bims-meract 2026-01-25 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–01–25
eighteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Targeting metabolic vulnerabilities: REV-ERB agonist SR9009 potentiates sorafenib efficacy in liver cancer.
Disruption of iron homeostasis sensitizes pancreatic cancer to irreversible electroporation.
IDH1 Reprograms Nucleotide Metabolism by Inducing Chromatin Remodeling and DHODH Transcription to Drive Chemoresistance in Nasopharyngeal Carcinoma.
TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia.
ERCC6L promotes cutaneous melanoma progression via PLK1-mediated aerobic glycolysis: Mechanisms and therapeutic implications.
Huaier Aqueous Extract Combined with Gefitinib Promotes ACSL4-Dependent Ferroptosis and Overcomes Gefitinib Resistance in Non-Small Cell Lung Cancer.
Targeting immunometabolism in cancer through pharmacological and lifestyle interventions.
Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming.
Ribosome biogenesis is increased in hepatocellular carcinoma and represents a potential therapeutic target.
The pseudouridine synthase PUS7 is associated with stemness and represents a potential therapeutic target in triple-negative breast cancer cells.
The UFL1-AKT positive feedback loop promotes breast cancer progression by enhancing lipid synthesis.
Glioma chemotherapeutic resistance is tied to membrane electrophysiological properties and glycosylation.
Metabolic vulnerabilities in ovarian cancer decoding the nexus between nutrient adaptation and therapy resistance.
BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia.
MCT1 inhibition remodels the tumor immune microenvironment for enhanced cancer immunotherapy.
Deploying the high-throughput virtual screening (HTVS) approach for the identification of new lactate dehydrogenase (LDH) inhibitors with anticancer assets.
TMEM11 promotes cisplatin resistance by inhibiting BNIP3-mediated mitophagy in bladder cancer.
Beyond metabolism: exploring the regulatory and therapeutic implications of lactate and lactylation in cancer-regulated cell death.

Cell Death Discov. 2026 Jan 19.

Targeting metabolic vulnerabilities: REV-ERB agonist SR9009 potentiates sorafenib efficacy in liver cancer.

Silvia Sabbioni, Paola Guerriero, Ram C Shankaraiah, Laura Masatti, Angelo Michilli, Cristian Bassi, Lucilla D'Abundo, Farzaneh Moshiri, Bruno De Siena, Edi Simoni, Laura Astolfi, Laura Gramantieri, Roberta Roncarati, Bahaeldin K Elamin, Massimo Bonora, Paolo Pinton, Carlo M Croce, Massimo Negrini, Elisa Callegari.

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer-related death worldwide. The prognosis is poor, with a median survival of 12-15 months in patients with advanced-stage disease. Early diagnosis and the development of new, more effective therapeutic strategies are needed to address the challenges posed by this malignancy. Although immune checkpoint inhibitors have replaced multikinase inhibitors as first-line therapy, sorafenib continues to represent a valuable option for patients with contraindications to newer treatments. Based on genome-wide RNA-seq analysis, which identified mitochondrial oxidative phosphorylation (OxPhos) and Hmox1 upregulation as potential pro-survival mechanisms in sorafenib-resistant cells, we investigated whether SR9009, a synthetic agonist of the nuclear receptor REV-ERBα/β, heme competitor, and inhibitor of mitochondrial respiration, could enhance the antitumor efficacy of sorafenib in liver cancer models. Co-treatment with SR9009 and sorafenib significantly enhanced cytotoxic effects in both mouse and human liver cancer cells. This synergistic activity was associated with increased levels of free heme and a complete inhibition of mitochondrial OxPhos. In vivo xenograft studies confirmed that the combination was effective even in sorafenib-resistant tumors. Furthermore, in a N-Nitrosodiethylamine (DEN)-induced HCC model, the combination therapy led to a reduction in size in over 90% of tumor nodules, representing a significant improvement over sorafenib alone. The combination was well tolerated, with no evident signs of acute toxicity. These findings support the concept that the efficacy of anticancer therapies can be enhanced by targeting the metabolic adaptations that tumor cells rely on for survival. Combining sorafenib with agents like SR9009, that disrupt metabolic homeostasis, may offer a promising strategy for treating advanced HCC.

