bims-meract 2026-10-04 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–10–04
23 papers selected by
Andrea Morandi, Università degli Studi di Firenze

circMTHFD1L-driven lipid metabolism in Cancer-associated fibroblasts confers oxaliplatin resistance in pancreatic cancer through O-GlcNAcylation-dependent chromatin recruitment of Ku70.
Metabolic Targeting of ASAH1 in Combination with Carnosine as a Therapeutic Strategy for TNBC.
Mitochondrial rewiring supports survival of triple negative breast cancer cells after ionizing radiation.
A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer.
Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.
IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma.
STC2 promotes cisplatin resistance through metabolic reprogramming and lactylation-mediated epigenetic regulation in cervical cancer.
Transketolase-like 1 potentiates PD-1 blockade in hepatocellular carcinoma by glycolysis to prime dendritic cell lactylation.
EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing Triple-Negative Breast Cancer to Glutaminase Targeting.
α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.
Placenta-Related PEG10 Inhibits mRNA Decay to Promote Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma.
TFAM loss drives oxaliplatin resistance by linking mtDNA release to STING-TBK1-mediated lysophagy.
Mitochondria-ER-lipid droplet crosstalk regulates metabolic adaptation to shear stress via VMP1.
Rbks plays a novel role in maintaining glycolipid metabolic homeostasis.
N6-methyladenosine promotes temozolomide resistance through mRNA stabilization in glioblastoma cells.
AARS2-SIRT5-Driven DLD K445 Lactylation Promotes Cuproptosis Resistance in Glioblastoma Stem Cells.
SPTLC2-driven sphingolipid reprogramming of neutrophils impairs anti-tumour immunity and drives liver cancer progression.
Targeting the DNHD1‑HDAC6 axis inactivates prostate cancer cell aggressiveness in vitro, suggesting potential therapeutic vulnerability.
A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
MYC-Dependent rRNA Catabolism Stress Dictates Survival Heterogeneity of Hepatocellular Carcinoma Cells Under Glutamine Deprivation.
Immunometabolic effects of oral testosterone for castration-resistant prostate cancer in the ACROBAT trial.
A myeloid-dormant metabolic transcriptome identifies a poor-prognosis subgroup in hyperdiploid multiple myeloma with targetable vulnerabilities.
Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance.

Cancer Lett. 2026 Sep 30. pii: S0304-3835(26)00627-0. [Epub ahead of print] 218863

circMTHFD1L-driven lipid metabolism in Cancer-associated fibroblasts confers oxaliplatin resistance in pancreatic cancer through O-GlcNAcylation-dependent chromatin recruitment of Ku70.

Qing Tian, Tianhao Huang, Ning Zhang, Yuting Mao, Tingting Li, Rihua He, Honghui Jiang, Haoxu Wu, Huimou Chen, Zehao Chen, Shangyou Zheng, Chonghui Hu, Yong Jiang, Shuxin Sun, Rufu Chen.

  Platinum-based chemotherapy resistance severely limits therapeutic efficacy and survival in pancreatic ductal adenocarcinoma (PDAC), yet the role of cancer-associated fibroblasts (CAFs) in driving this resistance remains elusive. We screened and validated circMTHFD1L (hsa_circ_0078269) as a stromal circRNA that is markedly upregulated in CAFs from oxaliplatin-resistance (OXA-R) PDAC, and its expression was correlating with poor patient survival. Gain- and loss-of-function assays demonstrated that circMTHFD1L in CAFs is necessary to confer oxaliplatin resistance, primarily through metabolic reprogramming of fatty acid (FA) biosynthesis. Mechanistically, circMTHFD1L directly interacts with the key FA synthesis enzyme acetyl-CoA carboxylase 1 (ACC1), thereby inhibiting its ubiquitination-mediated degradation and enhancing FA production. Tumor cells uptake FA from circMTHFD1L-high CAFs, resulting in increased intracellular uridine diphosphate N-acetylglucosamine availability, a key substrate for O-GlcNAcylation. This metabolic reprogramming promotes Ku70 O-GlcNAcylation and chromatin recruitment, thereby enhancing non-homologous end joining repair efficiency and driving resistance to oxaliplatin in PDAC. Therapeutic targeting of the circMTHFD1L/ACC1 axis in vivo resulted in marked suppression of tumor growth and restored sensitivity to oxaliplatin in orthotopic models. Additionally, we engineered a lipid nanoparticle-based delivery system for sh-circMTHFD1L plasmids and demonstrated that it enhanced the therapeutic efficacy of oxaliplatin in a patient-derived xenograft model. Clinically, high circMTHFD1L expression was positively correlated with ACC1 abundance and served as a poor prognostic prognosis. Collectively, our study reveals that CAF-derived circMTHFD1L drives oxaliplatin resistance in PDAC by stabilizing ACC1 to reprogram FA metabolism and promote Ku70 O-GlcNAcylation, identifying the circMTHFD1L/ACC1/Ku70 axis as a promising target to overcome chemoresistance.

Keywords:  Acetyl-CoA carboxylase 1; Cancer-associated fibroblasts; Chemoresistance; Chromatin recruitment; FA biosynthesis; Pancreatic ductal adenocarcinoma; circRNA

DOI:  https://doi.org/10.1016/j.canlet.2026.218863
Mol Metab. 2026 Sep 30. pii: S2212-8778(26)00135-3. [Epub ahead of print] 102451

Metabolic Targeting of ASAH1 in Combination with Carnosine as a Therapeutic Strategy for TNBC.

