bims-meract 2026-05-24 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–05–24
seventeen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Targeting Metabolism in Cancer Therapy: Inhibitors and Approaches.
Simvastatin reprograms lipid metabolism in B16.F10 melanoma cells to favor an early resistant phenotype.
Stress granules shape ferroptosis in cancer.
GPX8+ cancer-associated fibroblast-derived lactate contributes to lenvatinib resistance by facilitating BRPF1 expression through histone H3 lysine 18 lactylation in hepatocellular carcinoma.
ZDHHC14-driven RUNX2 S-palmitoylation attenuates ferroptosis and enhances chemoresistance in ovarian cancer via the YAP1/GLS1 axis.
Targeting ATP13A4-polyamine homeostasis axis to improve radiosensitivity of lung adenocarcinoma.
Redox regulation of EGFR activation by thioredoxin reductase 3 drives resistance to EGFR inhibitors in triple-negative breast cancer.
ER-phagy drives resistance to mitochondria-targeted therapy in breast cancer.
FASN for diffuse malignant peritoneal mesothelioma: a prognostic biomarker after CRS+HIPEC and a therapeutic target.
Mitochondria-targeted metformin analogs activate the ER stress-unfolded protein response pathway to drive apoptosis in pancreatic cancer.
ICAM2 promotes endocrine resistance via dynein-mediated OXPHOS activation in ER-positive breast cancer.
Extracellular vesicles from chemotherapy-induced senescent tumor cells reprogram hepatic phospholipid metabolism to promote pancreatic cancer liver metastasis.
Ketogenic Diet Prevents Obesity-Associated Pancreatic Cancer Independent of Weight Loss and Induces Pancreatic Metabolic Reprogramming.
CRL4AMBRA1-mediated progesterone receptor degradation drives progestin resistance and represents a therapeutic vulnerability in endometrial cancer.
Convergent targeting of FUNDC1-dependent mitophagy sensitises and overcomes resistance to EGFR inhibition.
Targeting AKR1C1 overcomes lenvatinib resistance in hepatocellular carcinoma through the STAT3-ABC transporters pathway.
Hypoxia-driven lncRNA SHIELD promotes GPX4 translation and protects against ferroptosis in hepatocellular carcinoma.

Cancer Treat Res. 2026 ;195 175-191

Targeting Metabolism in Cancer Therapy: Inhibitors and Approaches.

Bhabani Shankar Nayak, Bangmayee Dash, Sisir Nandi, Nebojša Pavlović, Mohamed Dkhi.

  Cancer cells show different abnormal metabolic pathways that promote their development and viability. A novel therapeutic strategy has emerged for the treatment of cancer by inhibiting major metabolic pathways, such as the glycolysis pathway, pentose phosphate pathway (PPP), fatty acid synthesis, glutaminase inhibitors, and metabolism associated with mitochondrial pathways. Metabolic reprogramming supports the formation of tumors and metabolic liabilities, which are used to treat various cancers. Metabolic research on cancer metabolism was based on Otto Warburg's research work, which is related to aerobic glycolysis. In combination with chemotherapies, the reprogramming of cancer metabolism has been efficacious in treating neoplastic cells. The success of the novel treatment demonstrates an emerging therapeutic approach towards cancer and its management, some of which are being examined in preclinical models. A number of metabolic molecules have been used to target the progression of preclinical observation, which are associated with nucleic acid synthesis and other major biochemical processes. With the advancement of multi-omics, single-cell, and other spatial technologies, we can easily track metabolism more accurately.

Keywords:  Cancer metabolism; Glutaminase inhibitors; Glycolytic inhibitors; Mitochondrial inhibitors; PPP inhibitors

DOI:  https://doi.org/10.1007/978-3-032-21861-2_9
Sci Rep. 2026 May 21.

Simvastatin reprograms lipid metabolism in B16.F10 melanoma cells to favor an early resistant phenotype.

Giorgiana-Gabriela Negrea, Loredana Balacescu, Ilie Ovidiu Pavel, Alina Sesarman, Manuela Banciu.