DOI: https://doi.org/10.1038/s41420-026-02940-3
Nat Commun. 2026 Jan 19.

Disruption of iron homeostasis sensitizes pancreatic cancer to irreversible electroporation.

Linrong Li, Shihao Su, Zhishan Wang, Shuguo Sun, Yugang Wang, Hui Xu, Xin Long, Tao Yin, Jun Zhao.

Irreversible electroporation (IRE) is an ablative treatment for pancreatic cancer. It utilizes high-intensity pulsed electric field (PEF) to eliminate cancer cells by irreversibly disrupting cell membranes. However, PEF intensity is distributed unevenly; and cancer cells may survive in regions where it falls below the threshold of complete ablation. We find that iron-base metal organic framework nanoparticles (MOF-Fe) sensitize pancreatic cancer cells to PEF by inducing iron overload and ferroptosis. But their efficacy is diminished by the upregulation of ferritin heavy chain 1 (FTH1), a cellular response to restore iron homeostasis. C20U4V, a proteolysis targeting chimera (PROTAC) derived from arachidonic acid, degrades FTH1 and potentiates MOF-Fe-induced ferroptosis. It is then encapsulated in reactive oxygen species (ROS)-responsive micelles. The resulting M-C20U4V, when combined with MOF-Fe, efficiently induces ferroptosis and boosts PEF ablation efficacy. Therefore, disruption of iron homeostasis represents a potential strategy to lower the risk of tumor recurrence after IRE.

DOI: https://doi.org/10.1038/s41467-026-68585-z
Cancer Res. 2026 Jan 22.

IDH1 Reprograms Nucleotide Metabolism by Inducing Chromatin Remodeling and DHODH Transcription to Drive Chemoresistance in Nasopharyngeal Carcinoma.

Yuheng Zhao, Chunxian Ou, Huimin Huang, Yujue Wang, Jiaxi Shen, Yaoyi Li, Qingmei He, Zeteng Han, Yuer Xie, Tianyun Zhong, Sha Xu, Na Liu, Gao-Yuan Wang, Jun Ma, Yingqin Li.

Metabolic reprogramming under therapeutic stress may represent a targetable vulnerability for cancer treatment. Elucidation of the metabolic alterations linked to chemotherapy in nasopharyngeal carcinoma (NPC) could uncover potential therapeutic strategies. Using proteomics and transcriptomic profiles, we identified wild-type IDH1 as a crucial metabolic enzyme upregulated in gemcitabine plus cisplatin chemotherapy (GP)-resistant NPC. IDH1 reprogrammed nucleotide metabolism in response to chemotherapy, linking DNA damage repair (DDR) to ferroptosis resistance via DHODH, thereby contributing to chemoresistance in NPC. Mechanistically, α-ketoglutarate (α-KG), a metabolite of IDH1, enhanced chromatin accessibility to promote DHODH transcription via α-KG-dependent dioxygenase ALKBH5-recruited HNRNPC. The DHODH inhibitor BAY2402234 markedly sensitized NPC cells to chemotherapy. Clinically, a prognostic model based on DDR and ferroptosis signatures effectively predicted disease relapse risk post-chemotherapy in NPC. This study links DDR to ferroptosis defense via the IDH1/α-KG/ALKBH5/DHODH axis, suggesting DHODH inhibition as a promising therapeutic strategy to overcome chemoresistance in tumors harboring wild-type IDH1.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2313
Nat Commun. 2026 Jan 20.

TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia.

Lingling Yang, Jun Lu, Weina Yun, Xinquan Yang, Jie Sun, Chaodong Ge, Fei Han, Xiang Li, Junxia Min, He Huang, Fudi Wang, Xi Jiang.

