bims-meract 2026-11-08 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–11–08
seventeen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Metabolic regulation of ATM-KAT8-RPA1 axis in DNA damage repair and chemoresistance.
Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
IDO1 methylation by EZH2 confers resistance to its targeted therapy in colorectal cancer through tryptophan-kynurenine metabolic rewiring.
CRISPR screens reveal MCT1-driven metabolic escape from SMAD3 inhibition as a therapeutic vulnerability.
KRAS Inhibitor Resistance Confers a Targetable Vulnerability to Ferroptosis in Pancreatic Ductal Adenocarcinoma.
Targeting oxidative phosphorylation with lixumistat overcomes PARP inhibitor resistance in ovarian cancer.
An inhibitor of the mitochondrial respiratory chain exerts synergistic anti-tumour effects when combined with alkylating agents.
Therapy-induced tumour senescence drives oxaliplatin resistance via ADORA1-dependent palmitic acid metabolic reprogramming in colorectal cancer.
The AMPK-ALDH7A1 axis drives metabolic reprogramming and anti-tumor immunity in hepatocellular carcinoma via KDM5C inhibition.
NFE2L1 promotes cisplatin resistance by attenuating ferroptosis through SLC27A2-mediated fatty acid metabolism in ovarian cancer.
Metabolic Stress Rewires DHODH from Oncogenesis to SLC7A11-driven Disulfidptosis and Radiosensitization in Esophageal Squamous Cell Carcinoma.
Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.
Lipid metabolism in cancer cells: implications and roles in ferroptosis.
Targeting the ANKRD54/ELOVL6 axis suppresses malignancy in BRAF mutant colorectal cancer by disrupting fatty acid metabolism and promoting ferroptosis.
Dual mTORC1/2 and Scd1 inhibition uncovers a therapeutic vulnerability in pancreatic cancer.
Ferroportin deficiency drives olaparib resistance in ovarian cancer via the cGAS-STING-STAT3 survival axis.
Rapid target engagement of KRAS G12C tricomplex inhibitor RO3903 overcomes resistance and drives durable tumor regression.

iScience. 2026 Nov 20. 29(11): 117908

Metabolic regulation of ATM-KAT8-RPA1 axis in DNA damage repair and chemoresistance.

Xin Ding, Jie Yang, Jinhuan Wu, Mingpeng Jin, Zhe Wang, Xiaoning Yang, Xuanhe Wang, Yifei Song, Bingsong Huang, Rui Li, Yu Li, Yiming He, Wen Zheng, Qianwen Wang, Zhikai Zeng, Yuping Chen, Jian Yuan.

  Post-translational modifications are recognized as critical regulators of the DNA damage response. In this study, we determined that replication protein A1 (RPA1), a modulator of homologous recombination (HR) repair, is lactylated at lysine 167 (K167) in response to DNA damage. This modification is catalyzed by the histone acetyltransferase KAT8 and is dependent on ATM-mediated phosphorylation of KAT8. Lactylation at K167 enhances the DNA-binding capacity of RPA1, which in turn facilitates HR repair. The inhibition of KAT8 or lactate dehydrogenase (LDH), which increases intracellular lactate level, markedly reduces RPA1 lactylation, impairs HR repair, and increases the sensitivity of tumor cells to chemotherapy in patient-derived xenograft (PDX) models. Furthermore, a cell-penetrating peptide (CPP) that selectively disrupts this modification can sensitize tumors to genotoxic treatment. These findings establish RPA1 lactylation as a critical regulator of HR repair and reveal a potential therapeutic strategy in which this modification can be targeted to overcome chemoresistance.

Keywords:  ATM; DNA damage; KAT8; RPA1; homologous recombination

DOI:  https://doi.org/10.1016/j.isci.2026.117908
Elife. 2026 Nov 04. pii: RP107123. [Epub ahead of print]14

Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.

Sarah M Chang, Muhammad Bin Munim, Sonia E Trojan, Huel Cox, Anna Shevzov-Zebrun, Keene L Abbott, Renee Chang, Matthew G Vander Heiden.

  The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine-limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine-depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affect cancer cell proliferation.

Keywords:  NAD+/NADH ratio; biochemistry; cancer biology; cancer metabolism; chemical biology; human; lipid depletion; mitochondria; serine

DOI:  https://doi.org/10.7554/eLife.107123
Cell Rep. 2026 Nov 05. pii: S2211-1247(26)01316-1. [Epub ahead of print]45(11): 118237

IDO1 methylation by EZH2 confers resistance to its targeted therapy in colorectal cancer through tryptophan-kynurenine metabolic rewiring.

Yuanjun Tang, Zhanya Huang, Yiting Jia, Yunyun Guo, Xuedi Cao, Renjing Jin, Qianqian Yin, Jiagui Song, Huiguang Chen, Xintong Zhang, Xin Zhou, Rui Cheng, Jianling Yang, Zhengyang Guo, Pengcheng Bu, Lixiang Xue.

