bims-meract 2026-05-17 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–05–17
nine papers selected by
Andrea Morandi, Università degli Studi di Firenze

Normoxic HIFα-mediated metabolic rewiring in cancer as a novel therapeutic target of tumor heterogeneity.
ACSS2 drives Lenvatinib resistance in hepatocellular carcinoma through palmitoylation.
MYO1G Facilitates Caveolin-1-Mediated Endocytosis of the N-Terminal Fragments of Gasdermin E to Restrain Pyroptosis and Chemotherapy Efficacy.
ENO1 lactylation drives bevacizumab resistance through metabolic reprogramming and angiogenesis in ovarian cancer.
Dual targeting of chemoresistance and ferroptosis in gastric cancer: DDR1/VEGFR2 inhibitor K-13 synergizes with docetaxel from preclinical models to phase Ib/II clinical trial.
Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells.
Targeting UXS1-Dependent Glucuronate Detoxification Potentiates Metformin's Anti-Tumor Efficacy in Lung Adenocarcinoma.
Targeting PRMT9 Overcomes Venetoclax Resistance in AML by Modulating Splicing and Inhibiting Translation.
Cannabinoid CB2 receptor drives trastuzumab resistance and predicts durable anti-HER2 response.

Cancer Metab. 2026 May 12. pii: 12. [Epub ahead of print]14(1):

Normoxic HIFα-mediated metabolic rewiring in cancer as a novel therapeutic target of tumor heterogeneity.

Anaís Sánchez-Castillo, Jairo G E Lommen, Denise Consten, Kim Savelkouls, Lydie M O Barbeau, Kasper M A Rouschop, Marc A Vooijs, Kim R Kampen.

   BACKGROUND: Hypoxia-inducible factors (HIF1α, HIF2α) influence radiotherapy responses in non-small cell lung cancer (NSCLC) and glioblastoma (GBM), tumors characterized by oxygen and HIF expression heterogeneity. As the function of HIFs in normoxic metabolic function remained unexplored, we investigated how loss of HIF1α or HIF2α affects metabolism, redox homeostasis, and radiotherapy sensitivity in normoxia, aiming to identify opportunities for combined metabolic inhibition.
METHODS: NSCLC HIF1α or HIF2α knockout (KO) and HIFα wildtype (WT) models were analyzed using 13C-glucose mass spectrometry tracing before and after radiotherapy treatment. Metabolic phenotypes were validated using serine/glycine (ser/gly) synthesis enzyme expression by immunoblot and quantitative PCR, redox by ROS flow cytometry analysis, and DNA methylation by 5mC dot-blot assessment. Pharmacological inhibition of ser/gly metabolism was performed in both NSCLC and GBM models using the repurposed serine-glycine conversion inhibitor sertraline using incucyte confluency monitoring.
RESULTS: Both HIF1α and HIF2α KO cells displayed reduced glycolysis and compensatory ser/gly pathway hyperactivation. HIF1α KO cells channeled ser/gly into nucleotide (particularly TTP) synthesis and glutathione (GSH)-mediated antioxidant defense, conferring radiotherapy resistance. In contrast, HIF2α KO cells preferentially used serine for α-ketoglutarate (α-KG) production, the enhanced NADH/methionine-dependent redox system and the methionine cycle to support enhanced DNA methylation. Subsequently, following irradiation, only the radiation resistant HIF1α KO cells further enhanced ser/gly metabolism, increasing AMP/ATP and GSH/GSSG (oxidized GSH) ratios, whereas HIF2α KO cells failed to adapt and accumulated oxidative stress. HIF1α KO cells were more sensitive to pharmacological inhibition of ser/gly metabolism by sertraline, particularly in combination with irradiation, which abrogated their radioresistant phenotype in both NSCLC and GBM models.
CONCLUSIONS: HIF1α-deficient cells rely on ser/gly synthesis for nucleotide production and antioxidant defense, promoting radiotherapy resistance while creating vulnerability to sertraline plus irradiation. HIF2α-deficient cells favor α-KG production and methionine-driven alternative redox and methylation pathways. Targeting ser/gly synthesis may overcome HIF-gradient-dependent radiotherapy resistance.