Ferroptosis, an iron-dependent, lipid peroxidation-driven programmed cell death, holds substantial promise for cancer therapy, yet its translational potential is hindered by widespread intrinsic resistance. While glutathione peroxidase 4 (GPX4) is a well-established ferroptosis suppressor, the epigenetic circuitry coordinating GPX4-related mechanisms remains elusive. Here, via genome-wide screening, we identify ten-eleven translocation 1 (TET1)-a key mediator of DNA 5-hydroxymethylation-as a master controller of cancer cell ferroptosis susceptibility. In acute myeloid leukemia (AML), TET1 enhances 5hmC deposition at the glutamate-cysteine ligase catalytic subunit (GCLC) promoter to activate glutathione/γ-glutamyl-peptide metabolism, fortifying GPX4-dependent defense. Concurrently, TET1 activates NFκB signaling to upregulate GTP cyclohydrolase-1 (GCH1), conferring GPX4-independent ferroptosis resistance. Critically, co-targeting TET1/GCLC/GCH1 with low-dose ferroptosis inducers exhibits potent therapeutic effects against both ferroptosis-sensitive and -resistant AML. Our work positions TET1 as a pivotal epigenetic hub governing ferroptosis surveillance, and provides a translatable strategy to overcome ferroptosis resistance in cancer, with AML as a paradigm.

DOI: https://doi.org/10.1038/s41467-026-68509-x
Life Sci. 2026 Jan 19. pii: S0024-3205(26)00024-X. [Epub ahead of print] 124216

ERCC6L promotes cutaneous melanoma progression via PLK1-mediated aerobic glycolysis: Mechanisms and therapeutic implications.

Mengdi Zhang, Shengbo Zhou, Bing Han, Yining Ge.

   AIMS: To elucidate the oncogenic role and mechanistic basis of ERCC6L in cutaneous melanoma, focusing on its impact on tumor metabolism and progression.
MATERIALS AND METHODS: Multi-omics bioinformatics analysis of public datasets (GEO, TCGA) defined the clinical relevance of ERCC6L. In vitro functional assays (CCK-8, colony formation, Transwell, flow cytometry) were performed in melanoma cell lines following genetic manipulation. Mechanistic studies employed gene set enrichment analysis, chromatin immunoprecipitation-quantitative PCR, dual-luciferase reporter assays, western blotting, and metabolic flux analysis. The functional significance of the ERCC6L-PLK1 axis was validated in an NSG mouse subcutaneous xenograft model.
KEY FINDINGS: ERCC6L is significantly upregulated in melanoma tissues, and its high expression is an independent prognostic factor for poor survival. Genetic ablation of ERCC6L potently inhibited melanoma cell proliferation, migration, invasion, and tumor growth, while promoting apoptosis. Mechanistically, ERCC6L transcriptionally activates PLK1 by directly binding to its promoter. This ERCC6L-PLK1 axis drives aerobic glycolysis (the Warburg effect), upregulating key glycolytic enzymes (GLUT1, LDHA, PKM2, HK2) and enhancing lactate production and ATP generation. Crucially, PLK1 inhibition or glycolysis blockade effectively reversed the tumor-promoting phenotypes induced by ERCC6L.
SIGNIFICANCE: Our study identifies ERCC6L as a novel upstream transcriptional regulator of PLK1 that fuels melanoma progression by reprogramming glucose metabolism. The ERCC6L-PLK1-glycolysis axis represents a promising prognostic biomarker and a potential therapeutic target for cutaneous melanoma.

Keywords:  Cutaneous melanoma; Excision repair cross-complementation group 6-like (ERCC6L); Glycolysis; Metabolic reprogramming; Warburg effect

DOI:  https://doi.org/10.1016/j.lfs.2026.124216
Curr Med Sci. 2026 Jan 20.

Huaier Aqueous Extract Combined with Gefitinib Promotes ACSL4-Dependent Ferroptosis and Overcomes Gefitinib Resistance in Non-Small Cell Lung Cancer.

Yi-Heng Du, Pei Zhang, Qian-Qian Xue, Zi-Hao Wang, Xuan Xiang, Yao Liu, Hao-Lei Wang, Qiong Zhou.