  Our previous studies demonstrated that simvastatin (SIM) inhibited B16.F10 murine melanoma cell proliferation in vivo and in vitro via strong suppressing the production of subunit α of hypoxia inducible factor 1 (HIF-1) (HIF-1 α)-a key regulator of cancer cell adaptation to hypoxia. However, beyond its known role in hypoxia, normoxic expression of HIF-1α in melanoma has been linked to increased cancer cell aggressiveness, underscoring its broader impact on tumor biology. Since the translation of HIF-1α is modulated by Akt, SIM effects on both regulatory factors in relation to cancer cell metabolism under normoxia were investigated. SIM- induced metabolic changes were analyzed at mRNA and at protein level. Our data suggested that SIM reprogrammed glucose metabolism to ensure replenishment of the tricarboxylic acid (TCA) cycle, favoring its biosynthetic role over its energy role. This shift supported lipid-derived signaling molecules synthesis including isoprenoids and prostaglandins, favoring traits associated with cell survival and drug tolerance. Additional validation in human A375 melanoma cells demonstrated comparable antiproliferative effects of SIM, while in silico cross-species transcriptomic analysis revealed shared suppression of cell-cycle-related programs together with context-dependent metabolic responses. Our results have important clinical implications, as they emphasize the potential of targeting key lipid metabolic pathways to overcome the adaptive mechanisms associated with normoxic HIF-1α expression. Thus, our data offer promise for novel combination therapies which disrupt the metabolic plasticity of melanoma, to ultimately improve therapeutic outcomes.

Keywords:  Metabolism; Normoxia; Resistance; Statins; Unsaturated fatty acids

DOI:  https://doi.org/10.1038/s41598-026-52873-1
Nat Cell Biol. 2026 May 22.

Stress granules shape ferroptosis in cancer.

Maria Livia Sassano, Patrizia Agostinis.

DOI: https://doi.org/10.1038/s41556-026-01950-8
Oncogene. 2026 May 22.

GPX8+ cancer-associated fibroblast-derived lactate contributes to lenvatinib resistance by facilitating BRPF1 expression through histone H3 lysine 18 lactylation in hepatocellular carcinoma.

Qinsi Wan, Jie Li, Mengzhou Guo, Jiahao Hu, Liangliang Bai, Meixia Zhang, Bimin Li, Yuan Fang, Xiaojing Du, Xingxing Zhang, Li Song, Sinuo Chen, Zhuoran Qi, Jinglin Xia, Bei Lv, Mingyan He.

Cancer-associated fibroblasts (CAFs) are necessary constituents of the tumor microenvironment, significantly promoting cancer cell proliferation, invasion, and therapeutic resistance through the secretion of various factors. This study elucidates a novel metabolic-epigenetic mechanism by which glutathione peroxidase 8-positive (GPX8⁺) CAFs confer lenvatinib resistance in hepatocellular carcinoma (HCC). We demonstrate that GPX8 overexpression in CAFs activates the PI3K/AKT/mTOR signaling pathway by suppressing endoplasmic reticulum stress, driving glycolytic reprogramming and lactate production. HCC cells import this CAF-derived lactate via monocarboxylate transporter 1 (MCT1), elevating histone H3 lysine 18 lactylation (H3K18la) levels. Increased H3K18la enrichment at the promoter of bromodomain and PHD finger-containing protein 1 (BRPF1) transcriptionally upregulates BRPF1 expression. Furthermore, we found that BRPF1 mediates lenvatinib resistance in HCC by promoting H3K14ac and inducing activation of the EGFR pathway. Pharmacological inhibition of MCT1 (AZD3965) or BRPF1 (GSK5959), effectively reversed lenvatinib resistance in vitro and in vivo. These findings establish the GPX8⁺ CAF/lactate/MCT1/H3K18la/BRPF1/EGFR axis as a pivotal driver of lenvatinib resistance and identify MCT1 and BRPF1 as actionable therapeutic targets for overcoming resistance in HCC.

DOI: https://doi.org/10.1038/s41388-026-03711-1
Apoptosis. 2026 05 18. pii: 146. [Epub ahead of print]31(6):

ZDHHC14-driven RUNX2 S-palmitoylation attenuates ferroptosis and enhances chemoresistance in ovarian cancer via the YAP1/GLS1 axis.

Tao Li, Bin Lv, Hai Lin, Hong Zhang, Yingchun Wan.

  Chemoresistance and ferroptosis inhibition in ovarian cancer (OC) may contribute to tumor progression. This study aimed to investigate the role of RUNX2 in regulating ferroptosis and cisplatin (CDDP) resistance in OC, along with its post-translational modification mechanisms. Parental and CDDP-resistant OC cell lines, as well as xenograft models in nude mice, were employed to explore the molecular functions of RUNX2. Cellular function and drug resistance were assessed using cell counting kit-8, colony formation, and flow cytometry. Ferroptosis activity was evaluated by measuring protein markers (FTH1, GPX4, and ASCL4), reactive oxygen species, Fe2+, GSH/GSSG, malondialdehyde, and lipid peroxidation levels. The palmitoylation of RUNX2 were assessed using acyl-biotin exchange, Click-iT pull-down, and palmitoyl acyltransferase assays. Based on the predicted sites, Flag-RUNX2 wild-type and mutant vectors were constructed, and Myc-ZDHHC14 was exogenously introduced to examine ZDHHC14-mediated RUNX2 palmitoylation. The results indicated that RUNX2 significantly suppressed ferroptosis and enhanced CDDP resistance in OC both in vitro and in vivo. Downstream, RUNX2 transcriptionally regulated YAP1 and activated the YAP1/GLS1 axis. Additionally, palmitoylation of RUNX2 was observed in OC cells. Bioinformatics analysis predicted the binding of RUNX2 with palmitoyltransferase ZDHHC14. Exogenous induction of Myc-ZDHHC14 drove RUNX2 palmitoylation, an effect that was abolished by the RUNX2-C13S mutation. Further in vitro and in vivo experiments confirmed that ZDHHC14-driven palmitoylation of RUNX2-C13S inhibited ferroptosis and chemosensitivity in OC by activating the YAP1/GLS1 axis. To conclude, ZDHHC14-driven S-palmitoylation of RUNX2 inhibits ferroptosis and CDDP sensitivity in OC by positively regulating the YAP1/GLS1 axis.