  Deciphering cancer metabolic reprogramming mechanisms can identify new targets to potentiate EZH2 inhibitor efficacy. Using an in vivo genome-wide CRISPR loss-of-function screen in a CRC mouse model, we pinpointed IDO1 as a key mediator of EZH2 inhibitor resistance. EZH2 blockade remodeled CRC cell metabolism by upregulating IDO1 protein and hyperactivating the tryptophan-kynurenine pathway. Both genetic and pharmacological inhibition of IDO1 suppressed tumor growth and rescued EZH2 inhibitor resistance in vitro and in vivo. Mechanistically, EZH2 directly binds and methylates IDO1. Methylation of IDO1 facilitates IDO1 ubiquitination and subsequent degradation. Accordingly, EZH2 inhibition stabilizes IDO1, augments tryptophan-kynurenine metabolic flux, and ultimately confers therapeutic resistance. In summary, our study identifies IDO1 as a non-histone substrate of EZH2 methyltransferase activity and validates that disrupting IDO1-mediated tryptophan metabolism is a viable strategy to overcome EZH2 targeted therapy resistance in cancers.

Keywords:  CP: cancer; CRISPR-Cas9 screening in vivo, tryptophan-kynurenine metabolism; EZH2; IDO1; colorectal cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.118237
Mol Cancer. 2026 08 07. pii: 265. [Epub ahead of print]25(1):

CRISPR screens reveal MCT1-driven metabolic escape from SMAD3 inhibition as a therapeutic vulnerability.

Antti Matvere, Gregory Menchon, Laetitia Martinetti, Amelie Menant, Loan Callac, Hugo Ferrari, Ulrich Jarry, Mathilde Gourdel, Aurelien Bore, Morgane Chassignolle, Victor Le Bars, Edouard Cadieu, Thomas Derrien, Marc Aubry, David Gilot, Remy Pedeux.

Resistance to therapy remains a critical challenge in cancer. This is exemplified by TGF-β pathway inhibitors which, despite broad clinical testing, have failed to deliver survival benefit. More precise SMAD3 targeting has shown preclinical promise, yet resistance mechanisms to SMAD3 inhibition remain entirely unknown. Using complementary genome-wide CRISPR activation and knockout screens, we discover that cancer cells escape SMAD3 inhibition through metabolic reprogramming. Strikingly, this escape is driven not by transcriptional bypass but by the lactate transporter MCT1, with the effect preserved across BRAF-mutated melanoma, KRAS-mutated lung adenocarcinoma, and mouse melanoma. Mechanistically, SMAD3 inhibition creates energetic stress that cancer cells exploit through MCT1. By conferring metabolic flexibility and switching toward glycolysis under drug pressure, MCT1 increases anabolic activity to drive lipid and cholesterol synthesis. Pharmacological and genetic MCT1 inhibition synergizes strongly with SMAD3 blockade to impair tumor viability in BRAF-mutated melanoma, while suppressing drug-tolerant cell emergence in BRAF inhibitor-resistant cells. Critically, this synergy extends to preclinical models, where co-inhibition of SMAD3 and MCT1 potently reduces tumor growth in vivo. Given the additional and well-established role of MCT1 in shaping the tumor immune microenvironment via lactate transport, these results position MCT1 as both a metabolic and immunological target and provide a strong rationale for the repurposing of TGF-β/SMAD3 pathway inhibitors in combination.

DOI: https://doi.org/10.1186/s12943-026-02757-9
Cancer Res. 2026 Nov 03.

KRAS Inhibitor Resistance Confers a Targetable Vulnerability to Ferroptosis in Pancreatic Ductal Adenocarcinoma.

Sihan Huo, Hailong Zhao, Tong Liu, Ruoxuan Wang, Yuyao Guo, Wenqin Hao, Minghe Fan, Ziyang Zhang, Xiangying Fu, Yueran Zhang, Lina Wang, Jingfeng Tang, Hua Wang, Ying Zhao.

KRAS inhibitors represent a promising therapeutic frontier in pancreatic ductal adenocarcinoma (PDAC) treatment. However, the clinical benefit of KRAS inhibitors in PDAC is limited by the frequent emergence of resistance. Here, we demonstrated that acquisition of resistance to KRAS inhibitors rendered PDAC cells hypersensitive to ferroptosis. Untargeted lipidomic profiling revealed that resistant cells underwent extensive lipid metabolic reprogramming characterized by selective enrichment of polyunsaturated fatty acid-containing phosphatidylcholines (PC-PUFAs) and a concomitant reduction in monounsaturated fatty acid-containing species (PC-MUFAs). The orphan nuclear receptor NR2F2 was a critical determinant of ferroptosis sensitivity in resistant cells. NR2F2 expression was markedly elevated upon acquisition of resistance, accompanied by substantial changes in its occupancy at regulatory elements of key lipid metabolic genes. By altering chromatin accessibility, NR2F2 drove PUFA biosynthesis and phospholipid remodeling, creating a ferroptosis-prone lipid state. Collectively, these findings establish NR2F2-driven lipid metabolic rewiring as an intrinsic ferroptosis liability in KRAS inhibitor-resistant PDAC and reveal ferroptosis induction as a therapeutic strategy to overcome resistance to KRAS-targeted therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-1490
Cell Death Dis. 2026 Aug 07. pii: 939. [Epub ahead of print]17(1):

Targeting oxidative phosphorylation with lixumistat overcomes PARP inhibitor resistance in ovarian cancer.