   OBJECTIVE: Huaier, a traditional Chinese medicine (TCM) approved by the National Medical Products Administration (NMPA) of China for cancer therapy, demonstrates broad antitumor activity. However, its potential to overcome resistance to gefitinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in non-small cell lung cancer (NSCLC) and the underlying mechanisms remain unclear. This study aimed to determine whether Huaier aqueous extract enhances the efficacy of gefitinib against resistant NSCLC and to elucidate the molecular basis of this effect.
METHODS: Cell proliferation was evaluated using the Cell Counting Kit-8 and colony formation assays. Apoptosis, reactive oxygen species (ROS), and lipid ROS were measured using flow cytometry, and mitochondrial morphology was examined using transmission electron microscopy. RNA sequencing and integrated bioinformatics analyses of GEO datasets were performed to identify ferroptosis-related genes, which were validated by qPCR and Western blotting. The in vivo efficacy was assessed using a PC-9GR xenograft model.
RESULTS: Huaier aqueous extract significantly enhanced the sensitivity of gefitinib-resistant NSCLC cells to gefitinib in vitro, and suppressed tumor growth in vivo. Mechanistically, the combined treatment activated the ferroptosis pathway, accompanied by the upregulation of acyl-CoA synthetase long-chain family member 4 (ACSL4). Pharmacological inhibition of ferroptosis or ACSL4 partially attenuated the antitumor effect, confirming their key roles in mediating the synergistic activity of Huaier aqueous extract and gefitinib.
CONCLUSIONS: Huaier aqueous extract reversed gefitinib resistance in NSCLC cells by promoting ACSL4-dependent ferroptosis, thereby providing a promising therapeutic strategy for improving EGFR-TKI efficacy.

Keywords:  ACSL4; Ferroptosis; Gefitinib resistance; Huaier; Non-small cell lung cancer (NSCLC); Traditional Chinese Medicine

DOI:  https://doi.org/10.1007/s11596-025-00158-5
PLoS Biol. 2026 Jan 20. 24(1): e3003617

Targeting immunometabolism in cancer through pharmacological and lifestyle interventions.

Rachael Julia Yuenyinn Tan, Yalei Liu, Weixin Chen, Yuteng Liang, Guang Sheng Ling.

Immunometabolism, a fundamental biogenic process that supports the function of immune cells, is often disrupted in diseases such as cancer. Tackling metabolic dysregulation at a cellular level has therefore emerged as a focus in drug development. However, as cellular metabolic rewiring takes place in response to both intrinsic factors, which can be targeted pharmacologically, and environmental changes, which cannot, fostering a homeostatic systemic metabolism through diet, exercise, and stress management is essential to support and sustain cellular fitness. This Essay conceptualizes immunometabolism as a process that can be regulated intrinsically and extrinsically and explores the potential for incorporating lifestyle changes and drug therapies that target immunometabolism into treatments for cancer.

DOI: https://doi.org/10.1371/journal.pbio.3003617
Cancer Immunol Res. 2026 Jan 20.

Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming.

Phaethon Philbrook, Matthew J Dean, Maria Dulfary Sanchez-Pino, Li Qin Zheng, Jovanny Zabaleta, Julio A Vázquez-Martínez, Darwin Chang, Jessica K Mandula, Timothy I Shaw, Dorota Wyczechowska, Jone Garai, Ramesh Thylur Puttalingaiah, Amirsalar Mansouri, Weishan Huang, Satyajit Das, Shiun Chang, Jose R Conejo-Garcia, Paulo C Rodriguez, Augusto C Ochoa.

GPR84 is a medium-chain free fatty acid receptor predominantly expressed in myeloid cells. Previous studies have identified GPR84 as an enhancer of the pro-inflammatory myeloid cell responses and a regulator of metabolic homeostasis. However, the role of GPR84 in T cell function and metabolism remains largely unexplored. This study tested the effect of GPR84 modulation on CD8+ T cell function and metabolism in vitro and examined its effect on antitumor function in adoptive cellular therapy models. Pharmacological antagonism with GLPG1205 or genetic deletion of GPR84 promoted T cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions. These functional changes were paralleled by changes in metabolic activity. Antagonism and genetic deletion increased glucose uptake, glycolysis, oxidative phosphorylation, and ATP production, which enhanced the overall cell energetic fitness, whereas agonism resulted in a quiescent energetic profile. Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T cell function and may further enhance adoptive cellular therapies.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0695
NAR Cancer. 2026 Mar;8(1): zcaf058

Ribosome biogenesis is increased in hepatocellular carcinoma and represents a potential therapeutic target.