Keywords:  Cancer metabolism; Hypoxia inducible factors; Tumor heterogeneity

DOI:  https://doi.org/10.1186/s40170-026-00433-6
Pharmacol Res. 2026 May 14. pii: S1043-6618(26)00163-5. [Epub ahead of print]229 108248

ACSS2 drives Lenvatinib resistance in hepatocellular carcinoma through palmitoylation.

Hao Xu, Hao Wang, Shi-Zhe Yu, Tian-Tian Zou, Sun-Zhe Xie, Ke-Yu Shen, Chen Zhang, Jian-Feng Xu, Jun-Jie Pan, SamI Yang, Da Xu, Ji-Song Chen, Jing Zhao, Fang Xie, Ying-Han Su, Wen-Wei Zhu, Lun-Xiu Qin.

  Lenvatinib, a first-line tyrosine kinase inhibitor for advanced hepatocellular carcinoma (HCC), faces clinical challenges due to acquired drug resistance. While metabolic reprogramming has been implicated in therapeutic resistance, the precise mechanistic links remain elusive. Here, we identified ACSS2-mediated metabolic-epigenetic crosstalk as a critical driver of Lenvatinib resistance. Transcriptomic and metabolomic profiling identified enhanced pyruvate metabolism in resistant HCC cells, with ACSS2 expression showing the strongest association with Lenvatinib resistance. Genetic manipulation experiments demonstrated that ACSS2 dictates therapeutic sensitivity, with knockdown restoring drug response and overexpression conferring resistance. Mechanistically, ACSS2-driven palmitate biosynthesis facilitates EGFR palmitoylation, which shields the receptor from ubiquitin-dependent degradation. This stabilization sustains oncogenic EGFR signaling, ultimately mediating therapeutic escape. Crucially, pharmacological inhibition of ACSS2 synergized with Lenvatinib to overcome resistance in both subcutaneous and hydrodynamic transfection HCC models. Our findings not only delineate the ACSS2/EGFR axis as a metabolic vulnerability in resistant HCC but also propose ACSS2-targeted therapy as a promising strategy to reverse Lenvatinib resistance, providing a novel therapeutic approach for advanced HCC management.

Keywords:  Hepatocellular carcinoma; Lenvatinib resistance; Palmitoylation; Tumor metabolism

DOI:  https://doi.org/10.1016/j.phrs.2026.108248
Cancer Res. 2026 May 14.

MYO1G Facilitates Caveolin-1-Mediated Endocytosis of the N-Terminal Fragments of Gasdermin E to Restrain Pyroptosis and Chemotherapy Efficacy.

Cong Ding, Jiawei Wu, Zhimin Xu, Chuqing Zhang, Chunxian Ou, Weipeng Chen, Hanmiao Wei, Zhenji Deng, Zhe Li, Liufen Long, Yanping Mao, Jun Ma, Xiaoyu Liang.

The N-terminal fragments of gasdermin (GSDM-NTs) form pores on the plasma membrane that initiate pyroptosis. However, the presence of GSDM-NT pores does not necessarily result in cell death, allowing some cells to survive GSDM-mediated pyroptosis. Understanding the regulators of response to the formation of GSDM-NT pores is crucial for revealing the strategies to harness the potential of pyroptosis for treating cancer. Here, we found that myosin 1G (MYO1G) enabled cells to resist death driven by membrane rupture. Mechanistically, MYO1G tethered gasdermin E (GSDME) NT pores to caveolin-1 (CAV1), thus facilitating CAV1-mediated endocytosis of pyroptotic pores. Pyroptosis triggered the transcriptional upregulation of MYO1G through stabilization of HIF1α, which resulted from the release of intracellular α-ketoglutarate (α-KG). Moreover, pharmacological inhibition of MYO1G or cholesterol synthesis promoted pyroptosis, boosted antitumor immunity, and synergized with chemotherapy to eradicate tumors. Clinically, MYO1G was validated as an indicator of poor short-term response to cisplatin-based chemotherapy and unfavorable long-term survival in patients with nasopharyngeal carcinoma (NPC). Overall, these findings provide further understanding of a protective mechanism against pyroptosis and identify potential therapeutic targets for cancer treatment.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0786
Drug Resist Updat. 2026 May 07. pii: S1368-7646(26)00064-6. [Epub ahead of print]87 101413

ENO1 lactylation drives bevacizumab resistance through metabolic reprogramming and angiogenesis in ovarian cancer.

