bims-meract 2026-06-28 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–06–28
fifteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer.
Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
Reciprocal signaling-metabolic crosstalk between fibroblasts and tumor cells drives cetuximab tolerance in head and neck cancers.
Targeting metabolic dependencies to reverse chemoradiotherapy resistance in colorectal cancer.
Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics.
Hypoxia-mediated chromatin accessibility reprogramming of CA9 induces treatment resistance in colorectal mucinous adenocarcinoma.
Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer.
REGγ Suppresses Ferroptosis and Induces Drug Resistance by Degrading WDR6 in Chondrosarcoma.
EGFR N-Glycosylation Catalyzed by NDST2 Promotes Lenvatinib Resistance in Hepatocellular Carcinoma.
PMVK drives hepatocarcinogenesis via SP1 phosphorylation-mediated lipid metabolic reprogramming.
SUMOylation-stabilized G6PD orchestrates metabolic rewiring for oxidative stress survival and chemoresistance in HCC via a PKCδ-phosphorylation trigger.
Transferrin in combination with induction chemotherapy improves outcomes in mouse models of acute myeloid leukemia.
Tumour endothelial cell reprogramming orchestrates angiocrine signalling to drive chemoresistance in breast cancer.
Ferroptosis-induced oxidative stress in therapy-resistant glioblastoma.

Breast Cancer Res. 2026 Jun 25.

Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer.

Sucheta Telang, Brian F Clem, Ariamna A Herrera Miret, Leanne Price, Susan M Dougherty, Anna Schmitz, Xinmin Yin, Xipeng Ma, Xiang Zhang, Jason Chesney, Yoannis Imbert-Fernandez.

   BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used in the treatment of estrogen receptor-positive (ER⁺) breast cancer; however, the metabolic adaptations induced by CDK4/6 inhibition remain incompletely defined. In ER⁺ breast cancer, estrogen signaling plays a central role in coordinating cell cycle progression and metabolic programs that support tumor growth. Glycolytic flux is regulated at the level of phosphofructokinase-1 (PFK1) through the inducible enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which is transcriptionally regulated by estrogen receptor signaling and has been shown to promote glycolysis and proliferation in ER⁺ breast cancer cells. Yet, how CDK4/6 inhibition intersects with estrogen-regulated glycolytic control to rewire glucose utilization in ER⁺ breast cancer has not been explored.
METHODS: Glucose metabolism was assessed using extracellular flux analysis, untargeted metabolomics, and stable isotope tracing with uniformly labeled 13C-glucose in ER+ breast cancer cell lines. In vivo metabolic tracing was performed following bolus administration of [U-13C]-glucose. The effects of pharmacologic PFKFB3 inhibition, alone and in combination with CDK4/6 inhibitors, were evaluated in vitro and in patient-derived xenograft (PDX) models. Statistical analyses were performed using appropriate tests with correction for multiple comparisons where applicable.
RESULTS: CDK4/6 inhibition increased glycolytic flux, as evidenced by elevated basal and compensatory glycolysis, accumulation of early glycolytic intermediates, and increased 13C labeling of fructose 1,6-bisphosphate. PFKFB3 deficiency significantly attenuated the CDK4/6 inhibitor-induced increase in glycolytic flux. Despite increased glycolysis, stable isotope tracing revealed markedly reduced incorporation of glucose-derived carbon into nucleotide biosynthesis and lipid-associated metabolites, consistent with reduced anabolic demand during G1 cell cycle arrest. In vivo glucose tracing demonstrated a dissociation between increased glycolytic flux and downstream biosynthetic utilization. Pharmacologic inhibition of PFKFB3 imposed additional constraints on glucose utilization and significantly enhanced the antitumor efficacy of CDK4/6 inhibition in PDX models.
CONCLUSIONS: CDK4/6 inhibition rewires glucose metabolism in ER+ breast cancer by increasing glycolytic flux while limiting downstream glucose utilization, resulting in heightened reliance on regulated glycolytic control to maintain metabolic homeostasis during cell cycle arrest. Disruption of this adaptive metabolic state through PFKFB3 inhibition enhances the antitumor effects of CDK4/6 inhibition and supports the therapeutic potential of targeting glycolytic regulation in combination with CDK4/6 inhibitor-directed therapies.

Keywords:  Breast cancer; CDK4/6 inhibitor; Estrogen receptor; Glucose metabolism; PFKFB3

DOI:  https://doi.org/10.1186/s13058-026-02336-2
Nat Commun. 2026 Jun 25.

Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.