Sa Deok Hong, Nar Bahadur Katuwal, Mithun Ghosh, Seong Min Park, Ju Hyun Kim, Seul-Gi Kim, Min Sil Kang, Yong Wha Moon.

Ovarian cancer remains the leading cause of gynecologic cancer mortality, yet nearly half of BRCA1/2-mutated ovarian cancer patients eventually develop resistance to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we investigated whether lixumistat, a novel oxidative phosphorylation (OXPHOS) inhibitor, could overcome PARP inhibitor resistance in preclinical BRCA1/2-mutated ovarian cancer models. Long-term olaparib exposure generated olaparib-resistant BRCA-mutated ovarian cancer cell lines and patient-derived tumor xenograft (PDTX) models. Olaparib-resistant cells exhibited elevated OXPHOS activity. Lixumistat, when combined with olaparib, demonstrated synergistic antitumor effects in both olaparib-sensitive and -resistant cell lines and PDTX models. Switching from olaparib monotherapy to combination markedly suppressed tumor growth in partially resistant and acquired-resistant PDTX models. These results suggest that early integration of lixumistat could enhance efficacy and delay PARP inhibitor resistance. Mechanistically, lixumistat restores PARP inhibitor sensitivity by inhibiting the OXPHOS-NAD⁺-poly(ADP)-ribosylation (PARylation) axis, which reduces NAD⁺ availability and subsequent PARylation. Exogenous NAD⁺ reversed these effects. Additionally, lixumistat downregulated the SNAIL-mediated IL6-phosphorylated STAT3 and phosphorylated retinoblastoma pathway, impairing cell-cycle progression and further enhancing PARP inhibitor efficacy. Together, these findings identify a novel OXPHOS-associated mechanism underlying PARP inhibitor resistance and establish lixumistat as a promising combinatorial strategy to potentiate PARP inhibitors in both PARP inhibitor-naive and -resistant ovarian cancer.

DOI: https://doi.org/10.1038/s41419-026-09140-y
Br J Pharmacol. 2026 Nov 06.

An inhibitor of the mitochondrial respiratory chain exerts synergistic anti-tumour effects when combined with alkylating agents.

Emiri Omori Takaki, Yuya Hidoh, Yutaka Obuchi, Yoko Nagai, Shingo Nishikori, Yuki Kuniyoshi, Yasuhiro Sawai, Naoto Ohi.

   BACKGROUND AND PURPOSE: Cancer cells exhibit the Warburg effect, but oxidative phosphorylation (OXPHOS) is also important for cancer cell proliferation. Metabolic reprogramming from glycolysis to OXPHOS is one mechanism of resistance to anti-tumour drugs. Here, we have synthesized and characterized OPB-111077, a novel, first-in-class orally available small-molecule compound, and investigated its anti-tumour activity and therapeutic potential in combination with alkylating agents.
EXPERIMENTAL APPROACH: Inhibition of mitochondrial function by OPB-111077 were assessed by measuring the oxygen consumption rate, ATP production and Complex I enzymatic activity. anti-tumour effects were evaluated in human haematological and solid tumour cell lines and in cell line-derived xenograft and lymphoma patient-derived xenograft models. Mechanistic studies included CRISPR screening, metabolomic analyses, and measurements of the oxygen consumption and extracellular acidification rates. Effects of OPB-111077 combined with alkylating agents were also assessed in mice.
KEY RESULTS: OPB-111077 inhibited mitochondrial respiratory chain Complex I, suppressed OXPHOS, and exerted anti-tumour effects in several models. OPB-111077 demonstrated synergism with the alkylating agent bendamustine, with simultaneous inhibition of both OXPHOS and glycolysis. Bendamustine reprogrammed cancer cells into an OXPHOS-dominant state, thereby enhancing the efficacy of OPB-111077.
CONCLUSION AND IMPLICATIONS: Based on these findings, we propose a novel anticancer therapeutic strategy of combining OXPHOS inhibitors with alkylating agents. OPB-111077 has demonstrated potential in combination therapy and was recently evaluated with bendamustine and rituximab in a Phase 1 clinical trial for patients with relapsed/refractory diffuse large B-cell lymphoma (NCT04049825).

Keywords:  DLBCL; OXPHOS inhibitor; metabolic reprogramming; synergistic anti‐tumour effect

DOI:  https://doi.org/10.1111/bph.70719
Oncogene. 2026 Nov 03.