Tian Zeng, Qianqian Wang, Lei Li, Xiongjin Tan, Jing He, Yan Liu, Xiaodong Wang, Rongfang He, Gouping Ding, Xinyi Zeng, Xing Tang, Xun Chen, Hao Huang, Yukun Li.

  Bevacizumab, a monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF), is a cornerstone therapy for ovarian cancer (OC). However, acquired resistance to bevacizumab remains a major clinical challenge. Metabolic reprogramming in the tumor microenvironment, particularly lactate-driven lactylation modifications, has been implicated in drug resistance; however, the specific mechanisms underlying bevacizumab resistance are poorly understood. This study identifies Enolase 1 (ENO1) lactylation as a key driver of drug resistance through the integration of lactylation proteomics in patient samples, functional validation in cell lines and in vivo models Patient-Derived Xenograft (PDX), zebrafish, and chicken Chorioallantoic Membrane (CAM)). We observed significantly elevated pan-lactylation in bevacizumab-resistant OC tissues, correlating with enhanced angiogenesis and poor prognosis. Mechanistically, alanyl-tRNA synthetase 1 (AARS1) mediated lactylation of ENO1 at lysine 71 (K71) augmented lactate synthesis and promoted histone lactylation marks (Lysine lactylation of histone H3 at lysine 9 (H3K9la) and Lysine Lactylation of Histone H3 at Lysine 14 (H3K14la)). This epigenetic reprogramming upregulated the transcription of the angiogenic factor Endothelial cell-specific molecule 1 (ESM1), establishing a positive feedback loop for ENO1 expression. Secreted ESM1 stabilized the transcription factor YY1 in endothelial cells by competitively inhibiting Smurf2-mediated ubiquitination, leading to YY1-dependent recruitment of E1A Binding Protein p300 (EP300) and Histone H3 Lysine 27 (H3K27) acetylation at the B-cell lymphoma 2-related protein A1 (BCL2A1) promoter. This cascade enhanced endothelial cell survival and angiogenesis, ultimately fostering resistance to bevacizumab. Our findings reveal a metabolic-epigenetic axis centered on ENO1 K71 lactylation that perpetuates resistance to bevacizumab, highlighting its potential as a therapeutic target to restore bevacizumab efficacy in OC.

Keywords:  Angiogenesis; Bevacizumab resistance; ENO1; Lactylation modification

DOI:  https://doi.org/10.1016/j.drup.2026.101413
Cell Death Differ. 2026 May 13.

Dual targeting of chemoresistance and ferroptosis in gastric cancer: DDR1/VEGFR2 inhibitor K-13 synergizes with docetaxel from preclinical models to phase Ib/II clinical trial.

Gaoshaer Yeerkenbieke, Xiaofan Duan, Yanjun Feng, Weijian Zhou, Mingwang Zhou, Yumei Zhang, Jiuli Zhou, Jin Li.

Chemotherapy remains a cornerstone therapeutic approach for gastric cancer (GC). However, the clinical efficacy of docetaxel is substantially limited by the emergence of drug resistance. Here, we discovered a novel DDR1/VEGFR2 inhibitor, K-13, and further confirmed its selectivity by comprehensive kinase profiling in vitro. Through screening of K-13 in combination with conventional chemotherapeutic agents in GC, we identified a pronounced synergistic effect between K-13 and docetaxel. The combination therapy demonstrated significant antitumor effects in GC cell lines, human GC patient-derived organoids (PDOs), human GC acquired docetaxel-resistant PDOs, subcutaneous xenograft models, and patient-derived xenograft (PDX) models. Mechanistically, K-13 synergized with docetaxel to inhibit Ribonucleotide Reductase M2 (RRM2) to block the AKT/mTOR pathway to reverse resistance and induce ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde accumulation (MDA), and iron overload. These findings were consistently validated across all preclinical models. The translational potential of this strategy is currently being evaluated in an ongoing phase Ib/II clinical trial, and two partial responses (PRs) have already been observed in patients receiving the combination therapy. These findings underscore dual inhibition of DDR1 and VEGFR2 as a promising therapeutic approach to overcome docetaxel resistance in GC. Graphical abstract: Targeting the dual inhibition of DDR1 and VEGFR2 provides a promising therapeutic strategy to overcome docetaxel resistance in GC. The combination potently inhibited tumor growth across cell lines, PDOs, and PDX models by suppressing RRM2 and blocking AKT/mTOR signaling, ultimately inducing ferroptosis. The translational potential of this strategy is being evaluated in an ongoing phase Ib/II clinical trial, and two partial responses (PRs) have already been observed in patients receiving the combination therapy.

