bims-meract 2026-05-31 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–05–31
fourteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Gasdermin C reprograms metabolism through the CAMKK2-AMPK axis to promote lung adenocarcinoma progression and radioresistance.
Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription.
Metabolic Plasticity and Enzalutamide Resistance: Emerging Roles of PGK1 in Prostate Cancer.
CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer.
Mitophagy‑Competent Cancer‑Associated Fibroblasts Fuel Chemoresistance by Rewiring Pyrimidine Metabolism in Pancreatic Cancer.
Fatty acid channelling into triglycerides and oxylipins drives ferroptosis resistance during oncogenic BRAF-induced senescence.
Starving leukemia: nicotinamide phosphoribosyltransferase-dependent nicotinamide adenine dinucleotide salvage links metabolic vulnerability to therapeutic sensitivity in acute myeloid leukemia.
SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.
Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.
Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.
Dual targeting of glutamine metabolism and lysosomal function in eliminating drug-tolerant KRAS-mutant cancer cells.
A multi-subunit autophagic capture complex facilitates degradation of ER-stalled MHC class I in pancreatic cancer.
Mitochondrial Carrier SLC25A13 Drives Ferroptosis Resistance and Immune Evasion via a STAT3-IFI6 Circuit in Breast Cancer.
Inhibition of TGM2 enhances cisplatin sensitivity in MSH2-deficient bladder cancer.

Cell Rep. 2026 May 22. pii: S2211-1247(26)00505-X. [Epub ahead of print]45(6): 117427

Gasdermin C reprograms metabolism through the CAMKK2-AMPK axis to promote lung adenocarcinoma progression and radioresistance.

Delong Ren, Yunyun Li, Mingquan Lu, Wuqiao Jiang, Hao Xu, Lijun Wu, K N Yu, Wei Han.

  Metabolic reprogramming is a hallmark of lung adenocarcinoma (LUAD) progression and therapeutic resistance. Gasdermin C (GSDMC) is frequently upregulated in patients with LUAD and correlates with poor prognosis. Under nutrient stress or ionizing radiation, phosphorylated STAT3 at Ser727 transcriptionally induces GSDMC, which translocates into the nucleus via the IPO7-KPNB1-NUP93 complex. In the nucleus, GSDMC functions as a scaffold molecule, recruiting NAT10 to mediate histone H3 acetylation and recruiting BAZ1B/SMARCA5 to modulate chromatin remodeling and chromatin accessibility. These changes facilitate CAMKK2-AMPK pathway activation. The GSDMC-CAMKK2-AMPK axis promotes metabolic reprogramming toward glycolysis and fatty acid oxidation, supporting LUAD cell proliferation and survival. Importantly, GSDMC contributes to LUAD radioresistance through the STAT3-GSDMC-CAMKK2-AMPK axis, and targeting any component of this pathway enhances radiotherapy sensitivity in preclinical models. Our findings identify a regulatory role for GSDMC in LUAD progression via metabolic reprogramming and support its potential as a preclinical candidate target to improve radiotherapy response.

Keywords:  CAMKK2-AMPK axis; CP: cancer; CP: metabolism; GSDMC; LUAD; lung adenocarcinoma;; metabolic reprogramming; radioresistance

DOI:  https://doi.org/10.1016/j.celrep.2026.117427
Nat Chem Biol. 2026 May 27.

Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription.

Zhiqiang Hu, Wei Lv, Ting Wen, Junyi Sun, Guimei Ji, Shuo Ru, Xue Sun, Zheng Wang, He Ren, Yudi Zhang, Pengkun Chen, Linlin Zhou, Shiqi Wu, Xiaoqian Jia, Shanshuo Liu, Zheng Zhu, Jiawei Xu, Tong Liu, Yuxiong Feng, Gaopeng Li, Yuan Ding, Yuhao Wang, Yang Luo, Chang Liu, Zhimin Lu, Zhigang Ren, Sheng-Zhong Duan, Daqian Xu.

