenge in targeting metabolism for cancer therapy.
METHODS: Based on transcription data from the TCGA database, Univariate Cox analysis, LASSO, and Multivariate Cox analysis were used to identify hub AAM-related lncRNAs and construct a risk model. Then K-M survival analysis, time-dependent ROC curve analysis, genetic alterations, functional enrichment, immune infiltration status, and immunotherapy response were conducted. Finally, the effect of the characteristic gene AL590681.1 across different HCC cell lines was assessed.
RESULTS: 24 lncRNAs were involved in AAM and prognostic factors, and 4 lncRNAs were in our risk model. Patients in the high-risk group had a lower OS rate than patients in the low-risk group. The high-risk group had more immunosuppressive immune cells infiltrating and expressing CD276, CTLA4 and TIGIT. Patients in the high-risk group could had better survival prospects with an anti-PD1 treatment. Finally, the key gene AL590681.1 was overexpressed in various HCC cell lines and could enhance HCC cell activity.
CONCLUSION: We developed a novel risk model for HCC patients with AAM-related lncRNAs, which could help predict the prognosis and response to immunotherapy.

Keywords:  Amino acid metabolism; Hepatocellular carcinoma; Immunotherapy response; LncRNA signature

DOI:  https://doi.org/10.1007/s12672-025-03789-1
Semin Cancer Biol. 2025 Oct 17. pii: S1044-579X(25)00126-9. [Epub ahead of print]

The Emerging Role of Metabolic Interventions in Uveal Melanoma.

Yuki Kuranaga, Yasmin Hatem, Hans E Grossniklaus, Sameh S Ali, Erwin G Van Meir.

  Uveal Melanoma (UM) is the most common primary intraocular malignancy in adults, presenting significant clinical challenges due to its aggressive nature and metastatic potential, which results in poor prognosis in some patients. Despite recent therapeutic advances, the survival rate for metastatic UM remains unsatisfactory, underscoring the need for innovative intervention strategies. A promising direction involves the exploitation of differentially activated metabolic pathways, which are increasingly recognized for their crucial roles in cancer cell growth and metastasis. UM exhibits significant metabolic plasticity, enabling adaptation to microenvironmental stresses. While solid tumors often depend on glycolysis for energy-a phenomenon known as the Warburg effect-recent studies highlight the role of mitochondrial oxidative phosphorylation (OXPHOS), glutaminolysis, as well as fatty acid oxidation (FAO) in UM progression and therapy resistance. This diverse reliance suggests that targeting metabolic plasticity-either alone or in combination with current treatments-could offer a viable therapeutic strategy. Emerging research connects the metabolic profile of UM cells to genetic and epigenetic changes, including through oncogenic pathways driven by GNAQ and GNA11 mutations, which affect mitochondrial function and energy metabolism. This metabolic reprogramming may confer survival advantages, particularly in the nutrient- and oxygen-limited ocular environment. Here, we review recent advances on how molecular aberrations in UM alter cancer cell metabolic and mitochondrial functions, and whether these represent opportunities for therapeutic targeting. Furthering our understanding of the specific metabolic and mitochondrial changes that drive UM progression and metastasis will lead to the discovery of novel metabolic and mitochondrial biomarkers for early diagnosis, prognosis, and treatment guidance, ultimately enabling the development of more effective therapeutic strategies that exploit the unique metabolic vulnerabilities of UM cells.

Keywords:  (OXPHOS); Fatty acid oxidation (FAO); GNAQ/GNA11 mutations; Glycolysis; Metabolic plasticity; Metabolic reprogramming; Oxidative phosphorylation; Therapy resistance; Uveal melanoma

DOI:  https://doi.org/10.1016/j.semcancer.2025.10.002