Zhongkun Liu, Lang Chen, Tong Zhang, Yuliang Wang, Panpan Ma, Xiangwei Zhang, Ronghui Liu, Ruiying Zhang, Xuanhao Zhang, Qingqing Su, Jinyan Huang, Da Wang, Qi Zhang, Cunqi Ye, Yun-Hua Liu.

Lipid accumulation is a hallmark of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment, yet effective strategies to reprogram this lipid-rich niche and restore anti-tumor immunity remain limited. Here, we show that diacylglycerol O-acyltransferase 1 (DGAT1) as a tumor-intrinsic metabolic checkpoint that promotes immune evasion. DGAT1 inhibition rewires tumor lipid metabolism by promoting increased fatty acid uptake and redistribution, thereby depleting extracellular free fatty acids that impair CD8⁺ T cell function. Mechanistically, decreased palmitate availability alleviates endoplasmic reticulum stress, preserves FOXO1 activity, and supports stem-like CD8⁺ T cell differentiation. This competitive lipid remodeling enhances memory potential, restrains terminal exhaustion, and sensitizes PDAC tumors to PD-1 checkpoint blockade in vivo. Together, our findings identify tumor-immune lipid crosstalk as a key barrier to effective immunity in PDAC and establish DGAT1 as a promising therapeutic target to restore T cell function and improve immunotherapy response.

DOI: https://doi.org/10.1038/s41467-026-74315-2
J Exp Clin Cancer Res. 2026 Jun 24.

Reciprocal signaling-metabolic crosstalk between fibroblasts and tumor cells drives cetuximab tolerance in head and neck cancers.

Engy Vigneron, Julie Vignau, Olivier Lowyck, Valentin Van den Bossche, Jérôme Ambroise, Yann Kieffer, Fatima Mechta-Grigoriou, Isabella Rizzi, Maria Virginia Giolito, Manon Desgres, Hannah Zaryouh, An Wouters, Antonella Mendola, Hajar Dahou, Marine Leclerc, Romain Boidot, Aurélien Warnant, Yvan Larondelle, Olivier Feron, Jean-Pascal Machiels, Sandra Schmitz, Cyril Corbet.

   BACKGROUND: Resistance to EGFR-targeted therapies, including cetuximab, remains a major barrier to effective treatment of head and neck squamous cell carcinoma (HNSCC). Lipid metabolism reprogramming, TGFβ signaling, and cancer-associated fibroblast (CAF) activation have each been linked to cetuximab resistance, but how these processes mechanistically converge remains unclear.
METHODS: We integrated transcriptomic, metabolic, and biochemical assays in HNSCC cell lines, co-culture systems with matched patient-derived non tumoral fibroblasts and CAFs, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs) to characterize tumor-stroma interactions during cetuximab treatment. Fluorescence-based fatty acid (FA) tracing and lipidomic analyses were used to assess FA flux. Functional relevance was tested through genetic and pharmacologic inhibition of TGF-β2 signaling and FA transfer. Clinical relevance was assessed by analyzing TGFB2 expression and plasma TGF-β2 levels in HNSCC patient cohorts.
RESULTS: Cetuximab-treated HNSCC cells specifically upregulated and secreted TGF-β2, which induced two coordinated adaptive programs: (i) autocrine metabolic rewiring promoting FA uptake, oxidation, and storage in tumor cells, and (ii) paracrine activation of fibroblasts toward a myofibroblastic, lipid-secreting phenotype. These TGFβ2-activated CAFs supplied FA that sustained oxidative metabolism and preserved EGFR/MAPK signaling in tumor cells, establishing a reciprocal feedback loop that maintained a reversible drug-tolerant state. Disrupting either TGF-β2 signaling or FA transfer abrogated this circuit and restored cetuximab sensitivity in HNSCC cells, spheroids, and PDOs. In PDX models, TGF-β2 inhibition delayed tumor regrowth following cetuximab treatment. Elevated TGFB2 expression and circulating TGF-β2 levels were associated with metabolic reprogramming and poorer clinical outcomes following cetuximab therapy.
CONCLUSIONS: Our findings define a tumor-stroma metabolic cooperation axis in which TGFβ2-driven lipid exchange sustains adaptive cetuximab tolerance in HNSCC. Targeting TGFβ2-mediated stromal reprogramming or FA transfer represents a promising strategy to delay or overcome resistance to EGFR-targeted therapies.

Keywords:  Cancer-associated fibroblasts; Cetuximab; Drug tolerance; Fatty acids; Head and neck cancer; Metabolism; Transforming growth factor beta; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-026-03765-9
J Exp Clin Cancer Res. 2026 Jun 23. pii: 143. [Epub ahead of print]45(1):

Targeting metabolic dependencies to reverse chemoradiotherapy resistance in colorectal cancer.