Patrick Ball, Ashok Mari, Romi Gupta.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited targeted therapies, leading to higher mortality compared with other breast cancer subtypes. In our previous study we identified N-acyl sphingosine amidohydrolase 1 (ASAH1) to be overexpressed in TNBC cells and demonstrated its role in promoting TNBC growth and progression. ASAH1 is a metabolic enzyme that converts ceramide into sphingosine and free fatty acids, thereby creating a favorable environment for tumor growth. To gain a more comprehensive understanding of the metabolic alterations associated with ASAH1 inhibition, we performed a large-scale metabolomic analysis of TNBC cells expressing ASAH1 shRNAs. Our analysis revealed a significant increase in carnosine levels following ASAH1 inhibition. Subsequent studies demonstrated that exogenous treatment of TNBC cells with carnosine inhibited their growth. Moreover, combining carnosine with ASAH1 inhibitors (carmofur or ceranib-2) resulted in potent synergistic inhibition of TNBC growth. Mechanistically, the combined treatment led to a greater reduction in mitochondrial membrane potential, increased mitochondrial superoxide production and further increased apoptosis. Collectively, these results identify a new metabolism-based combination therapeutic strategy for the effective treatment of TNBC.

DOI: https://doi.org/10.1016/j.molmet.2026.102451
bioRxiv. 2026 Sep 07. pii: 2026.09.03.748963. [Epub ahead of print]

Mitochondrial rewiring supports survival of triple negative breast cancer cells after ionizing radiation.

Steven W Wall, Karen Wang, Allison Greer, Mokryun L Baek, Audra Lane, Mariah J Berner, Jonathan T Lei, Ángel A Garcés, Sofia Khoury, Emily G Caggiano, Matthew D Meyer, Sarah Latka, Hugo Villanueva, Emil Schüler, Cullen M Taniguchi, Rutulkumar Patel, Gloria V Echeverria.

Triple negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Conventional treatments include neoadjuvant chemo-immunotherapy followed by surgical resection and may include further adjuvant immunotherapy and/or radiotherapy of the tumor bed and lymph nodes. Nonetheless, TNBC patients with residual disease have rapid metastatic recurrence. While the roles of metabolic and mitochondrial adaptations in chemotherapeutic resistance have been the subject of many studies, their importance in the context of ionizing radiation (IR) therapy remains poorly understood. We established longitudinal in vitro models of post-IR human TNBC, characterized by cellular regression to a residual phenotypic state, then eventual cell repopulation. This was accompanied by plastic adoption of unique metabolic, proteomic, and morphologic features that largely reverted when cells regrew. Following IR, residual cells exhibited extensive mitochondrial rewiring, including elevated mitochondrial content, oxidative phosphorylation (oxphos) rates, cristae structures, and metabolite levels. Concomitantly, levels of the short protein isoform of the mitochondrial inner membrane protein optic atrophy 1 (OPA1) were significantly elevated in residual cells, and OPA1 knockout ablated mitochondrial adaptations induced by IR. OPA1 genetic or pharmacologic perturbations led to improved cellular responses to IR. Metabolomic and proteomic analyses of radio-residual cells uncovered a coordinated program of antioxidant and redox capacity elevation with mitochondrial metabolism, which was corroborated by analyses of external datasets. Together, these findings provide evidence that TNBC cells surviving radiotherapy adopt an OPA1-dependent program of mitochondrial reorganization that supports their survival and regrowth, thereby positioning OPA1 as a therapeutic dependency that could improve radiotherapy efficacy in TNBC.

DOI: https://doi.org/10.64898/2026.09.03.748963
Sci Adv. 2026 Oct 02. 12(40): eaef1145

A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer.

Jenny Högström, Hanna M Doh, Aidan Kump, Boryana Petrova, Peng Wang, Jonathan D Lee, Kaisa Koivula, Nina Kozlova, Kayla A Cruz, Su Min Hong, Camila Perea, Arjun Garg, Michal Weitman, Conor L Evans, Jonathan L Coloff, Jaymin M Patel, Gerburg M Wulf, Laura C Collins, Naama Kanarek, Taru Muranen.

Resistance to standard-of-care therapies remains a major clinical challenge in the treatment of the most common breast cancer, the hormone receptor-positive (HR+) subtype. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes in early-stage HR+ disease, yet many patients relapse. Resistance mechanisms of relapsed tumors include genetic alterations, but in many cases, no genetic drivers are identified. Here, we investigated mechanisms underlying resistance to CDK4/6 inhibitors using breast cancer patient-derived models and tumors. We identified an unexpected, noncanonical nuclear function of fumarylacetoacetate hydrolase (FAH), an enzyme in the tyrosine catabolism pathway, as a driver of resistance. FAH translocated to the nucleus upon CDK4/6 inhibition, where it interacted with cyclin-dependent kinase 9 (CDK9), and promoted resistance. Nuclear FAH was enriched in tumors from relapsed patients, and inhibition of CDK9 reversed FAH-mediated resistance. These findings establish nuclear FAH as a biomarker of resistance and revealed CDK9 as a therapeutic vulnerability in CDK4/6 inhibitor-resistant HR+ breast cancer.

DOI: https://doi.org/10.1126/sciadv.aef1145
Cancer Res. 2026 Sep 28.

Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.

Thi Thinh Nguyen, Jane Ding, Mohit Bansal, Sunil Sudarshan, Han-Fei Ding.

The mevalonate pathway generates sterols and isoprenoids essential for membrane biosynthesis and signaling. Increased activity of the mevalonate pathway is a common feature of cancer and has emerged as a potential therapeutic vulnerability. Here, we showed that the mevalonate pathway sustains de novo serine biosynthesis and aspartate production by maintaining NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impaired oxidative phosphorylation, lowered the NAD⁺/NADH ratio, suppressed serine and aspartate biosynthesis, and activated the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limited purine and pyrimidine biosynthesis. Genetic and pharmacological disruption of ubiquinone synthesis recapitulated the metabolic defects, whereas expression of the bacterial NADH oxidase LbNOX restored the NAD⁺/NADH ratio and reversed the metabolic and growth defects induced by statin treatment. Importantly, impairment of NAD⁺ regeneration reduced PHGDH-dependent de novo serine synthesis, thereby sensitizing neuroblastoma cells to PHGDH inhibition. Accordingly, simvastatin enhanced the anti-proliferative effects of the PHGDH inhibitor NCT-503 in vitro and exhibited elevated anti-tumor activity in combination with NCT-503 in neuroblastoma xenograft models. Together, these findings establish ubiquinone-dependent NAD⁺ regeneration as a key mechanism linking the mevalonate pathway to amino acid and nucleotide biosynthesis and provide a mechanistic rationale for combined targeting of the mevalonate pathway and serine biosynthesis in cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-1063
Nat Commun. 2026 08 31. pii: 10375. [Epub ahead of print]17(1):

IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma.