Keywords:  Chemoresistance; Ferroptosis; Ovarian cancer; Palmitoylation; RUNX2; ZDHHC14

DOI:  https://doi.org/10.1007/s10495-026-02349-4
Int J Biol Macromol. 2026 May 19. pii: S0141-8130(26)02489-X. [Epub ahead of print]367 152562

Targeting ATP13A4-polyamine homeostasis axis to improve radiosensitivity of lung adenocarcinoma.

Aoyun Yan, Xiaoyan Han, Shijia Wang, Shangkun Xu, Renyi Jiang, Liming Zhu, Yumeng Huang, Ye Zhao, Juan Wang, Xuanyu Wang, Ni Chen.

  The radioresistance of lung adenocarcinoma poses a major challenge to radiotherapy efficacy, yet its underlying mechanisms remain poorly defined. ATP13A4, a member of the P5B-type ATPase family, plays an important role in brain function and neurodevelopmental disorders. While recent studies have highlighted its role in breast cancer, its function in lung adenocarcinoma remains unclear. Our bioinformatics analysis revealed that ATP13A4 expression declines with disease progression in lung adenocarcinoma tissues, correlating with unfavorable patient prognosis. Overexpression of ATP13A4 suppressed tumor growth, cell invasion, migration, and epithelial-mesenchymal transition. Notably, ATP13A4 overexpression markedly sensitized lung adenocarcinoma cells to radiation. Mechanistically, we found that ATP13A4 disrupted polyamine homeostasis. Its overexpression increased the overall polyamine pool size while concurrently accelerating the turnover of spermidine and spermine. This metabolic reprogramming ultimately enhanced the cell's sensitivity to ferroptosis, leading to a significant increase in cell death after X-ray irradiation. Our findings unveiled ATP13A4 as a key metabolic regulator in lung adenocarcinoma and proposed targeting the polyamine-ferroptosis axis as a promising strategy to improve radiosensitivity.

Keywords:  ATP13A4; Ferroptosis; Metabolic reprogramming; Polyamines; Radiosensitivity

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152562
Cell Death Discov. 2026 May 19.

Redox regulation of EGFR activation by thioredoxin reductase 3 drives resistance to EGFR inhibitors in triple-negative breast cancer.

Prahlad V Raninga, Göknur Giner, Sivanandhini Sankarasubramanian, Murugan Kalimutho, Marco J Herold, Antoine de Weck, Kum Kum Khanna.

Although 40-70% of TNBC cases overexpress EGFR, clinical responses to EGFR-targeted therapies have been minimal. This poor efficacy may result from intrinsic resistance mechanisms, inactive EGFR signaling, or reduced EGFR localization on the plasma membrane. To identify genetic determinants of EGFR inhibitor resistance, we performed a genome-wide CRISPR/Cas9 knockout screen in MDA-MB-231 cells. The screen revealed that loss of the redox-regulating enzyme Thioredoxin Reductase 3 (TXNRD3) sensitized TNBC cells to the EGFR inhibitor erlotinib. Functional validation showed that both siRNA-induced knockdown and pharmacological inhibition of TXNRD3 with the FDA-approved drug auranofin significantly enhanced the cytotoxic effects of EGFR inhibitors in EGFR-high TNBC cells. Mechanistically, TXNRD3 depletion or inhibition increased intracellular reactive oxygen species (ROS), leading to oxidation-dependent activation and phosphorylation of EGFR (Y1068) and subsequent activation of downstream signaling pathways in TNBC cells that otherwise lack active EGFR. The combined treatment of auranofin and EGFR inhibitors triggered GSDME-mediated pyroptosis in a ROS-dependent manner. Importantly, the combination of auranofin with erlotinib exhibited potent anti-tumor efficacy in vivo in both MDA-MB-231 xenograft and 4T1.2 syngeneic TNBC models. Collectively, our findings identify TXNRD3 as a redox-dependent regulator of EGFR activity and drug response in TNBC and demonstrate that auranofin-mediated TXNRD3 inhibition can re-activate EGFR signaling, thereby sensitizing TNBC tumors to EGFR-targeted therapy. This study provides a mechanistic rationale for repurposing auranofin in combination with EGFR inhibitors as a novel therapeutic strategy for EGFR-high TNBCs.