Therapy-induced tumour senescence drives oxaliplatin resistance via ADORA1-dependent palmitic acid metabolic reprogramming in colorectal cancer.

Yuqin Long, Xue Li, Yunxi Zhu, Yang Shen, Xiaotian Zhou, Ziqin Wei, Yin Yue, Jie Zhang, Changhong Miao.

Oxaliplatin-based neoadjuvant chemotherapy (NACT) is increasingly used in locally advanced colorectal cancer (CRC); however, early acquired resistance substantially limits its efficacy. We revealed an enrichment of therapy-induced senescence (TIS)-like phenotypes in short-term oxaliplatin-exposed CRC. Consistently, a similar upregulation of senescence markers was observed in oxaliplatin-resistant CRC cells. Senolytic treatment attenuated senescence features and restored oxaliplatin sensitivity in vitro and in vivo. Integrative analysis of RNA-sequencing data from resistant tumours and ABT263-treated resistant tumours identified adenosine A1 receptor (ADORA1) as a key mediator of senescence and oxaliplatin resistance. ADORA1 is highly expressed in CRC tumours and is further induced by oxaliplatin, with elevated ADORA1 levels enriched in chemoresistant patients and associated with poor outcomes following chemotherapy. Mechanistically, ADORA1 directly interacts with and stabilises fatty acid synthase (FASN) by suppressing its ubiquitin-mediated degradation, thereby promoting palmitic acid (PA) synthesis, lipid droplet accumulation and p53/p21-driven senescence. Conversely, ADORA1 knockdown attenuates these phenotypes and restores oxaliplatin sensitivity. Together, these findings identify the ADORA1-FASN-PA metabolic reprogramming as a central mechanistic link between TIS and oxaliplatin resistance in CRC, highlighting this pathway as a promising therapeutic target for overcoming early acquired resistance.

DOI: https://doi.org/10.1038/s41388-026-04024-z
Dev Cell. 2026 Nov 03. pii: S1534-5807(26)00392-8. [Epub ahead of print]

The AMPK-ALDH7A1 axis drives metabolic reprogramming and anti-tumor immunity in hepatocellular carcinoma via KDM5C inhibition.

Yue Tong, Jiayu Wang, Rui Ma, Min Wang, Tong Zhang, Hanhua Dong, Feng Ge, Cunqi Ye, Tailang Yin, Xilan Yu, Shanshan Li.

  Mitochondrial dysfunction is a feature of hepatocellular carcinoma (HCC), yet how respiratory suppression arises remains unclear. Here, we identify an evolutionarily conserved metabolic-epigenetic axis integrating metabolic regulation with tumor suppression and anti-tumor immunity. Through comparative studies in yeast, HCC cell lines, and orthotopic/autochthonous HCC mouse models, we demonstrate that AMP-activated protein kinase (AMPK)/Snf1-mediated phosphorylation of aldehyde dehydrogenase ALDH7A1/Ald6 promotes its nuclear translocation and local acetate production, leading to inhibition of histone lysine demethylase KDM5C/Jhd2. This results in H3K4 trimethylation (H3K4me3) accumulation at respiratory genes, activating their transcription and maintaining mitochondrial function. During HCC pathogenesis, loss of AMPK signaling disrupts this pathway, impairing ALDH7A1 nuclear translocation and enabling KDM5C-mediated respiratory suppression. Notably, AMPK-ALDH7A1-acetate-mediated KDM5C inhibition also potentiates cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, driving CD8+ T cell infiltration and synergizing with immune checkpoint blockade. Our work defines the evolutionarily conserved AMPK-ALDH7A1-KDM5C axis and establishes acetate as a dual regulator of mitochondrial metabolism and anti-tumor immunity, offering therapeutic strategies for targeting metabolic vulnerabilities in HCC.

Keywords:  acetate; cGAS-STING; epigenetic modifications; histone methylation; metabolic reprogramming; tumorigenesis; yeast

DOI:  https://doi.org/10.1016/j.devcel.2026.10.006
Cell Death Differ. 2026 Nov 04.

NFE2L1 promotes cisplatin resistance by attenuating ferroptosis through SLC27A2-mediated fatty acid metabolism in ovarian cancer.

Mengwen Zhang, Shumin Yan, Benzheng Zhao, Ning Ma, Keke Wang, Lin Hou, Si Chen, Mingyue Zhao, Jie Huang, Tong Ren, Xinxin Ci, Songling Zhang.