Understanding of the metabolic determinants influencing immunotherapy responsiveness remains limited. Here we performed a multiomics analysis of tumor biopsies from patients with hepatocellular carcinoma (HCC) treated with immune checkpoint blockade (ICB) and revealed that heightened expression of OXCT1, a rate-limiting enzyme in ketone body metabolism, was negatively correlated with ICB efficacy, whereas its metabolic substrate, β-hydroxybutyrate (BHB), displayed an opposite effect. Mechanistically, glucose deprivation in HCC cells promotes AMPK-mediated OXCT1 S113 phosphorylation, which exposes the nuclear localization sequence of OXCT1 to trigger its nuclear translocation. Nucleus-translocated OXCT1 associates with IRF1 to locally consume BHB and suppress histone H3K9 BHB at the major histocompatibility complex class I (MHC-I) and chemokine gene loci, leading to repressed transcription of these immune genes. Targeting the AMPK-OXCT1-IRF1 axis sensitizes tumor cells to ICB upon ketogenic diet. These findings reveal a mechanism by which a non-canonical function of nuclear OXCT1 coordinates the interplay between ketone body metabolic reprogramming and immunotherapy responsiveness.

DOI: https://doi.org/10.1038/s41589-026-02229-7
Endocrinology. 2026 May 24. pii: bqag063. [Epub ahead of print]

Metabolic Plasticity and Enzalutamide Resistance: Emerging Roles of PGK1 in Prostate Cancer.

Min Zhang, Xiaoqi Liu.

  Enzalutamide resistance remains a key challenge in the treatment of advanced prostate cancer (PCa), as clinical efficacy is frequently hindered by acquired resistance. While reactivation of AR signaling including AR splice variants, has been extensively studied, accumulating evidence indicates that metabolic reprogramming is a key adaptive response to sustained AR inhibition. As resistance advances, tumor cells exhibit metabolic plasticity, dynamically regulating glycolysis, mitochondrial respiration, lipid metabolism, and redox homeostasis to adapt to treatment pressure. In this context, phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme, has emerged as a potential mediator linking metabolic adaptation to therapy resistance. Beyond its ATP-generating function, PGK1 exhibits non-canonical functions, including regulation of mitochondrial metabolism, protein kinase activity, and stress-response signaling. These properties suggest that PGK1 may integrate AR-driven metabolic programs with downstream survival pathways under therapeutic pressure. Preclinical studies support a role for PGK1 in promoting glycolytic phenotypes and resistance-associated metabolic states. However, current evidence remains largely associative, and direct in vivo validation in prostate-specific models is limited. Moreover, whether PGK1 functions as a causal driver or downstream effector of resistance remains unresolved. This review summarizes current understanding of AR-metabolism coupling and evaluates PGK1 as a potential metabolic-signaling node in enzalutamide resistance, highlighting key knowledge gaps and future directions for metabolic targeting in PCa.

Keywords:  AR signaling; CRPC; Cancer metabolism; Enzalutamide resistance; PGK1

DOI:  https://doi.org/10.1210/endocr/bqag063
Cell Death Dis. 2026 May 28.

CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer.

Kuanbing Chen, Shi Zong, Kefeng Li, Li Yu.

Cisplatin resistance represents a major clinical challenge in small-cell lung cancer (SCLC), yet the underlying metabolic adaptations remain poorly understood. Here, we identify a novel regulatory axis centered on the fatty acid oxidation (FAO) enzyme carnitine palmitoyltransferase 1 A (CPT1A) that governs mitochondrial dynamics to drive chemoresistance. In cisplatin-resistant SCLC, CPT1A is markedly upregulated and undergoes functional acetylation. This modified CPT1A not only sustains cellular bioenergetics and redox balance through enhanced FAO but also directly recruits dynamin-related protein 1 (DRP1) to mitochondria. By facilitating DRP1-dependent mitochondrial fission, CPT1A orchestrates a metabolic adaptation that confers a survival advantage. Genetic or pharmacological inhibition of CPT1A reversed this phenotype, impairing mitochondrial fission, depleting energy stores, and resensitizing resistant cells to cisplatin. In vivo, targeting CPT1A markedly suppressed tumor growth and restored cisplatin sensitivity. Our results uncover an acetylated CPT1A-DRP1 axis as a critical metabolic vulnerability in cisplatin-resistant SCLC, providing a compelling therapeutic strategy to overcome treatment failure.

DOI: https://doi.org/10.1038/s41419-026-08868-x
Cancer Res. 2026 May 27.

Mitophagy‑Competent Cancer‑Associated Fibroblasts Fuel Chemoresistance by Rewiring Pyrimidine Metabolism in Pancreatic Cancer.