DOI: https://doi.org/10.1038/s41420-026-03157-0
Biomed Pharmacother. 2026 May 20. pii: S0753-3322(26)00523-8. [Epub ahead of print]200 119487

ER-phagy drives resistance to mitochondria-targeted therapy in breast cancer.

Aleksandra Bogucka, Daria Korewo-Labelle, Mariola Gimła, Elwira Smolińska-Fijołek, Anna Herman-Antosiewicz, Natalia Sowa-Rogozińska, Krzysztof Urbanowicz, Agnieszka Pyrczak-Felczykowska.

  Endoplasmic reticulum stress and ER-phagy are emerging regulators of cancer cell adaptation to metabolic and oxidative stress, yet their integration with mitochondrial dysfunction remains poorly understood. Here, we identify ER-phagy as a previously unrecognized adaptive response to ISOXUS, an isoxazole derivative of usnic acid with selective anticancer activity. ISOXUS, a mitochondrial respiratory complex II inhibitor, induces bioenergetic collapse, reactive oxygen species accumulation, and extensive ER-derived vacuolization. Using integrated transcriptomic and metabolomic analyses, we demonstrate that ISOXUS selectively triggers ER-phagy in mitochondria-dependent MCF-7 breast cancer cells, but not in more glycolytic triple-negative MDA-MB-231 cells, revealing a cell-type-specific stress adaptation program. ER-phagy induction is associated with upregulation of the ER-phagy receptor FAM134B and depends on ER stress signalling, as pharmacological ER stress inhibition suppresses this process. Multi-omics profiling uncovers coordinated repression of mitochondrial gene expression together with activation of ER-centered metabolic pathways, including amino acid metabolism, the tricarboxylic acid cycle, and one-carbon folate metabolism. Notably, we also identify UFMylation-related genes (CDK5RAP3, DDRGK1) as novel candidates involved in ER-phagy induced by ISOXUS. Moreover, mitochondrial inhibitors, rotenone and oligomycin, unexpectedly promote, while antioxidant a-tocopherol blocks ISOXUS-induced ER-phagy, and all compounds partially improve cell viability under ISOXUS treatment, implicating ROS-driven ER-phagy as a cytoprotective mechanism. Integrated analyses further reveal activation of the integrated stress response (ISR), dominated by the PERK-ATF4 axis, driving glutamine-dependent metabolic reprogramming and suppression of apoptosis-related pathways. The late-stage autophagy inhibition lowered the glutathione synthesis after ISOXUS treatment. Collectively, our findings uncover a previously unappreciated mitochondria-ER-ISR axis that governs metabolic adaptation to ISOXUS and identifies ER-phagy as a potential therapeutic vulnerability in breast cancer.

Keywords:  Breast cancer; Cancer resistance; ER stress; ER-phagy; ISOXUS; Integrated Stress Response; Metabolic adaptation; Mitochondrial complex II inhibition; Usnic acid derivative

DOI:  https://doi.org/10.1016/j.biopha.2026.119487
J Transl Med. 2026 May 21.

FASN for diffuse malignant peritoneal mesothelioma: a prognostic biomarker after CRS+HIPEC and a therapeutic target.

Valentina Doldi, Chiara Maura Ciniselli, Claudia Aurelio, Enrica Favini, Silvio Marco Veronese, Fabio Bozzi, Shigeki Kusamura, Dario Baratti, Silvia Martini, Paolo Verderio, Marcello Deraco, Marco Folini, Paolo Gandellini, Sandro Pasquali, Nadia Zaffaroni.

   BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and aggressive malignancy with limited therapeutic options and poor clinical outcomes. While metabolic reprogramming, including altered lipid metabolism, is a recognized hallmark of cancer, its contribution to DMPM progression and treatment response remains poorly understood.
METHODS: Gene expression profiling was performed on tumor samples from 45 DMPM patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC), comparing patients who developed recurrence within 30 months (N = 13) to those with later relapse or no recurrence (N = 32). Candidate prognostic markers were validated by immunohistochemistry in a cohort of 80 DMPM patients treated with CRS+HIPEC. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox regression analyses. To evaluate therapeutic potential, selective (cerulenin, C75) and non-selective (orlistat) fatty acid synthase (FASN) inhibitors were tested in patient-derived DMPM cell lines. Effects on cell proliferation, cell cycle progression, and apoptosis were assessed. Combination treatments with selinexor (XPO1/CRM1 inhibitor) or IAG-933 (inhibitor of FASN-derived palmitoyl-CoA activity) were also evaluated.
RESULTS: Fatty acid synthase (FASN) was significantly upregulated in tumors from patients with early recurrence. High FASN protein expression was associated with reduced PFS (HR = 1.93; p = 0.01) and OS (HR = 1.85; p = 0.02). Multivariate analysis confirmed FASN as an independent predictor of both PFS (HR = 2.24; p = 0.005) and OS (HR = 2.24; p = 0.014). In vitro, FASN inhibition significantly reduced DMPM cell growth, disrupted cell cycle progression, and induced apoptosis, with C75 showing the strongest effects. Combination treatment with FASN inhibitors and selinexor or IAG-933 resulted in enhanced growth inhibition and apoptosis compared with single-agent treatments.
CONCLUSIONS: FASN represents a novel independent prognostic biomarker in DMPM patients undergoing CRS+HIPEC and a promising therapeutic target. Given the limited treatment options for DMPM, combination strategies incorporating FASN inhibitors with selinexor or TEAD-pathway-targeting agents, supported by existing clinical trial data, may offer a rapidly translatable therapeutic approach.

Keywords:  Biomarker; CRS+HIPEC; Diffuse malignant peritoneal mesothelioma; FASN; TEADs; XPO1/CRM1

DOI:  https://doi.org/10.1186/s12967-026-08281-0
Cell Death Dis. 2026 May 22.

Mitochondria-targeted metformin analogs activate the ER stress-unfolded protein response pathway to drive apoptosis in pancreatic cancer.

Maria Poimenidou, Jordan M Bobek, Donovan Drouillard, Tyler Harris, Elisabeth Solis, Chad Darnell, Donna McAllister, Robert F Keyes, Mayumi Ishihara-Aoki, Kazuhiro Aoki, Daisy Sahoo, Balaraman Kalyanaraman, Brian C Smith, Michael B Dwinell.

Accumulating evidence indicates that evasion of apoptosis and metabolic reprogramming are necessary for pancreatic cancer growth, early invasion, and chemotherapeutic resistance. Building on our prior work, we investigated the anti-tumor potential of a rationally designed mitochondria-targeted variant of the anti-diabetic drug metformin, Mito-Met10, in cell culture models and orthotopic xenografts. Using MALDI-mass spectrometry imaging, therapeutic concentrations of fluorinated Mito-Met10 were shown to preferentially localize within pancreatic tumors relative to adjacent tissue and liver. Treatment suppressed tumor growth, reduced tumor weights, and increased apoptosis in vivo. Murine and human pancreatic cancer cells demonstrated potent anti-proliferative activity, with low micromolar IC50 values, and a concomitant induction of apoptotic programmed cell death in vitro. Seahorse metabolic flux analysis revealed reduced basal and ATP-linked mitochondrial respiration following Mito-Met10 treatment without a compensatory increase in glycolysis. Unbiased bulk RNA sequencing revealed significant enrichment of endoplasmic reticulum stress and unfolded protein response pathways, validated by qPCR across pancreatic cancer models, with broad upregulation of UPR-associated genes, establishing that Mito-Met10 activation of this stress response is conserved. Mito-Met10 caused extensive cytoplasmic vacuolization, mitochondrial swelling, and loss of mitochondrial membrane potential, indicative of severe organelle damage. Mito-Met10 activated PERK-eIF2α-ATF4-CHOP signaling, including upregulation of ATF4 and downstream pro-apoptotic transcriptional programs. Pharmacologic inhibition of ISR abrogated apoptotic signaling, demonstrating that PERK-eIF2α-ATF4-CHOP-mediated ISR activation functionally contributes to the anti-tumor effects of Mito-Met10. Consistent with these findings, orthotopic tumors from Mito-Met10-treated mice exhibited increased nuclear ATF4 staining compared with vehicle controls. Collectively, this study links mitochondrial stress to ER stress-associated apoptosis and identifies mitochondrial stress as a tractable vulnerability that can be manipulated to positively engage anti-tumor responses in pancreatic cancer.

DOI: https://doi.org/10.1038/s41419-026-08859-y
Cell Death Dis. 2026 May 18.

ICAM2 promotes endocrine resistance via dynein-mediated OXPHOS activation in ER-positive breast cancer.

Si Chen, Shiyi Wu, Jiajie Hu, Bohan Liu, Yuting Liu, Siyue Yang, Fen Tang, Yiqing He, Qinqing Liu, Yiwen Liu, Yan Du, Guoliang Zhang, Qian Guo, Feng Gao, Cuixia Yang.