Maximilian Hellkamp, Simon Gertken, Jonas Buchloh, Julius-Leonard Hellwig, Lukas Ben Kowitzke, Ningjun Duan, Ilaria Gaspardo, Stefan Küffer, Michael Linnebacher, Philipp Ströbel, Matthias Wirth, Volker Ellenrieder, Stefan Rieken, Jochen Gaedcke, Michael Ghadimi, Jürgen Wienands, Günter Schneider, Melanie Spitzner, Marian Grade.

  Neoadjuvant chemoradiotherapy (CRT) constitutes a standard treatment for locally advanced rectal cancer (RC), frequently followed by radical surgical resection. Yet, therapeutic responses vary widely, and intrinsic radioresistance remains a major barrier to cure. To uncover actionable determinants of CRT response, we established a panel of patient-derived colorectal cancer cell lines (PDCLs) followed by integrated phenotypic and functional characterization. We identified metabolic reprogramming as a hallmark of radioresistance and, through orthogonal validation experiments, confirmed elevated glycolytic and mitochondrial ATP production in (chemo)irradiation-resistant PDCLs. The causative relationship of this association and its potential for therapeutic intervention was shown by subsequent drug screening, showing resistance to most of the applied drugs and revealing a critical dependency on the monocarboxylate transporter (MCT1) and the glucose transporter 1 (GLUT1). Metabolism-targeting compounds re-sensitized resistant PDCLs to irradiation; especially inhibition of GLUT1 exhibits a robust radiosensitizing activity across models. Concordantly, GLUT1 expression correlated with poor response to neoadjuvant CRT in our own RC patient cohort and various publicly available patient datasets. Collectively, our study defines metabolic dependency as a key driver of CRT resistance in RC, and reveals glycolysis- and lactate-transport-associated pathway activities as targetable vulnerabilities. These findings provide a mechanistic basis for patient stratification and support the development of metabolism-directed strategies to overcome (chemo)radioresistance in RC.

Keywords:  GLUT1; MCT1; chemoradiotherapy; glycolysis; metabolism; rectal cancer; therapy resistance

DOI:  https://doi.org/10.1186/s13046-026-03755-x
Cell Death Dis. 2026 Jun 25.

Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.

Lauren Brakefield-Laird, Amit Budhraja, Peter M Hall, Dixie Brewington, Jamila Moore, Josi Lott, Yonghui Ni, Dennis Voronin, Oliver Grant-Chapman, Tresor O Mukiza, Tristen Wright, Yong-Dong Wang, Sandi Radko-Juettner, Shondra M Pruett-Miller, Stanley Pounds, Peter Vogel, Joseph T Opferman.

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

DOI: https://doi.org/10.1038/s41419-026-09037-w
Nat Cancer. 2026 Jun;7(6): 944-963

Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics.

Xin He, Lei Zhang, Yang Li, Song-Bai Liu, Zheng Li, Haojie Dong, Genevieve E Baker, Le Xuan Truong Nguyen, Wei Chen, Jinhui Wang, Zhilian Jia, Xiyuan Lu, Yi-Chun Lin, Zunsong Hu, Umesh Prasad Yadav, Meng Liu, Lianjun Zhang, Zhenhua Chen, Xiwei Wu, Jianjun Chen, Chun-Wei Chen, Stefano Tiziani, Weidong Hu, Ya-Huei Kuo, Sheng-Li Xue, Yong Zhang, Min Li, Yaoqiu Zhu, Guido Marcucci, Zhaohui Gu, J Jefferson P Perry, Yun Lyna Luo, Ling Li.

De novo purine synthesis is required to maintain tumor growth; however, its impact on therapy resistance remains unclear. Here, through a dynamic BH3-priming-based CRISPR screen, we found that deletion of ADSS2, which encodes the adenylosuccinate synthase 2 enzyme essential for adenosine monophosphate (AMP) synthesis, re-sensitizes drug-resistant acute myeloid leukemia cells to venetoclax and a myeloid cell leukemia-1 (MCL1) inhibitor. Single-cell sequencing analysis of patient-derived xenograft samples revealed a positive association of high ADSS2 activity in TP53-mutant cells with poor responsiveness to venetoclax. We developed an ADSS2 antagonist, which synergized with BH3 mimetics to promote apoptosis in preclinical models. Mechanistically, sensitization mediated by ADSS2 targeting correlated with downregulated AMP-activated protein kinase activity, which in resistant cells promotes mitophagy to eliminate damaged mitochondria after BH3 mimetic treatment. These data show that AMP synthesis promotes BH3 mimetic resistance and that combining ADSS2 targeting with BH3 mimetics represents a promising anti-cancer approach.