Sae Bom Lee, Allan Pavy, Nolan Beatty, Justin C Boucher, Jay K Mandula, Emiliano Roselli, Darwin C Chang, Rachel V Jimenez, Hiroshi Kotani, Kayla Reid, Julio Vazquez-Martinez, Payal Goala, Max Ilecki, Cooper J Sailer, Shannon L McSain, Showkat Hamid, Muhammad Junaid Tariq, Rosa A Sierra-Mondragon, Min Liu, John M Koomen, Jonathan Nguyen, Mohammad Hussaini, Timothy I Shaw, Xuefeng Wang, Jianmin Wang, Julieta Abraham-Miranda, Rawan Faramand, Michael D Jain, Meredith L Stone, Frederick L Locke, Paulo C Rodriguez, Yun Pyo Kang, Marco L Davila.

Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but many patients with large B cell lymphoma (LBCL) experience primary resistance or relapse. To uncover resistance mechanisms, here we examine pre-infusion tumor biopsies and observe that increased immunoregulatory macrophages correlate with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-γ) upregulates inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Proteomic profiling reveals that iNOS-expressing macrophages promote apoptosis and cell cycle arrest while downregulating protein synthesis machinery in CAR T cells. Metabolically, CAR T cells exhibit reduced glycolytic intermediates and altered tricarboxylic acid (TCA) cycle activity. Pharmacological inhibition of iNOS enhances CAR T cell treatment efficacy in vivo. Elevated levels of iNOS+CD14+ monocytes in leukaphereses are associated with non-durable responses to CAR T cells. Targeting iNOS in immunoregulatory macrophages, potentially by modulating CAR T-produced IFN-γ, could improve LBCL outcomes.

DOI: https://doi.org/10.1038/s41467-026-76972-9
Acta Biochim Biophys Sin (Shanghai). 2026 Sep 29.

STC2 promotes cisplatin resistance through metabolic reprogramming and lactylation-mediated epigenetic regulation in cervical cancer.

Shanshan Jin, Dongqin Gao, Yaling Xiahou, Junxia Tao, Danna Jia, Lijuan Huang, Zhizhen Liu, Shulin Hou, Jun Xie, Huimin Lv.

  Cervical cancer (CC) is a major threat to women's health globally, and the development of cisplatin (DDP) resistance is a key factor leading to treatment failure. Prior research from our group has demonstrated the significant involvement of stanniocalcin-2 (STC2) in mediating DDP-resistance in CC. This study explores the role of STC2 in promoting chemoresistance through metabolic and epigenetic reprogramming. We find that STC2 is significantly upregulated in SiHa/DDP cells, a DDP-resistant subline of SiHa, where it enhances the malignant phenotype and drives glycolytic metabolism, increasing lactate production. The accumulated lactate subsequently elevates global histone lactylation, notably at the H3K18la site. Integrated CUT&Tag and RNA-seq analyses identify RBM20 as a potential downstream target of H3K18la-mediated transcriptional activation. Knockdown of STC2 reverses these effects, promoting chemosensitivity to DDP. Our results unveil a novel STC2/glycolysis/lactylation/RBM20 axis underlying DDP resistance in CC, providing new insights into potential therapeutic strategies to overcome chemoresistance by targeting this pathway.

Keywords:  STC2; cervical cancer; chemoresistance; cisplatin; glycolysis; lactylation

DOI:  https://doi.org/10.3724/abbs.2026169
Signal Transduct Target Ther. 2026 Sep 28. pii: 418. [Epub ahead of print]11(1):

Transketolase-like 1 potentiates PD-1 blockade in hepatocellular carcinoma by glycolysis to prime dendritic cell lactylation.

Hengsong Cao, Tian Huang, Yue Chai, Zhengqing Lu, Shipeng Dai, Danyang Xu, Yanshu He, Na Yu, Yuliang Wang, Ziyuan Liu, Yidong Xia, Jie Zhao, Hongyu Wang, Dawei Rong, Yuchen Xie, Chongyu Wang, Pengyu Chen, Juyue Zhou, Li Liu, Zhuozheng Li, Hanyuan Liu, Xiao Li, Xuehao Wang, Weiwei Tang, Yongxiang Xia.

Hepatocellular carcinoma (HCC) exhibits a suboptimal response to immune checkpoint blockade (ICB) therapy; to overcome this resistance, we aimed to delineate key immune resistance factors via multi-omics analysis, develop strategies to block their immunosuppressive axes, and engineer a targeted nanosystem to enhance immunotherapy efficacy against PD-1 resistance in HCC. Using transcriptomic and proteomic data from anti-PD-1-treated HCC patients, along with functional validation in murine models and mechanistic molecular and cell biology studies, we identified transketolase-like 1 (TKTL1) as a dual-nature biomarker where overexpression predicted poor baseline prognosis yet enhanced response to ICB. Mechanistically, TKTL1 diverts glucose flux into glycolysis rather than pentose phosphate pathway (PPP), recruiting USP9X to deubiquitinate and stabilize HIF-1α, which upregulates HK2 to amplify glycolytic output and lactate accumulation. This metabolic rewiring orchestrates dual immunosuppressive circuits through HIF-1α-driven CCL4 secretion recruiting PD-L1high dendritic cells (DCs), coupled with lactate-induced TRIM28K408 lactylation that stabilizes PD-L1 by blocking ubiquitin-mediated degradation. We engineered a hepatoma-membrane-coated MnO₂ nanosystem (CQLH) co-delivering a TKTL1 inhibitor and lactate oxidase, which disrupted the TKTL1-HIF-1α-HK2 axis, depleted lactate, and reprogrammed the tumor microenvironment, thereby enhanced anti-PD-1 therapy to suppress tumor growth, especially in TKTL1high tumors. These findings define a critical "TKTL1-glycolysis-lactate-DC" axis driving anti-PD-1 sensitivity in HCC, position TKTL1 as both a potential biomarker for ICB response and a tractable therapeutic target, and demonstrate that the targeted CQLH nanosystem overcomes resistance and enhances anti-PD-1 efficacy, offering a precision immunotherapeutic strategy for TKTL1high HCC.