Acquired endocrine resistance in ER+ breast cancer (BC) involves metabolic reprogramming, yet key drivers are unclear. Multi-omics of endocrine-resistant BC revealed upregulated oxidative phosphorylation (OXPHOS) and identified intercellular adhesion molecule 2 (ICAM2) as a biomarker of high-OXPHOS cells. ICAM2-positive cells were significantly enriched in resistant tumors and predicted poor survival, and were functionally essential for maintaining resistance and promoting metastasis in vivo. Mechanistically, ICAM2 binds dynein light chain DYNLT3 and the mitochondrial complex I subunit MT-ND2, thereby facilitating dynein-mediated mitochondrial trafficking and further modulating the assembly of mitochondrial complex I. Disrupting this interaction through ICAM2 knockdown or dynein inhibition (Ciliobrevin D) effectively suppressed OXPHOS activity. Importantly, ERα inhibition alleviates the transcriptional repression of ICAM2 by ERα. Therapeutically, combining the complex I inhibitor IACS-10759 with fulvestrant potently inhibited both tumor growth and metastasis. Collectively, these findings reveal that ICAM2 drives endocrine resistance via dynein-dependent OXPHOS activation, revealing a targetable axis in refractory ER+ BC.In summary, we establish ICAM2 as a novel biomarker and driver of endocrine resistance in ER⁺ breast cancer. ICAM2⁺ cancer cells-enriched in treatment-resistant tumors-maintain elevated OXPHOS by assembling a functional complex with dynein and mitochondrial Complex I, thereby promoting mitochondrial trafficking. Disruption of this axis, either through ICAM2 depletion or Complex I inhibition, re-sensitizes tumors to therapy, revealing a targetable metabolic dependency in resistant disease.

DOI: https://doi.org/10.1038/s41419-026-08864-1
J Exp Clin Cancer Res. 2026 May 22.

Extracellular vesicles from chemotherapy-induced senescent tumor cells reprogram hepatic phospholipid metabolism to promote pancreatic cancer liver metastasis.

Bai'an Tao, Yecheng Xu, Wenteng Miao, Zhenmei Chen, Jichun Gu, Yujie Guo, Linjie Chen, Yang Di, Hang He, Chen Jin, Ji Li, Deliang Fu.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, with over one-third of patients developing liver metastasis following neoadjuvant chemotherapy (NAC). This study aimed to investigate how the effect of chemotherapy on the primary tumor shapes the hepatic pre-metastatic niches (PMNs), which remains poorly understood.
METHODS: RNA sequencing was performed in a PDAC cohort to identify transcriptomic features associated with metastasis. We employed orthotopic and liver metastatic tumor models in mice to investigate the effects of extracellular vesicles derived from chemotherapy-treated PDAC cells, referred to as senescence-associated extracellular vesicles (S-EVs), on the hepatic PMNs. Mechanistically, we integrated proteomics and metabolomics to elucidate the molecular mechanisms by which S-EVs mediate hepatic metabolic reprogramming. Further, we utilized hepatocyte-specific Ache-knockout mice to validate the molecular mechanisms through which S-EVs promote liver metastasis in vivo.
RESULTS: Chemotherapy-induced senescence in primary tumors correlated with PDAC liver metastasis and poor prognosis. S-EVs facilitated PMNs formation by promoting hepatic phosphatidylcholine (PC) accumulation. Mechanistically, S-EV-delivered hnRNPA1 stabilized AChE mRNA, thereby driving PC accumulation in the liver. In vitro co-culture system, PC depletion in hepatocytes successfully restored the impaired cytotoxicity of CD8⁺ T cells caused by S-EVs. Consistently, hepatocyte-specific Ache ablation in vivo restored S-EV-impaired CD8⁺ T cells cytotoxicity. Inhibition of AChE with pyridostigmine remodeled the hepatic PMNs and suppressed liver metastasis.
CONCLUSIONS: S-EVs from chemotherapy-induced senescent PDAC cells reshaped hepatic PMNs through AChE-dependent PC accumulation, thereby impairing CD8⁺ T cell cytotoxicity and promoting PDAC liver metastasis. Targeting AChE with pyridostigmine represented a promising strategy to prevent metastasis and augment the therapeutic efficacy of NAC.

Keywords:  Extracellular vesicles; Hepatic phospholipid metabolism; Neoadjuvant chemotherapy; Pancreatic cancer liver metastasis; Senescence

DOI:  https://doi.org/10.1186/s13046-026-03741-3
Cancer Res. 2026 May 19.

Ketogenic Diet Prevents Obesity-Associated Pancreatic Cancer Independent of Weight Loss and Induces Pancreatic Metabolic Reprogramming.