Shaobo Zhang, Hao Yuan, Muzi Guo, Zhijun Zhou, Yumeng Hu, Gaoyuan Lv, Haoran Qi, Yuanyuan Guo, Jing Han, Michael S Bronze, Courtney W Houchen, Min Li, Mingyang Liu.

Pancreatic cancer remains one of the deadliest malignancies, with gemcitabine-based chemotherapy as a mainstay treatment for most patients, yet resistance emerges almost universally. A defining feature of pancreatic cancer is its dense, fibroblast-rich stroma, where heterogeneous cancer-associated fibroblasts (CAFs) actively shape tumor biology and therapeutic response. Here, we elucidated a stromal-metabolic mechanism through which chemoresistant CAFs confer gemcitabine resistance. A subset of mitophagy-competent CAFs enhanced pancreatic cancer gemcitabine resistance. The EMT transcription factor ZEB1 acted as a master regulator of the CAF-driven chemoresistance program, and it was upregulated and epigenetically activated through SETD1A-mediated H3K4 methylation in gemcitabine-resistant CAFs. ZEB1 promoted BNIP3-mediated mitophagy in CAFs, leading to increased secretion of nucleotides that competitively inhibited gemcitabine incorporation into cancer cells while simultaneously supplying pyrimidine metabolism substrates for pyrimidine metabolism. Concurrently, ZEB1 transcriptionally activated CXCL8, engaging the CXCR1/2-MEK/ERK pathway in tumor cells and further augmenting pyrimidine metabolism via the RRM1/E2F1/G6PD axis, collectively diminishing gemcitabine cytotoxicity. Notably, combined inhibition of CXCR1/2 or G6PD with gemcitabine robustly suppressed tumor growth and restored chemosensitivity both in vitro and in vivo. Together, these findings uncover a key stromal-metabolic axis in pancreatic cancer, linking CAF mitophagy activity to metabolic remodeling in tumor cells and identifying ZEB1 and its downstream network as actionable targets to overcome chemoresistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5716
Cell Death Differ. 2026 May 26.

Fatty acid channelling into triglycerides and oxylipins drives ferroptosis resistance during oncogenic BRAF-induced senescence.

Markus S Hess, Kamal M Al-Shami, Carolina Dehesa Caballero, Julie Haenlin, Adriano B Chaves-Filho, Lisa Schlicker, Philipp Poeller, Felix C E Vogel, Ioanna Koltsaki, Deniz Gedik, Marta Campos Alonso, Susanne Walz, Carsten P Ade, Martin Eilers, Beate K Straub, Jochen S Utikal, Svenja Meierjohann, Mathias T Rosenfeldt, Marteinn T Snaebjornsson, Almut Schulze.

Oncogene-induced senescence (OIS), a cellular programme initiated by activation of oncogenic signalling, provides a barrier to transformation and is accompanied by major reprogramming of cellular metabolism. We show here that induction of OIS by BRAFV600E expression in human diploid fibroblasts led to global changes in the cellular lipidome, characterised by a strong increase in triglycerides (TG) and a marked reduction in membrane phosphoglycerides carrying polyunsaturated fatty acids (PUFA) in their acyl-chains. Induction of BRAFV600E OIS resulted in a marked resistance towards lipid peroxidation and ferroptosis. Inhibition of TG synthesis by blocking diacylglycerol O-acyltransferase 1 (DGAT1) resulted in PUFA re-distribution to membrane lipids and increased ferroptosis sensitivity of senescent cells. Inhibition of DGAT also altered the senescence-associated secretory phenotype (SASP) and enhanced the secretion of oxylipins by BRAFV600E OIS cells. Combined blockade of DGAT1-dependent TG and COX2-dependent oxylipin synthesis fully restored ferroptosis sensitivity in BRAFV600E OIS cells. Together, these findings indicate that channelling of PUFA towards TG synthesis confers protection from oxidative stress and ferroptosis during BRAFV600E OIS but also limits the production of pro-inflammatory lipid mediators, a key feature of the senescent phenotype.

DOI: https://doi.org/10.1038/s41418-026-01766-x
Transl Cancer Res. 2026 Apr 30. 15(4): 345

Starving leukemia: nicotinamide phosphoribosyltransferase-dependent nicotinamide adenine dinucleotide salvage links metabolic vulnerability to therapeutic sensitivity in acute myeloid leukemia.