DOI: https://doi.org/10.1038/s41392-026-02875-2
Cancer Res. 2026 Oct 02.

EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing Triple-Negative Breast Cancer to Glutaminase Targeting.

Lucas Porras, Marina Carrière, Ann-Sophie Gironne, Hugo Philippeau, Gabriel Alzial, Elise Quadri, Jeanne Cormery, Yousef Alaessa, Anie Monast, Faustine Gorse, Myriame St-Arnaud, Mariana De Sa Tavares Russo, Sylvie Nathalie Christine Mader, Daina Z Avizonis, Sébastien Lemieux, Morag Park, Geneviève Deblois.

EZH2, the catalytic subunit of the histone methyltransferase complex PRC2, is overexpressed and associated with poor prognosis in triple-negative breast cancer (TNBC). Although EZH2 inhibition significantly alters chromatin landscapes and gene expression, it has limited impact on the growth of TNBC models, suggesting adaptive compensatory mechanisms. Here, we demonstrated that EZH2 inhibition causes the accumulation of misfolded proteins and double-stranded RNA (dsRNA), triggering an essential integrated stress response (ISR) through PKR and PERK activation. By inducing ISR-mediated ATF4, EZH2 inhibition enhanced amino acid flux and promoted glutaminolysis to support TNBC cell survival. Pharmacological targeting of this metabolic axis with a glutaminase inhibitor in combination with EZH2 inhibition significantly impaired TNBC cell proliferation and tumor growth. These findings reveal a stress-driven metabolic adaptation that sustains TNBC survival upon EZH2 blockade and highlight inhibition of this pathway as a strategy to enhance the efficacy of EZH2 inhibitors in TNBC.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0801
Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2606579123

α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.

Fei Li, Xiaorong Xie, Tongran Xu, Yu Tang, Yuting Xia, Yali Tang, Shijie Yuan, Mengdi Zhu, Xuwei Wu, Lan He, Shu-Hai Lin, Ran He.

  Tumor-associated macrophages (TAMs), the most abundant immune cell subset in the tumor microenvironment (TME), exhibit phenotypic plasticity and exert critical roles in tumor progression and antitumor immunity. Targeting TAM polarization has emerged as a promising strategy for cancer immunotherapy, yet the key regulators governing this process remain incompletely defined. Here, we identified α-aminobutyric acid (AABA) as a pro-tumor metabolite that drives M2-like polarization of TAMs to promote tumor progression. Mechanistically, AABA binds to asparagine synthetase (ASNS), reinforcing the mTORC2-IRF4 signaling axis to reprogram TAMs, switching macrophage metabolism from glycolysis to oxidative phosphorylation, a hallmark of pro-tumor M2-like phenotypes. Moreover, tumor-derived AABA was transported into macrophages by monocarboxylate transporters 1 and compromised the therapeutic efficacy of PD-1 checkpoint inhibition. Collectively, our findings uncover AABA as a previously unrecognized signaling metabolite to control TAM polarization, providing insights into the metabolic crosstalk within the TME and offering a potential therapeutic target to improve cancer immunotherapy outcomes.

Keywords:  asparagine synthetase; mTORC2; macrophage; tumor microenvironment; α-aminobutyric acid

DOI:  https://doi.org/10.1073/pnas.2606579123
Cancer Res. 2026 Oct 02.

Placenta-Related PEG10 Inhibits mRNA Decay to Promote Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma.

Xinyi Yao, Bi Wu, Caini Yang, Zhaoyu Lin, Mengting Zhang, Shuang Tao, Jie Chen, Yongxin Huang, Xuyao Chen, Yun Li, Yuntan Qiu, Duanqing Tian, Chengyu Jia, Jingyuan Zhang, Daning Lu, Rui Zhang, Yin Zhang, Dong Yin.

Tumors display marked similarities with embryos, exploiting embryonic developmental programs. Beyond the embryo, the placenta also shares features with malignant tumors, such as invasion, immune evasion, and rapid nutrient exchange, highlighting the need for mechanistic investigations of tumor development through the lens of placental biology. In this study, by screening placental-specific genes with aberrant expression in hepatocellular carcinoma (HCC), we found that the paternally expressed gene 10 (PEG10, a retrovirus-like gene) was overexpressed in HCC and associated with poor patient prognosis. Liver-specific deletion of Peg10 significantly impeded hepatocarcinogenesis and tumor progression in a hydrodynamic tail vein injection-induced HCC mouse model. PEG10 drove tumor cells to co-opt the metabolic phenotype of trophoblast cells by upregulating key glucose metabolic regulators glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Mechanistically, as an RNA-binding protein (RBP), PEG10 inhibited the Staufen1-mediated mRNA decay (SMD) pathway, stabilizing GLUT1 and HK2 mRNA to enhance glucose uptake and aerobic glycolysis. Furthermore, retinoic acid pharmacologically suppressed PEG10 expression, effectively abrogating the adaptive metabolic advantage and acting synergistically with sorafenib to restrict tumor growth. Collectively, this study reveals how HCC aberrantly reactivates the placental gene PEG10 to orchestrate oncogenic glucose uptake and metabolism, identifying it as a compelling therapeutic target for metabolic intervention in cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0490
Oncogene. 2026 Oct 02.

TFAM loss drives oxaliplatin resistance by linking mtDNA release to STING-TBK1-mediated lysophagy.

Xiao-Xuan Wang, Xin-Han Wang, Zi-Hong Fan, Xiao-Feng Ding, Jian-Rui Zhong, Bing-Ming Zhu, Jie Lyu, Su-Jie Wang, Qing-Yu He, Yang Wang, Jing Zhang.