Approaches that promote ferroptosis have emerged as promising therapeutic strategies for chemotherapy-resistant cancers; however, the mechanisms regulating ferroptosis during acquired therapeutic resistance remain incompletely understood. Using RNA sequencing, we identified that Nuclear Factor Erythroid-2 Related Factor 1 (NFE2L1) is upregulated in cisplatin-resistant ovarian cancer (OC) cells and patient tissues, as well as in ferroptosis-resistant models. Genetic knockdown of NFE2L1 resensitized cells to cisplatin both in vitro and in vivo. Notably, this effect was largely reversed by ferroptosis inhibitors, which significantly rescued cell survival following NFE2L1 depletion under cisplatin treatment. Further experiments demonstrated that modulating NFE2L1 expression affects the response to ferroptosis inducers by regulating iron accumulation and lipid peroxidation. Mechanistically, NFE2L1 silencing increased the transcription of long-chain fatty acid transport protein 2 (SLC27A2/FATP2). Chromatin immunoprecipitation and dual-luciferase reporter assays showed that NFE2L1 bound directly to the SLC27A2 promoter, where it competitively inhibited the recruitment of the transcription factor SP1. As a key member of the long-chain acyl-CoA synthetase family, FATP2 promotes the uptake and activation of long-chain fatty acids, processes that have been implicated in the regulation of ferroptosis. Subsequent LC-MS-based lipidomic analysis revealed that NFE2L1 reprogrammed intracellular fatty acid metabolism, characterized by increased polyunsaturated fatty acid (PUFA) levels and decreased monounsaturated fatty acid (MUFA) levels within phosphatidylethanolamines (PEs), thereby increasing cellular susceptibility to ferroptosis. Consistent with these findings, supplementation with exogenous unsaturated fatty acids modulated NFE2L1-mediated ferroptosis sensitivity. Collectively, our findings reveal a novel NFE2L1/SLC27A2 axis that drives cisplatin resistance in OC by suppressing ferroptosis, and suggest a potential therapeutic strategy for treating cisplatin-resistant ovarian cancer.

DOI: https://doi.org/10.1038/s41418-026-01897-1
Cancer Lett. 2026 Nov 06. pii: S0304-3835(26)00722-6. [Epub ahead of print] 218958

Metabolic Stress Rewires DHODH from Oncogenesis to SLC7A11-driven Disulfidptosis and Radiosensitization in Esophageal Squamous Cell Carcinoma.

Xin Li, Yenan Wu, Minyi Lu, Wenyan Gao, Mengmeng Lu, Yaoyi Zhu, Yongling Ji, Zhihua Liu, Aiping Luo.

  Metabolic plasticity enables tumors to adapt to fluctuating nutrient environments, yet the non-canonical functions of metabolic enzymes under stress remain largely unexplored. Here, we established a pyrimidine biosynthesis-associated gene score (PBAGS) that predicts survival in esophageal squamous cell carcinoma (ESCC) and identified dihydroorotate dehydrogenase (DHODH) as a critical driver with a context-dependent dual role. Under glucose-replete conditions, DHODH functions as a canonical oncogene, promoting pyrimidine and cysteine metabolism, alongside UDP-GlcNAc production; accordingly, its inhibition by leflunomide suppresses tumor growth. Strikingly, under glucose starvation, DHODH undergoes a functional switch to become a "molecular executioner." Mechanistically, starvation triggers the DHODH-OGT axis to maintain site-specific O-GlcNAcylation of SLC7A11 at Ser26, thereby stabilizing SLC7A11. This modification promotes excessive cystine accumulation and subsequent actin cytoskeleton collapse, ultimately triggering disulfidptosis. Accordingly, inhibition of DHODH abolishes this modification and rescues cells from starvation-induced death. Clinically, DHODH-SLC7A11 axis correlates tightly with GLUT1 expression. Mimicking glucose starvation using GLUT1 inhibitor BAY-876 significantly enhances radiosensitivity in ESCC PDX models that harbor high DHODH/SLC7A11 expression. Collectively, our findings uncover that under glucose starvation, DHODH and SLC7A11 co-dependency synergistically promotes disulfidptosis, suggesting that targeting the metabolic context offers a potent strategy to sensitize ESCC to radiotherapy.

Keywords:  DHODH; Disulfidptosis; Metabolic stress; O-GlcNAcylation; Radioresistance; SLC7A11

DOI:  https://doi.org/10.1016/j.canlet.2026.218958
J Clin Invest. 2026 Nov 02. pii: e205579. [Epub ahead of print]136(21):

Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.

Yu Deng, Matthew J Niederhuber, Zhichuan Zhu, Austin J Hepperla, Le Yu, Quentin Hahn, Joshua Hartsell, Tooba Rashid, Piotr A Mieczkowski, Hemant Kelkar, Jeremy M Simon, Yanqiong Zhang, Alessandra Livraghi-Butrico, Meredith J Zeller, Joseph Gc Kennedy, Jazmin F DePriest, Jiong Li, Yan Zhang, Xing Qiu, H Ümit Kaniskan, Jian Jin, Corbin D Jones, Laura E Herring, Douglas H Phanstiel, Xiaojing Liu, Jesse R Raab, Brian D Strahl, Pengda Liu.

  Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor critical for host defense against microbial infections. To prevent aberrant activation, nuclear cGAS is restrained by nucleosome tethering or by barrier-to-autointegration factor-mediated restriction of its access to DNA. However, its physiological roles beyond enzymatic suppression in the nucleus remain poorly understood. Here, we present a genome-wide map of cGAS chromatin localization in human cells and unexpectedly find its binding beyond nucleosome tethering, where cGAS is recruited to chromatin by AP-1 transcription factors via a potentially previously uncharacterized transactivation domain. Integrated CUT&RUN, RNA-seq, and metabolomics analyses reveal that cGAS transcriptionally regulates cholesterol homeostasis. Mechanistically, cGAS promotes LGALS3 transcription, which inhibits ACAA2 activity to suppress fatty acid oxidation and acetyl-CoA production, thereby lowering intracellular cholesterol levels. Reduced cholesterol lowers plasma membrane phosphatidylinositol [3,4,5] triphosphate [PI(3,4,5)P3] levels and decreases mTOR complex 2 (mTORC2) activation. In contrast, cGAS depletion results in cholesterol accumulation and elevated PI(3,4,5)P3, driving mTORC2/Akt signaling, promoting xenografted tumor growth, and conferring resistance to DNA-damaging agents. In vivo, the elevated hepatic cholesterol levels observed in cGas-/- mice were largely reversed by inhibition of Akt but not STING, whereas cGAS deficiency had minimal effects on lung physiology. Collectively, our findings uncover an unexpected role for nuclear cGAS in orchestrating a transcriptional program that links lipid metabolism to cell proliferation, stress response, and cholesterol homeostasis in liver.

Keywords:  Cell biology; Epigenetics; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI205579
Biochim Biophys Acta Rev Cancer. 2026 Nov 05. pii: S0304-419X(26)00221-0. [Epub ahead of print] 189749

Lipid metabolism in cancer cells: implications and roles in ferroptosis.

Rosita Curcio, Eugenia Nicol Manti, Federico Di Cocco, Simone Scagnoli, Grazia Chiellini, Bruna Cerbelli, Cristian Scatena, Marco Fiorillo.

  Lipid metabolism is extensively reprogrammed in cancer to support tumor growth, survival, metastasis, and therapeutic adaptation. Among these metabolic alterations, cholesterol metabolism has emerged as a central regulator of cellular homeostasis, extending well beyond its classical structural role in biological membranes. Increasing evidence indicates that sterol metabolism influences ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, through multiple interconnected mechanisms involving membrane organization, redox homeostasis, and metabolic adaptation. In this review, we provide an integrated overview of the cholesterol-ferroptosis axis by organizing current evidence into three complementary regulatory strata. The biophysical stratum encompasses the role of cholesterol and membrane organization in modulating lipid packing, membrane architecture, and susceptibility to lipid peroxidation. The metabolic stratum focuses on the contribution of the mevalonate pathway to ferroptosis defense through glutathione peroxidase 4, ferroptosis suppressor protein 1, dihydroorotate dehydrogenase, and GTP cyclohydrolase 1/tetrahydrobiopterin-dependent antioxidant systems, as well as the emerging roles of sterol intermediates such as squalene and 7-dehydrocholesterol The signaling and microenvironmental stratum highlights how oncogenic pathways together with hypoxia, nutrient limitation, extracellular acidosis, and other tumor microenvironmental pressures reshape cholesterol metabolism and influence ferroptosis sensitivity. We further discuss several unresolved biological paradoxes, including the dual effects of cholesterol accumulation on membrane protection and lipotoxicity, the context-dependent consequences of mevalonate pathway inhibition, and the remarkable metabolic plasticity that limits the efficacy of cholesterol-targeting therapies. Finally, we discuss emerging therapeutic opportunities based on mechanism-driven combination strategies and emphasize the need to integrate genomic, lipidomic, and metabolic profiling to identify context-dependent vulnerabilities within the sterol-ferroptosis network. Collectively, this framework highlights cholesterol metabolism as a dynamic regulator of ferroptosis and provides a conceptual basis for the development of more precise therapeutic approaches targeting metabolic adaptation in cancer.

Keywords:  Biochemical signaling; Cancer; Cancer metabolism; Cholesterol; Ferroptosis; Lipid metabolism

DOI:  https://doi.org/10.1016/j.bbcan.2026.189749
J Exp Clin Cancer Res. 2026 Aug 11. pii: 231. [Epub ahead of print]45(1):

Targeting the ANKRD54/ELOVL6 axis suppresses malignancy in BRAF mutant colorectal cancer by disrupting fatty acid metabolism and promoting ferroptosis.

Yichao Hou, Di Wu, Yanyu Wei, Bohui Yu, Donghan Shao, Dachun Cao, Ping Wang, Mei Guo, Hang Yin, Li Huo, Wenjun Gu, Yaping Liu, Qingwei Zhang, Dong Wang.