Ericka Vélez-Bonet, Kristyn Gumpper-Fedus, Kaylin M Chasser, Zachary A Hurst, Adaliz Torres-Rosado, Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Alexus Liette, Grace Vulic, Fouad Choueiry, Huan Zhang, Andrew Gold, Jiangjiang Zhu, Sue E Knoblaugh, Stacey Culp, Jeff S Volek, Zobeida Cruz-Monserrate.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity increases the risk of PDAC through metabolic dysregulation and inflammation. The ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in non-obese PDAC using genetically engineered mouse models (GEMMs). We hypothesized that KD may also prevent obesity-associated PDAC progression by altering body composition and cancer metabolism. Therefore, male PDAC GEMMs were subjected to diet-induced obesity (DIO) using high-fat diets or maintained on a low-fat diet (LFD) for 15 weeks. Mice were then randomized to continue the initial diets or switch to a KD or matched control diet for 6 weeks. Body weight and composition, glucose tolerance, ketone levels, pancreas histology, and tissue metabolomics were assessed. Furthermore, murine pancreas-derived organoids from DIO or LFD fed GEMMs were treated with a ketone body and analyzed using untargeted metabolomics. In obese PDAC GEMMs, KD delayed cancer progression independent of weight loss, an effect not observed in non-obese LFD-fed mice. KD-mediated PDAC suppression was associated with enrichment of pancreatic metabolic pathways that support non-glucose energy production. Ketone-treated organoids recapitulated a subset of the KD-associated metabolic differences observed in vivo, suggesting a direct metabolic effect on cancer cells. These findings suggest potential benefits of a KD in preventing obesity-associated PDAC. The diet-cancer metabolic interactions highlight potential opportunities for dietary or metabolic interventions to prevent PDAC in high-risk obese populations.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2379
Int J Biol Sci. 2026 ;22(9): 4976-4996

CRL4AMBRA1-mediated progesterone receptor degradation drives progestin resistance and represents a therapeutic vulnerability in endometrial cancer.

Yaru Sheng, Ting Ni, Xiaoyi Ding, Jiaying Huang, Xueya Zhao, Xinyao Li, Qingting Li, Jing Wang, Xiaoming Yang, Lin Zhang, Xuan Zheng, Dan Cao, Rongjia Su, Xiaojing Lu, Jin Hou, Yudong Wang.

  Medroxyprogesterone acetate (MPA) is a major fertility-preserving therapeutic option for patients with endometrial cancer (EC); however, MPA resistance markedly restricts the efficacy of conservative treatments. Downregulation of the progesterone receptor (PR) expression is a key determinant of MPA resistance; however, the underlying molecular mechanisms have not been elucidated comprehensively. In this study, we identified AMBRA1, a substrate-specific adaptor of CUL4-RING E3 ubiquitin ligase (CRL4), as a critical regulator of PR stability and the MPA response. AMBRA1 expression was significantly increased in MPA-resistant EC tissues, and its overexpression induced an MPA-resistant phenotype. Mechanistically, AMBRA1 promotes ubiquitin-mediated degradation of PR by targeting lysine 388 in a CRL4AMBRA1 complex-dependent manner. Moreover, pharmacological inhibition of the CRL4AMBRA1 complex with MLN4924, an FDA-approved antitumor drug that blocks NEDD8-dependent Cullin-RING ligase activation, stabilizes PR and markedly restores MPA sensitivity in MPA-resistant EC cell lines and patient-derived organoid models. Collectively, these findings suggest that the CRL4AMBRA1 ubiquitin ligase facilitates PR degradation, inducing resistance to MPA. Furthermore, this study identified the CRL4AMBRA1 complex as a potential therapeutic target for overcoming MPA resistance in EC.

Keywords:  endometrial cancer; medroxyprogesterone acetate resistance; progesterone receptor; ubiquitination modification

DOI:  https://doi.org/10.7150/ijbs.133072
Clin Transl Med. 2026 May;16(5): e70685

Convergent targeting of FUNDC1-dependent mitophagy sensitises and overcomes resistance to EGFR inhibition.

Fan Xu, Xiaoshan Wang, Min Li, Yi Li, Xiaojuan Li, Qingqing Yan, Fanming Kong, Qihong Huang, Xin Cao, Ying Xue.

  Combination therapies are critical for enhancing and prolonging the efficacy of EGFR inhibitors. Here, we uncover FUNDC1-dependent mitophagy as a key protective mechanism in EGFR-mutant non-small cell lung cancer (NSCLC). We discover that nitidine, a bioactive component of the traditional Xihuang Pill formulation, synergises with the EGFR inhibitor osimertinib. Mechanistically, nitidine and osimertinib synergistically disrupt FUNDC1-mediated mitophagy, leading to mitochondrial dysfunction and accumulation of reactive oxygen species in EGFR-mutant NSCLC. We further show that both osimertinib and nitidine decrease HIF-1α protein levels, thereby downregulating FUNDC1 expression. Nitidine-induced downregulation of HIF-1α and FUNDC1 depends on the mitochondrial transporter ABCB6. Notably, acquired resistance to osimertinib exhibits adaptive downregulation of FUNDC1, rendering resistant EGFR-mutant NSCLC cells more sensitive to nitidine. Collectively, these findings position nitidine as a promising therapeutic strategy to enhance the efficacy of EGFR inhibitors and overcome osimertinib resistance in EGFR-mutant NSCLC.