Acquired resistance to oxaliplatin (Oxa) represents a major clinical challenge in the treatment of colorectal cancer (CRC). Lysosomes are intracellular degradative organelles that enable cancer cells to adapt to metabolic and environmental stress; however, their precise regulatory roles in drug resistance remain poorly understood. Here, we report that lysosomal damage and its selective autophagic clearance (lysophagy) occur frequently in both Oxa-treated CRC cells and Oxa-resistant (OxaR) CRC cells. Through quantitative proteomics, we identified the significant downregulation of mitochondrial transcription factor A (TFAM) as a key event in Oxa-treated and OxaR cells. Mechanistically, Oxa-induced TFAM loss leads to mitochondrial DNA (mtDNA) leakage into the cytosol, which activates the STING-TBK1 signaling axis. This pathway subsequently enhances lysophagic flux, providing cancer cells with a survival advantage under Oxa stress. Crucially, pharmacological inhibition of TBK1 abrogates this adaptive lysophagy, restoring Oxa sensitivity and suppressing tumor growth in both xenograft and patient-derived organoid models. Collectively, our study reveals a novel TFAM-mtDNA-STING-TBK1 signaling axis that promotes chemoresistance through the co-option of lysophagy, highlighting TBK1 as a viable therapeutic target to overcome Oxa resistance in CRC.

DOI: https://doi.org/10.1038/s41388-026-03990-8
Curr Biol. 2026 Oct 02. pii: S0960-9822(26)01198-X. [Epub ahead of print]

Mitochondria-ER-lipid droplet crosstalk regulates metabolic adaptation to shear stress via VMP1.

Maria Laura Rojas, Maribel Lara Corona, Carla Alemany, Juliane Da Graça, Nicolas Goudin, Ivan Nemazanyy, Ida Chiara Guerrera, Aurore Claude-Taupin, Etienne Morel.

  Kidney tubular epithelial cells adapt to physiological urinary flow through rapid metabolic remodeling,1,2 but the mechanisms coordinating this response remain poorly understood. Shear stress promotes lipid catabolism and mitochondrial activity in these cells,3,4 but how changes in mitochondrial dynamics contribute to this metabolic adaptation remains poorly understood.5,6,7,8,9 Here, we show that physiological shear stress rapidly remodels mitochondrial morphology in kidney epithelial cells in vitro and in the zebrafish pronephros, characterized by the emergence of a distinct pool of donut-shaped mitochondria. This remodeling is accompanied by a transient stabilization of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs), occurring independently of any increase in overall ER volume. Using split-TurboID proximity labeling and mass spectrometry, we detected subtle changes in the molecular environment of MERCs during shear stress, including increased proximity of proteins implicated in lipid transfer and membrane contact-site biology. We further show that shear stress promotes the formation of ER-lipid droplet (LD)-mitochondria contact sites and facilitates the local transfer of fatty acids from LDs to mitochondria. This lipid transfer requires vacuolar membrane protein 1 (VMP1), a component of membrane contact sites, whose depletion perturbs LDs and compromises metabolic adaptation to shear stress. Together, our findings identify ER-LD-mitochondria contact sites as dynamic platforms that coordinate lipid transfer and mitochondrial remodeling during the early adaptation of kidney epithelial cells to physiological shear stress, highlighting membrane contact sites as important components of the cellular response to mechanical forces.

Keywords:  contact sites; endoplasmic reticulum; kidney epithelial cells; lipid droplets; metabolic adaptation; mitochondria; shear stress; zebrafish

DOI:  https://doi.org/10.1016/j.cub.2026.09.021
Acta Biochim Biophys Sin (Shanghai). 2026 Sep 29.

Rbks plays a novel role in maintaining glycolipid metabolic homeostasis.

Zhongbin Yang, Houyu Li, Zeying Wang, Hongge Ju, Qi He, Liran He, Jingye Zhou, Caixia Shi, Feifei Zhu, Kun Hou, Lili Li, Zehong Zhang, Yu Tai, Qiang Ma, Xiaojing Li, Jing Jin, Zhi Liu, Yan Su.

  Elevated urinary D-ribose has been observed in patients with diabetes and Alzheimer's disease, although the underlying mechanism remains unclear. Since ribokinase (Rbks) catalyzes the phosphorylation of D-ribose to ribose-5-phosphate, we hypothesize that the Rbks gene plays a crucial role in regulating systemic glucose and lipid metabolism. To test this hypothesis, we generate Rbks-knockout (KO) C57BL/6J mice using CRISPR/Cas9 and conduct a 16-week phenotypic observation. Although KO mice exhibit normal physical appearance and body weight, they show reduced food consumption and water intake. Serum levels of total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) are decreased, accompanied by hepatic accumulation of T-CHO. Proteomic analysis identifies 117 differentially expressed proteins associated with glycolipid metabolism and oxidative phosphorylation. Metabolomic profiling reveals 414 altered metabolites enrich in lipid metabolism, central carbon metabolism, and amino acid metabolism pathways. Among these alterations, the most prominent change is enhanced hepatic cholesterol and bile acid (BA) synthesis, which is supported by elevated hepatic T-CHO levels and increased mRNA expressions of 3-hydroxy-3-methylglutaryl-CoA reductase ( Hmgcr) and squalene epoxidase ( Sqle). This study reveals a novel role for Rbks in maintaining glucose-lipid metabolic homeostasis, especially with potential implications for understanding metabolic disorders characterized by altered cholesterol flux.

Keywords:  D-ribose; cholesterol; metabolic homeostasis; ribokinase

DOI:  https://doi.org/10.3724/abbs.2026126
NAR Cancer. 2026 Dec;8(4): zcag027

N6-methyladenosine promotes temozolomide resistance through mRNA stabilization in glioblastoma cells.

Emily A Dangelmaier, Dorthy Fang, Isabel P Hardy, Kyal Sin Htet, Nicole S Harry, Renee Pascoe, Je Won Yang, Clara D Wang, Sigrid Nachtergaele.