   BACKGROUND: BRAF-mutant (BRAF-MT) colorectal cancer (CRC) represents a clinically aggressive subtype characterized by distinct biological features and significantly worse prognosis compared to BRAF wild-type (BRAF-WT) CRC, with median survival reduced by approximately 40%. The therapeutic resistance of BRAF-MT CRC stems primarily from BRAF-driven dysregulation of tumor cell proliferation. However, the molecular mechanisms underlying the aggressive phenotype and potential therapeutic vulnerabilities remain incompletely understood.
METHODS: Bioinformatic analyses were employed to identify candidate genes. A combination of in vitro (cell proliferation, clonal formation), ex vivo (patient-derived and mouse intestinal organoids), and in vivo (xenograft models) assays were used to assess oncogenic function. Mechanistic investigations included Western blotting, qRT-PCR, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays to delineate the regulatory axis. Fatty acid metabolism and ferroptosis were evaluated by a combination of metabolomic, biochemical, and cellular assays.
RESULTS: Bioinformatic screening identified ankyrin repeat domain 54 (ANKRD54) as selectively overexpressed in BRAF-MT CRC and significantly associated with adverse prognosis. Inhibition of ANKRD54 markedly suppressed clonogenic potential, cellular proliferation in vitro, organoid formation in both PDOs and cKI mouse-derived organoids, and tumor growth in vivo. Mechanistically, lysine acetyltransferase 2 A (KAT2A) promoted ANKRD54 transcriptional activation through H3K27 acetylation. ANKRD54 subsequently formed a functional complex with CCAAT/enhancer binding protein beta (CEBPB), cooperatively inducing ELOVL fatty acid elongase 6 (ELOVL6) expression. This KAT2A-mediated ANKRD54/CEBPB/ELOVL6 transcriptional axis reprogrammed fatty acid metabolism, selectively suppressing ferroptosis in BRAF-MT CRC. Pharmacological targeting of either ANKRD54 or ELOVL6 substantially enhanced the therapeutic efficacy of Vemurafenib-based treatment in BRAF-MT CRC models. Clinical data corroborated that elevated ANKRD54 expression promoted malignant progression and predicted poor outcomes through this ELOVL6-dependent metabolic pathway.
CONCLUSIONS: This study elucidates a novel KAT2A-mediated ANKRD54/CEBPB/ELOVL6 axis driving aggressive tumor behavior through regulating fatty acid metabolic and ferroptosis evasion. These findings establish ANKRD54 and ELOVL6 as promising therapeutic targets for combination strategies to overcome therapeutic resistance in BRAF-MT CRC patients.

Keywords:  ANKRD54; BRAF mutation; Colorectal Cancer; ELOVL6; Fatty Acid; Ferroptosis

DOI:  https://doi.org/10.1186/s13046-026-03809-0
Oncogene. 2026 Oct 31.

Dual mTORC1/2 and Scd1 inhibition uncovers a therapeutic vulnerability in pancreatic cancer.

Chao Fang, Yuanyuan Yu, Yiping Yin, Zhao Shi, Zhaiyue Xu, Britta Statz, Yina Qiao, Hongzhen Li, Yifeng Sun, Jingxiong Hu, Tamer Abdelaal, Kathleen Schuck, Lei Wang, Thomas Hank, Max Heckler, Martin Loos, Ingrid Herr, Franco Fortunato, Ihsan Ekin Demir, Helmut Friess, Shanshan Shen, Christoph W Michalski, Bo Kong.

Hyperactivation of the mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, is common in pancreatic ductal adenocarcinoma (PDAC). However, clinical use of mTOR inhibitors has shown limited efficacy due to rapid adaptive resistance. Using inducible genetically engineered mouse models and matched organoids, we delineated distinct complex-specific adaptations. Loss of mTORC1 delayed tumor progression but induced compensatory PI3K/Akt signalling hyperactivation, while concurrently suppressing inflammatory cancer-associated fibroblasts and desmoplasia through Il-1ra. In contrast, mTORC2 loss impaired de novo sphingolipid synthesis, shifted lipid composition toward saturation, increased the saturated-to-monounsaturated fatty acid ratio, enriched plasma membrane lipid rafts, and amplified interferon-γ signaling. This lipid reprogramming generated a synthetic-lethal dependency on stearoyl-CoA desaturase 1 (Scd1). Pharmacological co-inhibition of mTORC1/2 and Scd1 prevented adaptive PI3K/Akt signalling rebound, remodelled the tumor stroma, enhanced interferon-γ responses, and synergized with anti-PD-1 therapy. These findings establish dual targeting of mTOR signaling and Scd1 as a rational therapeutic strategy for PDAC.

DOI: https://doi.org/10.1038/s41388-026-04026-x
Clin Transl Med. 2026 Nov;pii: e70885. [Epub ahead of print]16(11):

Ferroportin deficiency drives olaparib resistance in ovarian cancer via the cGAS-STING-STAT3 survival axis.

Jiagui Song, Zhengyang Guo, Decao Yang, Ping Yu, Yinjia Li, Zhuhui Yuan, Xiaojuan Ma, Xianlong Li, Hongyan Guo, Lixiang Xue, Tong Liu.