Sille Blangstrup Geisler, Kezia Catharina Oxe, Stavroula Boukoura, Ekaterina Dulina, Dorthe Helena Larsen.

Globally, liver cancer is the sixth most prevalent cancer type and the third leading cause of cancer-related deaths, making the need for improved treatment evident. We conducted a pan-cancer tissue microarray analysis to identify cancer types with upregulated ribosome biogenesis, potentially suitable for treatment with nucleolar-targeting compounds. Our screening identified liver cancer as a potential candidate. Gene expression analysis confirmed upregulation of nucleolar factors facilitating ribosome biogenesis that correlated with poor prognosis. In hepatocellular carcinoma (HCC) cell lines, constituting around 80% of liver cancer cases, we confirmed the upregulation of the nucleolar proteins Treacle, UBF, and Fibrillarin, involved in transcription and processing of ribosomal RNA (rRNA). Measurements of rRNA also confirmed increased nucleolar activity. We treated the HCC cell lines with nucleolar-targeting compounds and observed increased sensitivity in the HCC cell lines. Notably, nucleolar targeting compounds demonstrated a broader therapeutic window than that observed for Sorafenib, a clinically approved targeted therapy. Furthermore, we investigated how nucleolar factors change during HCC stages and found a progressive increase in Treacle and Fibrillarin in advanced stages of HCC. Our results demonstrate aberrant nucleolar activity in HCC and propose targeting ribosome biogenesis as a therapeutic strategy to improve HCC patient outcomes.

DOI: https://doi.org/10.1093/narcan/zcaf058
Sci Rep. 2026 Jan 19. 16(1): 2411

The pseudouridine synthase PUS7 is associated with stemness and represents a potential therapeutic target in triple-negative breast cancer cells.

Lu Lu, Lian Xue, Shiyao Jiang, Guangchun He, Xiyun Deng.

  Triple-negative breast cancer (TNBC) represents a highly aggressive subtype of breast cancer characterized by increased recurrence rates and poor prognosis, primarily due to the lack of effective therapeutic targets. Pseudouridine synthases (PUSs) are a class of enzymes that are responsible for catalyzing the isomerization of uridine to pseudouridine in RNA, thereby contributing to cancer progression. In the present study, we examined the roles of PUSs in modulating the biological properties of TNBC using bioinformatics and experimental investigations. Increased gene expression levels of PUSs, particularly PUS7, were identified in TNBC tissues from the TCGA RNA-seq dataset and were found to be associated with unfavorable survival of TNBC patients. In addition, increased protein levels of PUS7 were identified in TNBC patient tissues and cell lines compared with non-TNBC. The increased PUS7 expression was in line with the stemness of TNBC cells. Knockdown of PUS7 in MDA-MB-231 and MDA-MB-468 cells inhibited stemness, migration, and colony formation. Transfection with a PUS7-Mut construct, which eliminated the enzymatic activity of PUS7, reversed the stimulating effects of PUS7 on stemness, migration, and colony formation in TNBC cells. This study highlights the influence of PUS7 on the biological properties of TNBC through its enzymatic activity, providing valuable insights and potential avenues for the identification of effective therapeutic targets for TNBC.

Keywords:  Pseudouridine synthase; Stemness; Targeted therapy; Triple-negative breast cancer

DOI:  https://doi.org/10.1038/s41598-025-25684-z
Nat Commun. 2026 Jan 20. 17(1): 614

The UFL1-AKT positive feedback loop promotes breast cancer progression by enhancing lipid synthesis.

Fei Meng, Yating Du, Junjie Liang, Huiyan Li, Jingjing Wang, Kexin Tang, Ruixue Kong, Huanran Sun, Tingting Yin, Junru Qin, Xiaomeng Yang, Changliang Shan, Min Liu, Guiwen Yang, Jichun Zhang, Yijie Wang, Jun Zhou, Yan Chen.