DOI: https://doi.org/10.1038/s41418-026-01751-4
J Biol Chem. 2026 May 14. pii: S0021-9258(26)02022-3. [Epub ahead of print] 113150

Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells.

Chengmeng Jin, Siying Zeng, Hao Wu, Xun Hu.

  Intracellular lactic acidosis, a metabolic state newly defined in this study, is characterized by a coupled increase in intracellular lactate and proton concentrations, resulting in higher levels inside cancer cells than outside. This finding expands the Warburg paradigm: lactic acidosis is not merely extracellular but intracellular, reshaping metabolism through direct biochemical mechanisms. Acidic pH and elevated lactate jointly suppress glycolysis by inhibiting HK, PFK1 and GAPDH, enforcing a low-flux, energy-efficient state. Meanwhile, pyruvate enters the TCA cycle through a pyruvate - lactate -export - reimport - lactate - pyruvate cycle that both fuels mitochondrial metabolism and maintains lactic acidosis intracellularly and extracellularly. Lactic acidosis also reprograms anaplerosis by promoting lactate-derived oxaloacetate formation and reducing glutamine dependence. Together, these findings establish lactic acidosis as an active regulator of cancer metabolism, revealing a distinct metabolic state. This coupled lactate-proton state drives coordinated metabolic reprogramming across glycolysis and mitochondrial metabolism. representing a fundamental tumor adaptation that may be exploited to disrupt cancer metabolic resilience.

Keywords:  TCA cycle; Warburg effect; glycolysis; lactic acidosis; tumor microenvironment

DOI:  https://doi.org/10.1016/j.jbc.2026.113150
Adv Sci (Weinh). 2026 May 10. e10542

Targeting UXS1-Dependent Glucuronate Detoxification Potentiates Metformin's Anti-Tumor Efficacy in Lung Adenocarcinoma.

Qihai Sui, Zhencong Chen, Guangyao Shan, Zhengyang Hu, Xing Jin, Jiaqi Liang, Yanjun Yi, Jiacheng Yin, Haochun Shi, Xifei Jiang, Junjie Xi, Zongwu Lin, Cheng Zhan, Fenghao Sun, Wei Jiang.

  Despite the widely reported experimental anti-tumor effects, metformin's role remains exceedingly complex, with contradictory results in clinical trials. Our study, based on metabolomics analysis of lung adenocarcinoma (LUAD) samples, xenografts, and cells, unveils a novel process that metformin promotes the conversion of UDP-glucose (UDPG) to UDP-glucuronic acid (UDPGA) in glucuronic acid metabolism. Mechanistically, metformin activates UDP-glucose 6-dehydrogenase (UGDH) through AMPK-mediated phosphorylation of UGDH(S476), a previously unstudied phosphorylation site, impeding the binding of UDP-Xyl to UGDH and the subsequent allosteric inhibition. Consequently, metformin-treated cells are more reliant on UXS1, a downstream metabolic enzyme of UGDH, for detoxifying UDPGA based on the "kitchen-sink" model. Through comprehensive virtual screening of a compound library, we identified that plantainoside is a potent UXS1-targeting agent. Remarkably, when combined with metformin, plantainoside exhibits a superior synergistic lethal effect in LUAD cells, organoids, xenografts, and spontaneous models. Moreover, this combination not only directly targets tumor cells but also synergistically boosts CD8+ T cells and suppresses the differentiation of macrophages, thereby significantly enhancing immunotherapy efficacy. Collectively, our results shed light on metformin's complicated role by revealing its novel impact on glucuronic acid metabolism and dependence on UXS1; thus, targeting UXS1 combined with metformin represents a highly promising new strategy.

Keywords:  UGDH; UXS1; glucuronic acid metabolism; lung cancer; metformin

DOI:  https://doi.org/10.1002/advs.202510542
Blood. 2026 May 12. pii: blood.2026034144. [Epub ahead of print]

Targeting PRMT9 Overcomes Venetoclax Resistance in AML by Modulating Splicing and Inhibiting Translation.