   BACKGROUND: Ovarian cancer (OC) remains the most lethal gynaecological malignancy, and acquired resistance to PARP inhibitors such as olaparib represents a major clinical challenge. Although dysregulation of iron metabolism has been implicated in tumorigenesis, the specific role of the iron exporter SLC40A1 (ferroportin, FPN) in mediating olaparib resistance remains poorly understood. The study aimed to elucidate the clinical significance of FPN deficiency and to explore therapeutic strategies for reversing olaparib resistance.
METHODS: FPN expression was evaluated in OC samples from a clinical cohort of 19 patients, stratified by olaparib responsiveness, to determine its prognostic value. Functional mechanisms were investigated using multiple OC cell lines, patient-derived organoids (PDOs), and mouse xenograft models. We integrated analyses of iron homeostasis, ROS dynamics, DNA repair capacity, and innate immune signaling, with a focus on the cGAS-STING-STAT3 signaling cascade. The therapeutic potential of combining olaparib with the ferroptosis inducer erastin or the STING inhibitor C-176 was assessed as a strategy to overcome FPN deficiency-driven resistance.
RESULTS: Clinically, FPN expression was significantly downregulated in olaparib-resistant tissues compared with sensitive controls (p < 0.05), and low FPN levels were strongly associated with poor therapeutic outcomes. Mechanistically, FPN deficiency promoted intracellular iron accumulation and ROS generation, which led to increased ferroptosis vulnerability, impaired homologous recombination repair (HRR) and concomitant activation of the cGAS-STING-STAT3 inflammatory axis, thereby driving olaparib resistance. Notably, in vivo studies demonstrated that combining olaparib with either erastin or C-176 significantly suppressed tumour growth and restored drug sensitivity compared with monotherapy (p < 0.01), supporting the translational potential of targeting this axis.
CONCLUSIONS: Our study establishes a clinically relevant mechanistic connection between ferroportin deficiency and cGAS-STING-STAT3-mediated olaparib resistance in OC. We identify the FPN-ROS-cGAS-STING-STAT3 axis as an actionable vulnerability in resistant OC, indicating that this pathway is a promising therapeutic target to overcome olaparib resistance.
HIGHLIGHTS: FPN loss drives olaparib resistance and predicts poor outcomes in ovarian cancer. FPN loss causes iron and ROS accumulation, impairing HRR and activating the cGAS-STING-STAT3 axis. The cGAS-STING-STAT3 pro-survival program drives olaparib resistance. STING inhibition restores olaparib sensitivity in resistant ovarian cancer.

Keywords:  FPN; Olaparib resistance; cGAS–STING; ferroptosis

DOI:  https://doi.org/10.1002/ctm2.70885
Proc Natl Acad Sci U S A. 2026 Nov 10. 123(45): e2621263123

Rapid target engagement of KRAS G12C tricomplex inhibitor RO3903 overcomes resistance and drives durable tumor regression.

Xiangyu Yao, Songfan Wang, Jin Xie, Fei Chen, Hongxia Qiu, Gang Li, Zhenze Jiang, Weixing Zhang, Xiaoxiao Jiang, Jianguo Chen, Xin Shu, Dan Zhao, Yumeng Li, Yuying Bian, Ke Huang, Litian Jin, Shuai Chen, Zhipeng Yan, Haixia Liu, Wei Zhu, Hong Shen, Xinyi Huang, Chiho Li, Beimeng Yang.

  The clinical durability of first-generation KRAS G12C inhibitors is constrained by resistance mechanisms, primarily the rapid, receptor tyrosine kinase (RTK)-mediated reactivation of KRAS to its drug-insensitive, guanosine triphosphate (GTP)-bound (ON) state. Here, we perform a systematic comparative characterization of clinical and investigational KRAS G12C inhibitors, including Sotorasib, Adagrasib, Divarasib, and Elironrasib, and our structurally optimized tricomplex ON inhibitor, RO7783903 (RO3903). We demonstrate that the covalent tricomplex inhibitors RO3903 and Elironrasib effectively outpace dynamic nucleotide cycling, conferring resilience to potent RTK stimulation and overcoming the secondary KRAS mutations that drive clinical resistance to guanosine diphosphate (GDP)-bound (OFF) state inhibitors. Notably, RO3903 potently inhibits tumor growth in a dose-dependent manner across multiple preclinical models, including an orthotopic intracranial model. Furthermore, RO3903 exhibits synergistic efficacy when combined with inhibitors targeting OFF-state KRAS G12C, YAP-TEAD, EGFR/MET, or FAK, as well as with anti-PD1 antibody and anti-PD1/VEGF bispecific antibody immunotherapies. The high potency, fast target engagement, and brain tumor inhibition of RO3903 position this molecule as a valuable tool reagent and a promising partner for combination strategies to achieve durable tumor regression.

Keywords:  KRAS G12C tricomplex inhibitor; adaptive resistance; combination therapy; target engagement

DOI:  https://doi.org/10.1073/pnas.2621263123