UFMylation, a ubiquitin-like modification, is crucial for cellular processes and is linked to human diseases, including cancer. However, its role in cancer remains unclear. Here, we report that UFL1 promotes breast tumor growth by remodeling lipid metabolism. Mechanistically, UFL1 interacts with and UFMylates AKT, enhancing its localization at the endoplasmic reticulum and phosphorylation by PDK1 and mTORC2, thereby increasing AKT-mediated lipid synthesis. Moreover, AKT phosphorylates UFL1, boosting its activity. Thus, UFL1 and AKT form a positive feedback loop, accelerating lipid synthesis and breast tumor growth. Clinically, UFL1 levels are increased in human breast tumors and are associated with poor clinical outcomes in breast cancer patients. Importantly, UFMylation inhibitors sensitize breast cancer cells to AKT inhibitors and anticancer drugs. Our findings reveal a critical role for UFMylation in lipid metabolism and identify the UFL1-AKT axis as a potential therapeutic target in breast cancer.

DOI: https://doi.org/10.1038/s41467-026-68492-3
Bioeng Transl Med. 2026 Jan;11(1): e70069

Glioma chemotherapeutic resistance is tied to membrane electrophysiological properties and glycosylation.

Alan Y L Jiang, Andrew R Yale, J Nicole Hanamoto, Nicole S Lav, Vi Phuong Dang, Clarissa C Ro, Christopher R Douglas, Kaijun Di, Jacob Deyell, Daniela A Bota, Lisa A Flanagan.

  Diffuse gliomas are brain tumors that include oligodendroglioma, astrocytoma, and glioblastoma (GBM), the most common and deadly primary brain tumor. A major challenge in glioma treatment is resistance to the first-line chemotherapeutic, temozolomide (TMZ). Plasma membrane properties of cells with increased chemotherapeutic resistance are not well understood, despite the fact that the membrane is the first point of contact with the environment and greatly shapes cell behavior. Plasma membrane glycosylation impacts cell function, and we found significant differences in glycosylation of TMZ-resistant cells. We further identified plasma membrane electrophysiological properties predicting glioma cell TMZ resistance. We enriched cells with higher TMZ resistance by sorting glioma cells based on electrophysiological properties, indicating the relevance of membrane properties to chemotherapeutic resistance. These findings could lead to rapid separation methods for patient tumor cells, a better understanding of the molecular profiles of resistant cells, and novel treatment options for gliomas.

Keywords:  cell sorting; chemoresistance; dielectrophoresis; glioblastoma; temozolomide

DOI:  https://doi.org/10.1002/btm2.70069
J Adv Res. 2026 Jan 18. pii: S2090-1232(26)00072-X. [Epub ahead of print]

Metabolic vulnerabilities in ovarian cancer decoding the nexus between nutrient adaptation and therapy resistance.

Xiaoyu Guo, Zongang Liu, Xiaoman Li, Bingzheng Zhou, Jingyi Chen.

   BACKGROUND: Ovarian cancer (OC) is a leading cause of gynecologic cancer-related mortality, primarily due to frequent therapy resistance and disease recurrence. Growing evidence indicates that metabolic reprogramming serves as a critical adaptive mechanism, allowing cancer cells to survive therapeutic stress.
AIM OF REVIEW: This review aims to decode the interplay between nutrient adaptation and therapy resistance in OC. It examines how alterations in key metabolic pathways contribute to treatment resilience and disease progression, and explores the potential of targeting metabolic vulnerabilities to improve therapeutic outcomes.
KEY SCIENTIFIC CONCEPTS OF REVIEW: We discuss how OC cells utilize metabolic pathways-including glycolysis, OXPHOS, glutamine metabolism, and lipid utilization-to promote survival, DNA repair, and immune evasion. Metabolic plasticity enables shifts between nutrient sources, driving resistance to platinum-based agents, PARP inhibitors, and anti-angiogenic therapies. These adaptations vary across subtypes, such as high-grade serous and clear cell carcinomas, and are influenced by specific mutations. Targeting metabolic enzymes-such as GLS, CPT1, OXPHOS complexes, or NAD+ synthesis-offers a promising strategic direction. Metabolic profiling may allow stratification of OC patients and pave the way for precision medicine approaches to overcome treatment resistance.