N6-methyladenosine (m6A) regulates nearly every aspect of messenger RNA (mRNA) processing and function, impacting downstream gene expression programs. Changes in m6A have been implicated in many different types of cancer, and inhibition of m6A installation is emerging as a cancer therapeutic strategy. However, chemoresistance remains a significant clinical challenge in the treatment of glioblastoma (GBM). We established GBM cell culture models of acquired temozolomide (TMZ) resistance, analyzed the role of m6A in controlling resistance-associated pathways, and assessed the effects of METTL3 inhibition. We show that m6A stabilizes key genes and pathways promoting TMZ resistance, and that METTL3 inhibition can reverse this and restore TMZ sensitivity. These findings highlight that TMZ resistance can occur independent of a glioma stem cell population and that changes in m6A need not be driven by changes in METTL3 expression. Collectively, our results suggest that genes associated with TMZ resistance are stabilized by m6A methylation even as the majority of the transcriptome remains subject to m6A-mediated mRNA decay. Moreover, these data highlight METTL3 inhibition as a promising therapeutic approach to overcoming TMZ resistance in GBM.

DOI: https://doi.org/10.1093/narcan/zcag027
Adv Sci (Weinh). 2026 Sep 29. e78046

AARS2-SIRT5-Driven DLD K445 Lactylation Promotes Cuproptosis Resistance in Glioblastoma Stem Cells.

Mingtian Ding, Haibiao Xu, Cen Liu, Yangyin Ding, Shuai Wang, Jun Yin, Tao Fu, Xiao Jiang, Yuning Chen, Hui Luo, Rui Li, Zhengxin Chen, Huibo Wang.

  Therapy-resistant glioblastoma stem cells (GSCs) drive tumor progression and recurrence in glioblastoma (GBM). Cuproptosis is a copper-dependent form of regulated cell death triggered by aggregation of lipoylated mitochondrial proteins, but the mechanisms underlying cuproptosis resistance in GSCs remain unclear. Lactylome profiling identifies dihydrolipoamide dehydrogenase (DLD) as a key lactylation target regulating cuproptosis. Mechanistically, lactate-dependent alanyl-tRNA synthetase 2 (AARS2) catalyzes DLD K445 lactylation, while SIRT5 reverses this modification via NAD+-dependent delactylation. DLD K445 lactylation does not disrupt pyruvate dehydrogenase (PDH) complex assembly or DLD stability, but suppresses PDH activity and DLAT lipoylation, limiting copper-triggered DLAT aggregation and cuproptosis. Genetic disruption of DLD K445 lactylation restores DLAT lipoylation and sensitizes GSCs to elesclomol-copper (ES-Cu). Inhibiting lactate metabolism, activating SIRT5, or a cell-penetrating peptide targeting DLD K445 all boost ES-Cu efficacy in patient-derived glioblastoma organoids and intracranial xenografts. Our work establishes DLD K445 lactylation as a metabolic driver of cuproptosis resistance and validates the AARS2-DLD-SIRT5 axis as a druggable therapeutic target for GBM.

Keywords:  cuproptosis; glioblastoma stem cells; lactylation

DOI:  https://doi.org/10.1002/advs.78046
Oncogene. 2026 Sep 28.

SPTLC2-driven sphingolipid reprogramming of neutrophils impairs anti-tumour immunity and drives liver cancer progression.

Zhe Yang, Yun Wang, Jianhao Li, Zishuo Wang, Jianan Chen, Ding Zhang, Guorui Zhao, Liwen Liu, Zhibo Liu, Ning Wang, Ranran Sun.

Liver cancer exhibits limited and heterogeneous responses to immune checkpoint blockade, underscoring the need to elucidate tumour microenvironmental mechanisms sustaining immune dysfunction. Here, we integrated single-cell transcriptomic annotation with BayesPrism deconvolution across multiple bulk cohorts and combined these analyses with in vivo liver cancer models, functional assays, and mechanistic investigations to define tumour-associated neutrophil (TAN) programmes linked to clinical outcome. We identified a neutrophil subset characterized by elevated sphingolipid metabolism as the predominant poor-prognosis signature, with SPTLC2 serving as the key molecular marker. High SPTLC2 expression defining this sphingolipid metabolism-high neutrophil population correlated significantly with advanced disease stage, inferior overall survival, and increased tumour infiltration. Tumour cell co-culture induced SPTLC2 upregulation and enhanced sphingolipid metabolic activity in neutrophils. Functional assays verified that myriocin, an SPTLC2 inhibitor, suppressed the proliferation and metastasis of Liver cancer cells and remodelled the antitumour immune function of neutrophils. Myriocin attenuated neutrophil sphingolipid metabolism and restored ROS production and neutrophil extracellular trap (NETosis) formation, revealing a critical regulatory role for sphingolipid metabolism in neutrophil-mediated innate immunity, as corroborated by single-cell analyses showing impaired innate immune function in sphingolipid metabolism-high neutrophils. Mechanistically, we uncovered an SPTLC2-dependent sphingolipid-lipid raft checkpoint that remodels plasma membrane microdomains to constrain neutrophil anti-tumour effector functions. Specifically, myriocin restored NOX2-dependent ROS generation by reducing ceramide accumulation in lipid rafts, thereby facilitating p47phox-p22phox interaction and productive NOX2 complex assembly in tumour-conditioned neutrophils. Collectively, these findings reveal a previously unrecognized immunometabolic axis governing TAN dysfunction in liver cancer, establish SPTLC2 as a rational combinatorial target for cancer immunotherapy, and highlight the therapeutic potential of targeting sphingolipid metabolism to restore neutrophil-mediated antitumour immunity and restrain hepatocellular carcinoma progression.

DOI: https://doi.org/10.1038/s41388-026-03996-2
Oncol Rep. 2026 Nov;pii: 198. [Epub ahead of print]56(5):

Targeting the DNHD1‑HDAC6 axis inactivates prostate cancer cell aggressiveness in vitro, suggesting potential therapeutic vulnerability.