Yang Li, Xin He, Lei Zhang, Haojie Dong, Xin Wang, Yuan Che, Umesh Prasad Yadav, Meng Liu, Lianjun Zhang, Shuaishuai Ge, Guohua Wu, Yu-Hsuan Fu, Wei Chen, Ya-Huei Kuo, Liang Chen, Guido Marcucci, Shaoyuan Wang, Ling Li.

Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is required for cancer cell proliferation, but whether PRMTs mediate resistance to therapy remains elusive. Here, we have performed loss-of-function screens in venetoclax-resistant (VEN-R) AML patient-derived xenograft (PDX) cells and found that PRMT9 plays a critical role in promoting VEN resistance. Specifically, VEN-R AML samples exhibited high levels of PRMT9, and PRMT9 inhibition re-sensitized the AML cells to VEN treatment. In preclinical resistant models, genetic ablation of PRMT9 synergized with VEN to eradicate AML cells. Consistently, pharmacologic inhibition of PRMT9 combined with VEN yielded similar effects in VEN-R AML mouse models. Mechanistically, PRMT9 ablation disrupted RNA splicing by inducing exon-skipping of mRNA encoding ALG13, an UDP-N-Acetylglucosaminyltransferase subunit, downregulating expression of a VEN-efflux transporter encoded by the adenosine triphosphate binding cassette subfamily C member 1 (ABCC1) gene. PRMT9 inhibition also suppressed protein synthesis, downregulating short-lived oncoproteins, such as MCL1. These findings establish a connection between PRMT9-mediated arginine methylation and poor VEN responsiveness, also demonstrate that targeting PRMT9 may represent a viable strategy to overcome VEN resistance.

DOI: https://doi.org/10.1182/blood.2026034144
Oncogene. 2026 May 11.

Cannabinoid CB2 receptor drives trastuzumab resistance and predicts durable anti-HER2 response.

Marta Seijo-Vila, Sofía A Balsinde, Sandra Blasco-Benito, Isabel Tundidor, María Rubert-Hernández, Ana Montero-Calle, Rodrigo Barderas, Laura E Kilpatrick, Simon Platt, Noemi Karsai, Isabel Philps, Olga M Antón, Déborah Gómez-Domínguez, Ignacio Pérez de Castro, Carmen González-Lois, Diego García-Fresnadillo, Gala Silvestre-Egea, Antonio J Sánchez-López, Esther Ramírez-Medina, María Catalina Rivas Prieto, Belén Almoguera Pérez-Cejuela, Luis Manso, Sandra Zazo, Noemí López-Ejeda, Francisco Palomino-Duque, María Turienzo-Durán, Nuria G Martínez-Illescas, María Salazar-Roa, Sonia Castillo-Lluva, Stephen J Hill, Manuel Guzmán, Eduardo Pérez-Gómez, Cristina Sánchez.

Acquired or innate lack of response to standard HER2-targeted therapies remains a clinical issue in patients with HER2-positive breast cancer. Here, we investigated the role of the cannabinoid CB2 receptor (CB2R) in trastuzumab resistance. In human breast cancer samples, a decreased expression of HER2-CB2R heterodimers following neoadjuvant treatment, due to CB2R downregulation, was linked to poor long-term outcomes. Using various preclinical models, we demonstrate that CB2R drives trastuzumab resistance. Mechanistically, CB2R loss enabled cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB2R to HER2-EGFR heterodimers, thus reducing dependence on HER2 and increasing reliance on EGFR-mediated pathways. Moreover, EGFR inhibition restored trastuzumab sensitivity. In summary, we reveal an unprecedented role for CB2R as a key regulator of oncogenic and immune signaling in response to anti-HER2 therapy and its potential as a predictive biomarker of therapeutic efficacy. We also propose dual HER2/EGFR targeting and non-CB2R-selective cannabinoid therapies as potential strategies to overcome CB2R-mediated trastuzumab resistance. Together, these findings position the endocannabinoid system as a pivotal and actionable node to elucidate, anticipate, and counteract resistance to HER2-targeted therapies.

DOI: https://doi.org/10.1038/s41388-026-03814-9