Keywords:  Glycolysis; Ovarian cancer; Oxidative phosphorylation (OXPHOS); Therapy resistance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jare.2026.01.047
Ann Hematol. 2026 Jan 19. 105(1): 32

BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia.

Florian Robert, Cherif Badja, Soraya Boushaki, Andrea Degasperi, Yasin Memari, Sophie Momen, Theodoros I Roumeliotis, Zuza Kozik, Malgorzata Gozdecka, Jyoti Choudhary, George Vassiliou, Gene Cc Koh, Serena Nik-Zainal.

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co-repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH's role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

Keywords:  Acute myeloid leukemia; BCOR; DHODH; DHODH inhibition; Leukemia; Synthetic lethality; Targeted therapy

DOI:  https://doi.org/10.1007/s00277-026-06773-z
Mol Cancer Ther. 2026 Jan 19.

MCT1 inhibition remodels the tumor immune microenvironment for enhanced cancer immunotherapy.

Yipeng Zhang, Chun Liu, Fuxin Han, Chuan Tong, Yelei Guo, Yuting Lu, Weidong Han, Yao Wang.

Despite advances in cancer immunotherapies such as immune checkpoint blockade (ICB), durable patient responses remain constrained, which is largely due to the highly suppressive tumor immune microenvironment (TIME). Here, by analyzing pan-cancer patient cohorts and experimental validation, we found that MCT1 expression is broadly upregulated in malignant and myeloid compartments within the TIME. MCT1 expression is also associated with worse survival, suppressive TIME state, and poor treatment response to ICB therapy. Functionally, MCT1-mediated lactate uptake by tumor cells and tumor-associated macrophages (TAMs) suppresses CD8⁺ T cell activation, and cytotoxicity in the ex vivo co-culture models. Mechanistically, lactate exposure and uptake via MCT1 in tumor cells and TAMs induces IL-10 production, which contributes to the inhibition of the anti-tumor response of CD8⁺ T cells. Moreover, in MC38 and LLC mouse cancer models, pharmacologic MCT1 inhibition reprograms the immunosuppressive myeloid populations, improves CD8⁺ T cell infiltration and function, and triggers tumor regression. Therefore, these results indicate that MCT1 has the potential to be a biomarker for patients across cancer types, and to be a promising therapeutic target for enhanced cancer immunotherapy.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1026
Sci Rep. 2026 Jan 21.

Deploying the high-throughput virtual screening (HTVS) approach for the identification of new lactate dehydrogenase (LDH) inhibitors with anticancer assets.

Yaxun Huang, Sangeeta Benni, Umesh Prasad Yadav, M Arockia Babu, Akash Verma, Thakur Gurjeet Singh, Nisha Bansal, Yulong Zhang.

The tumor cells frequently rely on glycolysis to produce adenosine 5'-triphosphate (ATP), even when sufficient oxygen is available to allow oxidative phosphorylation (the Warburg effect). In these malignancies, the breakdown of glucose to pyruvate, instead of reaching the mitochondria, is transformed to lactate by an enzyme called lactate dehydrogenase (LDH) and then expelled by the cells, further fuelling the tumour microenvironment (TME). LDH facilitates the translation of pyruvate to lactate, hence replenishing the required NAD + equivalents for the ongoing glycolysis process. Having a pivotal role in cancer cells' prognosis and survival, and affecting the TME. To date, no inhibitors have yet been approved against the LDH. However, numerous clinical trials are ongoing, and results are yet to be awaited. Considering the existing gap, we present herein a high-throughput virtual screening (HTVS) approach to identify new compounds that effectively inhibit LDH activity. We generated the pharmacophore model based on 28 LDH enzyme inhibitors from previous literature. The model was used to screen 500,000 ligands in addition to their molecular docking and drug-likeness filtering. The analysis led to the identification of 5 hits, which were further subjected to the MD simulations. Further considering the outcome of molecular dynamics results, we selected ligands 15 and 422 to corroborate their anticancer potential via inhibiting the LDH enzyme. The biological validation revealed that both ligands, 15 and 422, possess IC50 values of 147.34 and 206.35 nM, respectively, against LDH. The anticancer potential analysis of DU-145 and PC-3 also established their anticancer properties, and both compounds were found to marginally elevate oxidative stress, change mitochondrial membrane potential, and induce apoptosis in DU-145 cells.