An Ni Lee, Chia Chang Wu, Su Wei Hu, Chih Heng Chen, Yi Te Chiang, Wei Tang Kao, Kai Yi Tzou, Chia Hung Liu, Shao Wei Dong, Yu Ting Wang, Yueh Lin Lee, Siou Bi Li, Che An Wu, Chiao Chun Liao, Ming Hsien Chan, Po Han Chiu, Chien Hsiu Li.

  Prostate cancer progression toward an aggressive, therapy‑resistant disease state remains a major clinical challenge, indicating a need to identify novel molecular drivers of such progression and actionable therapeutic targets. The present study analyzed the role of dynein heavy chain domain 1 (DNHD1), a previously uncharacterized regulator of malignancy, in prostate cancer. Integrative transcriptomic analyses across The Cancer Genome Atlas and independent clinical cohorts revealed that DNHD1 is markedly upregulated in advanced‑stage prostate cancer and positively correlated with increasing Gleason scores. Elevated DNHD1 expression was associated with poor overall survival and disease‑free survival, which supports its clinical relevance as a prognostic biomarker. Functional analyses demonstrated that DNHD1 promoted tumor cell proliferation, colony formation, migration and invasion in vitro. Molecular correlation modeling and pathway analyses revealed histone deacetylase 6 (HDAC6) as a key downstream effector of DNHD1. DNHD1 expression was positively correlated with and regulated HDAC6 expression in clinical datasets. Gain‑of‑function and loss‑of‑function experiments further revealed that HDAC6 is required for DNHD1‑mediated oncogenic phenotypes in prostate cancer, positioning HDAC6 as a functional mediator downstream of DNHD1. The DNHD1‑HDAC6 axis was associated with cilium assembly‑related pathways, suggesting a previously unrecognized association between ciliary regulation and prostate cancer progression. HDAC6 inhibition with tubastatin A effectively suppressed DNHD1‑driven tumor growth and motility, as well as increased acetylated α‑tubulin and decreased androgen receptor signaling. These findings indicated a potential therapeutic vulnerability within the DNHD1‑HDAC6 axis. They implied that in prostate cancer, the DNHD1‑HDAC6 axis, a novel regulatory pathway, promotes aggressiveness and that HDAC6 is a targetable mediator of DNHD1‑driven malignancy. This axis can be considered a prognostic indicator and mechanistic foundation for developing targeted therapeutic strategies for advanced prostate cancer.

Keywords:  bioinformatic; dynein heavy chain domain 1; histone deacetylase 6; prognosis; prostate cancer

DOI:  https://doi.org/10.3892/or.2026.9204
Nature. 2026 Sep 30.

A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.

Alessandra Esposito, Ibrahim Bayramoglu, Chiara Varriale, Maria Pia Cavaliere, Maria Elsa Brunetti, Rossella Agostinis, Rachel M Jansen, Dan A Tudorica, Yongjia Duan, Martina Spacci, Alessia Calcagnì, Carolin D Strobl, Verena Passerini, Fabrizio Andreone, Jlenia Monfregola, Julia Richter, Francesca Sacco, Wolfram Klapper, Oliver Weigert, Andrea Ballabio, Roberto Zoncu, James H Hurley, Joern Dengjel, Gennaro Napolitano.

Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs1,2. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene3. Yet how FLCN:FNIP activity is regulated has remained unclear. Here we identify a nutrient-independent lysosomal signalling pathway that regulates FLCN through v-ATPase-driven recruitment of TBK1 or ULK1 (TBK1/ULK1) to lysosomes, via the TAX1BP1 adaptor. This enables TBK1/ULK1-mediated FNIP1 phosphorylation at S296, resulting in inhibition of FLCN and nuclear translocation of TFEB. Recurrent ATP6V1B2 v-ATPase mutations, found in patients with follicular lymphoma, constitutively activate this pathway, leading to hyperactivation of TFEB and follicular lymphoma proliferation. Our work uncovers a lysosomal signalling pathway that is critical for lysosomal adaptation and tumorigenesis.

DOI: https://doi.org/10.1038/s41586-026-11093-3
Cancer Res. 2026 Sep 29.

MYC-Dependent rRNA Catabolism Stress Dictates Survival Heterogeneity of Hepatocellular Carcinoma Cells Under Glutamine Deprivation.

Zeyu Yan, Dan Wu, Jingyun Wu, Caiyu Shi, Mengmeng Feng, Yu Li, Gang Wang, Xinwei Liu, Jibin Li, Guoqing Qi, Xianli He, Tingting Ren, Jinliang Xing.

Tumor cells commonly exhibit a preferential uptake of glutamine to support the heightened metabolic demands. However, the therapeutic potential of targeting glutamine metabolism is severely limited by the heterogeneous responses of cancer cells to glutamine deprivation. In this study, we identified a ribophagy-adenosine-MYC positive feedback loop that was activated and determined cell fate under glutamine deprivation. In sensitive cells, highly expressed MYC acted as a scaffold to recruit Unc-51 like autophagy activating kinase 1, which phosphorylated ribosomal protein L12 to initiate ribophagy. This process drove extensive rRNA catabolism and a burst of reactive oxygen species, ultimately leading to cell death. Moreover, adenosine generated during this cascade enhanced MYC expression via its 3'-UTR region, locking the loop into a self-reinforcing hyperactivated state. In contrast, tolerant cells exhibited lower MYC expression, which constrained the loop to a low-activity and subcritical steady state, thereby enabling survival under glutamine deprivation. Consequently, MYC-high tumors were vulnerable to glutaminase inhibition alone (CB-839), while MYC-low tumors required combination therapy with CB-839 and a pro-oxidant (elesclomol) to achieve tumor eradication. This study establishes MYC expression as a key determinant of sensitivity to glutamine deprivation, reveals the central role of ribophagy within the glutamine deprivation-triggered positive feedback loop, and uncovers a non-canonical, scaffold-like function of MYC in rRNA catabolism. These findings highlight a potential combination strategy to overcome a major bottleneck in targeting glutamine metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0575
Mol Cancer Res. 2026 Sep 30.