Juan Luiz Coelho-Silva, Diego Antonio Pereira-Martins, João Agostinho Machado-Neto.



Keywords:  Acute myeloid leukemia (AML); B-cell lymphoma 2-mediated apoptosis (BCL2-mediated apoptosis); mitochondrial dysfunction; nicotinamide adenine dinucleotide metabolism (NAD+ metabolism); nicotinamide phosphoribosyltransferase inhibition (NAMPT inhibition)

DOI:  https://doi.org/10.21037/tcr-2026-1-0292
Cancer Lett. 2026 May 26. pii: S0304-3835(26)00379-4. [Epub ahead of print] 218616

SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.

Xiaoyan He, Zhengwei Zhao, Teng Wei, Lisi Zheng, Jincui Yang, Xinrong He, Yicai Cheng, Xiaoyi Zhan, Zejuan Li, Kelin Wu, Stephanie Roessler, Yunting Jian, Chuli Fu, Guang-Rong Yan, Junyao Xu, Qiangnu Zhang.

Hepatocellular carcinoma (HCC) exhibits diminished capacity for oxidative utilization of long-chain fatty acids (LCFAs). However, the strategic and mechanistic basis by which HCC cells enact metabolic reprogramming to adapt to impaired LCFAs oxidation and sustain viability remains incompletely defined. Here we report that solute carrier family 27 member 5 (SLC27A5), the specific transporter for LCFAs, is broadly downregulated in HCC cells, resulting in reduced LCFAs uptake. In HCC cells with impaired LCFAs oxidation, diminished LCFAs import caused by SLC27A5 loss does not lead to energy deficiency, but instead prevents lipotoxicity derived from unutilized LCFAs, thereby supporting HCC cell growth. Impaired LCFAs oxidation suppresses peroxisome proliferator-activated receptor alpha (PPAR-α) signaling, which in turn represses SLC27A5 transcription, accounting for the widespread downregulation of SLC27A5 in HCC. Owing to reduced LCFAs uptake, HCC cells with low SLC27A5 rely on the glutamine reductive pathway for fatty acid biosynthesis to maintain total fatty acid levels, rendering these cells highly sensitive to glutaminase inhibition. In conclusion, we demonstrate that SLC27A5 downregulation represents a response to defective LCFAs oxidation in HCC, and reduced LCFAs uptake consequent to low SLC27A5 expression constitutes a survival adaptation that enables HCC to tolerate impaired LCFAs oxidation. Glutaminase inhibitors may serve as a precision therapeutic strategy for HCC characterized by low SLC27A5 expression.

DOI: https://doi.org/10.1016/j.canlet.2026.218616
Nat Cancer. 2026 May 25.

Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.

Alan Y L Wong, Jacob W Myers, Gyan Prakash, Alice Ma, Jeannette R Brook, Boryana Petrova, Baran Bulut, Ralph White, Catherine Merz, Maeve de Souza, Adam G Maynard, Peng Wang, Amy Yu, Nancy K Pohl, Michal Weitman, Lewis B Silverman, Kimberly Stegmaier, L Stirling Churchman, Peter D Cole, Donita C Brady, Naama Kanarek.

The nutrient-sparse cerebrospinal fluid (CSF) poses a major challenge to spreading cancer cells. Despite this challenge, leukemia cells spread to the CSF, requiring aggressive central nervous system (CNS)-directed treatment that can lead to neurotoxicity. Here we used a targeted in vivo CRISPR screen to identify nutritional dependencies of systemic and CNS acute lymphoblastic leukemia (ALL). We show that copper depletion, either by genetic deletion of the transporter SLC31A1 or by dietary intervention, slows the growth of both systemic and CNS leukemia in a xenograft model. Mechanistically, copper depletion inhibits complex IV and nucleotide synthesis to slow the growth of leukemia cells. Furthermore, dietary depletion of copper combined with the standard-of-care therapy methotrexate inhibits leukemia progression in cell-line-derived and patient-derived xenograft models. Our findings identify copper as an actionable micronutrient to disrupt nucleotide synthesis in ALL and proposes copper depletion as a way to boost leukemia therapy in the hard-to-treat CNS.

DOI: https://doi.org/10.1038/s43018-026-01177-4
Cell Metab. 2026 May 27. pii: S1550-4131(26)00185-3. [Epub ahead of print]

Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.