Keywords:  ABCB6; EGFR‐mutant NSCLC; FUNDC1‐mediated mitophagy; mitochondrial dysfunction; nitidine; osimertinib resistance

DOI:  https://doi.org/10.1002/ctm2.70685
J Gastrointest Oncol. 2026 Apr 30. 17(2): 87

Targeting AKR1C1 overcomes lenvatinib resistance in hepatocellular carcinoma through the STAT3-ABC transporters pathway.

Yue Zhang, Lu Zheng, An-Qiang Feng, Cheng-Wen Zhao, Xin-Wei Xu, Han Wu, Yang Yu, Feng Gu, Yong-Qiang Chen.

   Background: Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related deaths worldwide. Lenvatinib, a widely used treatment, often has its efficacy limited by acquired resistance. Accumulating evidence indicates that the aldo-keto reductase 1 (AKR1) family plays a key role in tumor treatment resistance. This study aims to explore the mechanism of AKR1 family regulating lenvatinib resistance and identify new drugs to overcome it.
Methods: The establishment of lenvatinib-resistant HCC cells (HuH7/R and Hep3B/R) was achieved through long-term exposure to lenvatinib. The expression of the AKR1 family genes in these cells was identified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Plasma AKR1C1 was quantified by enzyme-linked immunosorbent assay (ELISA). The effect of AKR1C1 on lenvatinib-resistant HCC cells was assessed by transfecting small interfering RNA (siRNA) and the AKR1C1 inhibitor, flufenamic acid (FFA). The mechanism by which AKR1C1 regulates lenvatinib resistance in liver cancer cells was investigated through the application of co-immunoprecipitation and signaling pathway inhibitor assays.
Results: AKR1C1, a member of the AKR1 family, was overexpressed in lenvatinib-resistant HCC cells and in the plasma of lenvatinib-resistant HCC patients. Bioinformatics studies revealed that high AKR1C1 mRNA expression was linked to a less favourable prognosis in HCC patients. The transfection of siRNA-AKR1C1 can overcome lenvatinib resistance. Mechanistically, AKR1C1 was demonstrated to interact with and activate STAT3, which in turn upregulated the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), thereby conferring lenvatinib resistance. AKR1C1 inhibitor FFA, a non-steroidal anti-inflammatory drug, effectively reversed lenvatinib resistance, restricting the growth of lenvatinib-resistant HCC cells.
Conclusions: AKR1C1 may drive lenvatinib resistance in HCC by activating the STAT3-ATP-binding cassette (ABC) transporters pathway, thereby providing both a potential predictive biomarker and a therapeutic target for intervention.

Keywords:  AKR1C1; Hepatocellular carcinoma (HCC); flufenamic acid (FFA); lenvatinib resistance

DOI:  https://doi.org/10.21037/jgo-2025-aw-892
Mol Cell. 2026 May 22. pii: S1097-2765(26)00280-7. [Epub ahead of print]

Hypoxia-driven lncRNA SHIELD promotes GPX4 translation and protects against ferroptosis in hepatocellular carcinoma.

Kejia Liu, Ying Liu, Rick F Thorne, Fanzheng Meng, Yao Liu, Mian Wu, Lianxin Liu.

  Targeting ferroptosis, a form of regulated cell death, holds potential for improving treatment efficacy in a range of cancers including hepatocellular carcinoma (HCC). The selenoprotein glutathione peroxidase 4 (GPX4) plays a crucial role in suppressing ferroptosis by converting toxic phospholipid hydroperoxides into non-toxic lipid alcohols, yet the mechanisms regulating its synthesis remain poorly understood. This study identifies SHIELD (suppressor of hypoxia-induced lipid peroxidation and death), a long noncoding RNA (lncRNA) and direct HIF-1α target, as a regulator of ferroptosis in HCC. SHIELD inhibits ferroptosis by interacting with the RNA-binding protein GRSF1, which forms a ternary complex with GPX4 5'-UTR to enhance GPX4 mRNA translation and expression. Furthermore, targeting SHIELD with antisense oligonucleotides (ASOs) in combination with sorafenib significantly reduced tumor growth in patient-derived xenograft models. This discovery paves the way for improving the efficacy of tyrosine kinase inhibitors in HCC, which addresses the challenge of therapeutic resistance.

Keywords:  GPX4; LncRNA; ferroptosis; hepatocellular carcinoma; translation

DOI:  https://doi.org/10.1016/j.molcel.2026.04.026