Immunometabolic effects of oral testosterone for castration-resistant prostate cancer in the ACROBAT trial.

Sarah Zipkowitz, Karli Redinger, Sheila Jonnatan, Varsha Vakkala, Jiayun Lu, Kathleen Schultz, Irina Rifkind, Amber Michalik, Serina King, Keith McIntyre, Victoria Sinibaldi, Mark C Markowski, Catherine H Marshall, Channing J Paller, Hao Wang, Shifeng S Mao, Samuel R Denmeade, David E Sanin, Elizabeth A Thompson, Laura A Sena.

High-dose testosterone is an emerging treatment option for selected patients with castration-resistant prostate cancer (CRPC), but its efficacy is limited by frequent primary and acquired resistance. Preclinical studies suggest that high-dose testosterone induces tumor metabolic reprogramming that promotes resistance, however clinical validation is lacking. In the prospective ACROBAT trial, we performed longitudinal plasma metabolomic profiling and high-dimensional immune cell phenotyping of 10 patients with CRPC treated with high-dose oral testosterone undecanoate. Testosterone exposure increased circulating metabolites within the arginine-ornithine-polyamine axis, including guanidoacetic acid, creatine, homoarginine, and N1-acetylspermidine. Notably, non-responders exhibited elevated levels of circulating polyamines, including putrescine. Although we observed no significant changes in circulating immune cell subset frequencies, integrative analyses revealed positive associations between polyamine-related metabolites and immunosuppressive myeloid populations, including monocytic myeloid-derived suppressor cells. Collectively, these data provide clinical evidence that high-dose testosterone therapy increases polyamine synthesis from arginine, which is associated with therapy resistance and abundance of immunosuppressive myeloid cells. Implications: High-dose testosterone treatment of patients with castration-resistant prostate cancer enrolled on the ACROBAT trial increased circulating polyamines, which were associated with non-response to treatment and greater abundance of circulating immunosuppressive myeloid cells.

DOI: https://doi.org/10.1158/1541-7786.MCR-26-0573
Blood Cancer J. 2026 Aug 11. pii: 169. [Epub ahead of print]16(1):

A myeloid-dormant metabolic transcriptome identifies a poor-prognosis subgroup in hyperdiploid multiple myeloma with targetable vulnerabilities.

Naroa Barrena, Edurne San José-Enériz, Luis V Valcárcel, Danel Olaverri-Mendizabal, Estibaliz Urizar-Compains, Leire Garate, Estíbaliz Miranda, Paula Rodriguez-Marquez, Romika Kumari, Patxi San Martín-Uriz, Juan Roberto Rodriguez-Madoz, Leonor Puchades-Carrasco, Caroline A Heckman, Paula Rodriguez-Otero, Francisco J Planes, Xabier Agirre, Felipe Prósper.

Aberrant metabolism, a hallmark of cancer, reveals vulnerabilities across human tumors. Here, we demonstrate that transcriptomic alterations of metabolism-related genes (metabolic transcriptome) in multiple myeloma (MM), classify patients into six metabolic-transcriptional groups characterized by specific metabolic pathways and cytogenetic alterations, independent of currently described myeloma risk groups. Interestingly, hyperdiploid patients clustered into 2 groups (MM5 and MM6) with significantly distinct Progression-Free and Overall Survival. The MM5 group, with worse prognosis, showed a significant enrichment in myeloid and dormant cell signatures. Regulon analysis identified myeloid transcription factors (TFs) as regulators of metabolic, myeloid, and dormant genes in MM5. In addition to myeloid genes acting as potential biomarkers and therapeutic targets, the metabolic gene ACSL1 plays a crucial role in MM5, decreasing cell proliferation by affecting metabolism and mitochondrial function, sensitizing MM to BCL-2 family inhibitors. These findings highlight ACSL1 as a promising therapeutic target for MM5 and provide new insights into MM metabolic heterogeneity that may guide future precision medicine strategies.

DOI: https://doi.org/10.1038/s41408-026-01604-w
Nat Commun. 2026 Aug 26. pii: 10240. [Epub ahead of print]17(1):

Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance.

Jianyong Liu, Qing-Li He, Jianya Zhou, Ajay M Vaghasia, Roshan Chikarmane, Glenn Hauk, Archana Rachakonda, Nicole Castagna, Ruchama C Steinberg, Minh-Tam Pham, Jordan M Gregg, Alok Mishra, Yuhan Yang, Talha Anwar, Roy Elias, Pengshan Li, Jasmine Yun-Tong Kung, Anthony C O'Donnell, Nicole M Anders, Teresia M Wanjiku, Philipp Nuhn, Joong Sup Shim, Hugh Giovinazzo, David M Esopi, Kunhwa Kim, Jonathan Coulter, Rulin Wang, Jianying Zhou, Michelle A Rudek, Kathleen Gabrielson, Angelo M De Marzo, James M Berger, Jun O Liu, William G Nelson, Srinivasan Yegnasubramanian.

Abnormal DNA hypermethylation mediated by DNA methyltransferases (DNMT) is a nearly universal hallmark of human cancers. However, while DNA methyltransferase inhibitors (DNMTi) such as decitabine and azacitidine are effective in treating myelodysplatic syndrome/leukemia, they have had limited utility for the majority of other cancers. Through a chemical library screen, we identify that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, and multiple of its analogs, significantly augment the epigenetic and anti-cancer effects of decitabine in vitro and in vivo. These effects are attributable to inhibition of DCTPP1-mediated cleavage of 5-aza-deoxycytidine triphosphate, the convergent activated metabolite of nucleoside DNMTi, leading to enhanced drug incorporation into genomic DNA, increased DNMT degradation, enhanced DNA demethylation and associated transcriptional reprogramming. We show that high DCTPP1 expression mediates cell-intrinsic resistance to nucleoside DNMTi, and that triptolide and its analogs could overcome this resistance. These findings nominate combining DNMTi with triptolide or its analogs as a rational cancer therapeutic strategy.

DOI: https://doi.org/10.1038/s41467-026-76852-2