Chesta Jain, Muqit Essani, Roshan Kumar, Nupur K Das, Rashi Singhal, Nicholas J Rossiter, Brandon Chen, Wesley Huang, Zheng Hong Lee, Sumeet Solanki, Yuezhong Zhang, Peter Sajjakulnukit, Li Zhang, Prarthana J Dalal, David A Hanna, Cristina Castillo, Harrison S Greenbaum, Shannon E McCollum, Elena M Stoffel, Joel K Greenson, L James Maher, Costas A Lyssiotis, Ruma Banerjee, Yatrik M Shah.

  Colorectal cancer (CRC) cells are addicted to iron, which fuels nucleotide synthesis, mitochondrial respiration, and proliferation. Yet paradoxically, high intracellular iron is cytotoxic to most cells, raising the question of how CRC cells tolerate and exploit iron-rich environments. Ferroptosis, an iron-dependent form of cell death, is thought to mediate iron toxicity. However, whether most ferroptosis regulators, identified through synthetic chemical screens or small molecule activators, play a role in modulating iron toxicity, particularly in vivo, remains unclear. Here, using multi-omics profiling, CRISPR screening, and in vivo models, we uncover a heme-succinate dehydrogenase (SDH)-coenzyme Q (CoQ) axis that enables CRC cells to buffer iron-induced oxidative stress. Heme-dependent SDH reduces CoQ, which redistributes to mitochondrial and plasma membranes to detoxify lipid reactive oxygen species (ROS) as a radical-trapping antioxidant. These findings reveal that CRCs co-opt metabolic cofactors both for growth and for survival under physiologically toxic iron levels, uncovering new vulnerabilities for therapy.

Keywords:  colorectal cancer; iron toxicity; mitochondrial antioxidant; oxidative stress

DOI:  https://doi.org/10.1016/j.cmet.2026.04.020
Commun Biol. 2026 May 26.

Dual targeting of glutamine metabolism and lysosomal function in eliminating drug-tolerant KRAS-mutant cancer cells.

Hiroki Furukawa, Keitaro Umezawa, Yuchen Sun, Hinata Chiba, Marin Kubonishi, Hayato Naito, Yuri Miura, Kousei Ito, Shigeki Aoki.

KRAS inhibitors are reshaping the cancer-treatment landscape; however, durable responses remain limited by drug-tolerant persister cells that survive initial therapy and drive relapse. We show that KRAS-mutant pancreatic and lung cancer cells enter a reversible drug-tolerant (TR) state upon KRAS inhibition, marked by proliferative arrest and extensive metabolic adaptation. Integrated proteomic and metabolomic analyses reveal lysosome-linked remodeling and relatively broad metabolic reprogramming in TR cells. Dual blockade of glutamine metabolism and lysosome-associated processes selectively compromises TR-cell viability under KRAS inhibition, which is rescued by α-ketoglutarate (α-KG). N-acetyl-L-cysteine phenocopies the rescue, and α-KG supplementation lowers intracellular reactive oxygen species levels, supporting a model in which α-KG acts predominantly as a redox-supportive metabolite rather than a Tricarboxylic Acid Cycle intermediate, in the TR state, with lysosome-associated processes contributing to redox balance. These findings define drug-tolerant redox vulnerability and provide a rationale for co-targeting glutamine metabolism and lysosome-associated processes during KRAS inhibitor therapy.

DOI: https://doi.org/10.1038/s42003-026-10374-x
Mol Cell. 2026 May 29. pii: S1097-2765(26)00311-4. [Epub ahead of print]

A multi-subunit autophagic capture complex facilitates degradation of ER-stalled MHC class I in pancreatic cancer.

Marine Berquez, Alexander L Li, Matthew A Luy, Anthony C Venida, Simon McDowall, Thomas O'Loughlin, Gilles Rademaker, Abhilash Barpanda, Jingjie Hu, Julian Yano, Arun P Wiita, Luke A Gilbert, Peter M Bruno, Rushika M Perera.