DOI: https://doi.org/10.1038/s41598-026-36385-6
Cancer Lett. 2026 Jan 20. pii: S0304-3835(26)00034-0. [Epub ahead of print] 218271

TMEM11 promotes cisplatin resistance by inhibiting BNIP3-mediated mitophagy in bladder cancer.

Yuan Huang, Chen Chen, Mingqiang Su, Wanteng Ye, Shu Wei, Kuangye Long, Yunjie Huang, Haiyong Chen, Zhangfeng Zhong, Lina Hou, Jinge Zhang, Wanlong Tan, Fei Li.

  Cisplatin-based chemotherapy stands as the first-line treatment for metastatic bladder cancer (BCa), yet only 35% of patients show initial responsiveness, with resistance commonly developing. Therefore, investigating cisplatin-sensitizing targets is warranted for overcoming resistance. In this study, the transmembrane protein 11 (TMEM11) was explored for its role in mediating cisplatin resistance in BCa. Single-cell and bulk RNA sequencing, together with assay for transposase-accessible chromatin using sequencing were utilized. The analyses revealed that TMEM11 was upregulated in cisplatin-resistant cells and associated with mitochondrial metabolic reprogramming and poor prognosis. Spatial transcriptomics and proteomics further confirmed the spatial co-localization of TMEM11 with metabolic pathways enriched in resistant tumors. Functional experiments demonstrated that TMEM11 inhibited BNIP3-mediated mitophagy and apoptosis, thereby stabilizing mitochondrial function to promote cisplatin resistance. Mechanistically, TMEM11 suppressed BNIP3 and impaired mitophagy flux, leading to enhanced survival of cancer cells under cisplatin stress. In vivo, TMEM11 knockdown reduced tumor growth and sensitized tumors to cisplatin treatment. Furthermore, molecular docking and experimental validation identified Curcumin as a high-affinity TMEM11 inhibitor capable of restoring cisplatin sensitivity. This study uncovered the TMEM11-BNIP3 axis as a novel driver of cisplatin resistance in BCa, and proposed pharmacological targeting of TMEM11 as a precise therapeutic strategy to overcome cisplatin resistance.

Keywords:  Bladder cancer; Cisplatin resistance; Mitophagy; TMEM11

DOI:  https://doi.org/10.1016/j.canlet.2026.218271
Cell Death Dis. 2026 Jan 22.

Beyond metabolism: exploring the regulatory and therapeutic implications of lactate and lactylation in cancer-regulated cell death.

Cong Chen, An Lin, Jiacheng Zhao, Xia Lin, Qianwei Ye, Jufeng Guo, Jian Liu, Aizhai Xiang.

Lactate, a key byproduct of glycolysis in tumor cells, has emerged as more than just a metabolic waste product. Increasing evidence reveals that lactate and its associated post-translational modification (PTM), lactylation, play multifaceted roles in regulating various forms of regulated cell death (RCD), thereby contributing to cancer proliferation, therapy resistance, and immune exclusion. Notably, evasion of RCD is a hallmark of cancer and targeting RCD may represent a promising therapeutic strategy for cancer treatment. In this review, we focus on summarizing the dual and context-dependent roles of both lactate and lactylation in modulating distinct types of RCD, including apoptosis, autophagy, ferroptosis, pyroptosis, and cuproptosis. Moreover, we further discuss how RCD processes impact lactate metabolism and highlight the therapeutic potential and current challenges of targeting the lactate-lactylation-RCD axis in cancer treatment.

DOI: https://doi.org/10.1038/s41419-026-08410-z