  Pancreatic ductal adenocarcinoma (PDAC) evades immune surveillance in part through autophagic capture and lysosomal degradation of major histocompatibility complex class I (MHC-I), though the basis for this vulnerability is unclear. Using synchronized endoplasmic reticulum (ER) exit assays, we show that PDAC cells retain MHC-I in the ER and inefficiently traffic it to the plasma membrane. We identify an autophagic capture complex composed of the ER-phagy receptor TEX264 and the cargo receptor NBR1 that targets MHC-I for degradation. Suppression of either receptor restores total and surface MHC-I levels. Capture is linked to antigen loading, as impaired peptide loading increases MHC-I binding to the TEX264-NBR1 complex, while high-affinity peptides reduce binding and promote increased surface localization. A genome-wide CRISPRi screen identified the ER-localized E3 ligase NFXL1 as a mediator of MHC-I ubiquitylation and capture. Elevated NFXL1 correlates with reduced MHC-I expression and poor prognosis, highlighting a targetable pathway regulating PDAC immunogenicity.

Keywords:  ER-phagy; MHC-I; autophagy; lysosome; pancreatic cancer

DOI:  https://doi.org/10.1016/j.molcel.2026.05.005
Adv Sci (Weinh). 2026 May 25. e75818

Mitochondrial Carrier SLC25A13 Drives Ferroptosis Resistance and Immune Evasion via a STAT3-IFI6 Circuit in Breast Cancer.

Yingze Zhu, Yuhan Tang, Yingcui Chen, Zhuoqi Zhang, Yige Lu, Xinyue Wang, Qiyuan Shi, Wenhui Zhao, Hui Pang.

Triple-negative breast cancer (TNBC) remains poorly responsive to immunotherapy, and how ferroptosis can be leveraged to enhance antitumor immunity is unclear. Here, we identify the mitochondrial aspartate/glutamate carrier SLC25A13 as a key immunometabolic driver in TNBC. SLC25A13 is upregulated in breast cancer, predicts poor prognosis, and is associated with reduced CD8+ T-cell infiltration. Functionally, SLC25A13 promotes tumor growth, migration, and metastasis while suppressing ferroptosis and weakening CD8+ T-cell-mediated cytotoxicity. Mechanistically, SLC25A13 interacts with STAT3, enhances complex I-linked oxidative phosphorylation, restrains mitochondrial ROS, and promotes STAT3 activation and nuclear translocation. Nuclear STAT3 directly induces IFI6, which preserves mitochondrial function, limits lipid peroxidation and Fe2 + accumulation, and thereby confers ferroptosis resistance and immune evasion. Through structure-guided screening, we identified HY-QS02682823 as a small-molecule degrader of SLC25A13 that triggers lysosome-dependent SLC25A13 loss, enhances ferroptosis, restores CD8+ T-cell effector function, and improves the efficacy of anti-PD-1 therapy in syngeneic TNBC models. These findings identify the SLC25A13-STAT3-IFI6 axis as a key regulator of ferroptosis resistance and immune evasion in TNBC.

DOI: https://doi.org/10.1002/advs.75818
Cell Death Discov. 2026 May 28.

Inhibition of TGM2 enhances cisplatin sensitivity in MSH2-deficient bladder cancer.

Wenjie Wei, Xingyuan Xiao, Chao Ren, Hui Zhang, Jiayin Sun, Miao Wang, Liang Wang, Hebing Chen, Guosong Jiang, Chao Huang.

MSH2 (mutS homolog 2) gene, a key component of the DNA mismatch repair system, garners significant attention for its influence on cancer progression and prognosis. Loss of MSH2 protein decreases the chemosensitivity of bladder cancer (BCa) to cisplatin (CDDP). However, precision therapeutic strategy based on MSH2 deficiency is not available clinically. Herein, we reported that knockout of MSH2 reduced the sensitivity of BCa to CDDP. Importantly, GK921, a TGM2-specific inhibitor, increased tumor cell killing by CDDP in MSH2-deficient BCa. GK921 also promoted the chemotherapeutic sensitivity of Msh2-knockout mice to CDDP. In addition, Hi-C analysis indicated that MSH2 deficiency rewired chromatin accessibility of the TGM2 promoter region, leading to recruit more transcription factors. Accordingly, we found that the enrichment levels of transcription factor AP-1 in TGM2 promoter region were increased in MSH2-knockout BCa cells, thereby promoting the expression of TGM2 transcriptionally. This study uncovers that CDDP effectiveness depends on TGM2 levels in MSH2-deficient BCa and that the combination of CDDP with TGM2 inhibition may represent a promising therapeutic strategy for MSH2-deficient BCa patients.

DOI: https://doi.org/10.1038/s41420-026-03182-z