DOI: https://doi.org/10.1038/s43018-026-01184-5
J Gastroenterol. 2026 Jun 24.

Hypoxia-mediated chromatin accessibility reprogramming of CA9 induces treatment resistance in colorectal mucinous adenocarcinoma.

An Huang, Haopeng Hong, Zhuang Sun, Zhaoya Gao, Yong Yang, Jiajia Chen, Yonghui Sun, Zhengrong Li, Ming Li, Jin Gu.

   BACKGROUND: Mucinous adenocarcinoma (MAC) represents a subtype of colorectal cancer (CRC) characterized by insensitivity to chemoradiotherapy, necessitating urgent development of novel therapeutic strategies specifically targeting tumor biology of MAC.
METHODS: Integrated analysis of ATAC-seq and RNA-seq data was performed to identify pivotal targets mediating treatment resistance in MAC. Subsequently, clinical specimens were collected for immunohistochemistry, RT-qPCR, and Kaplan-Meier survival analysis. Functional validation of the target was conducted through in vitro experiments encompassing colony formation, drug sensitivity assessments, synergy testing, and immunofluorescence. The translational potential of the target was evaluated in vivo.
RESULTS: Integrated ATAC-seq and RNA-seq analyses identified hypoxia and dysregulated ferroptosis as critical features of MAC, screening carbonic anhydrase 9 (CA9) as a pivotal gene implicated in MAC treatment resistance. CA9-specific inhibitor synergized with 5-fluorouracil to exert enhanced antitumor effects. Additionally, CA9 knockdown or inhibition arrested tumor cell proliferation and migration, promoted intracellular reactive oxygen species generation, induced mitochondrial shrinkage, increased mitochondrial iron content, reduced glutathione levels, and triggered lipid peroxidation. Inhibitors of either ferroptosis or apoptosis antagonized CA9 inhibitor-mediated cell death. In vivo experiments demonstrated that CA9 knockdown or inhibition significantly delayed tumor growth. Co-immunoprecipitation revealed that CA9 interacts directly or indirectly with multiple ferroptosis-associated proteins.
CONCLUSION: This study identifies the hypoxic tumor microenvironments and dysregulated ferroptosis as pivotal molecular characteristics of MAC, and proposes a novel mechanism underlying treatment resistance in MAC: Hypoxia remodels chromatin accessibility through epigenetic modifications, to dysregulate CA9 expression, which may subsequently modulate cellular susceptibility to ferroptosis, culminating in treatment resistance, and targeting CA9 may improve the therapeutic efficacy of MAC, although further studies are needed to establish direct causality.

Keywords:  Chromatin accessibility; Colorectal cancer; Hypoxia; Mucinous adenocarcinoma; Treatment resistance

DOI:  https://doi.org/10.1007/s00535-026-02461-x
Oncol Res. 2026 ;34(7): 21

Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer.

Jinhui Che, Zhiyuan Chen, Feng Zhang, Shuo Zhu, Shengya Cao, Ou Li, Rong Li, Jun Zheng, Yubin Liu.

  Objective: Advanced liver cancer, a highly lethal and increasingly prevalent malignancy, frequently develops sorafenib resistance, with aberrant mitochondrial dynamics and metabolism implicated in its pathogenesis. This study aimed to investigate their interplay and assess combination therapies against sorafenib-resistant liver cancer. Methods: Mitochondrial morphology was assessed using immunofluorescent staining. Besides, the mitochondrial metabolic profile was evaluated by measuring the oxygen consumption rate, glucose uptake, and lactate production. Dynamin-related protein 1 (Drp1) expression was determined through immunohistochemical staining, western blotting, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell counting, colony formation, and cell cycle assays were conducted to evaluate in vitro cell growth. Furthermore, time-lapse cell motility and Transwell assays were employed to assess cell migration and invasion capacities, respectively. Orthotopic xenograft models were utilized to demonstrate the therapeutic effects of the combined administration of the oxidative phosphorylation (OXPHOS) inhibitor IACS-010759 and the Drp1 inhibitor mdivi-1. Result: Importantly, our findings revealed that Drp1-mediated mitochondrial fission and the metabolic switch from OXPHOS to aerobic glycolysis were dominant in sorafenib-resistant liver cancer cells and strongly correlated with tumor prognosis (hazard ratio = 3.899, 95% confidence interval: 1.167-13.022, p = 0.027). Drp1 knockdown or inhibition impaired the invasive and metastatic capabilities of these cancer cells but promoted cell cycle progression and cellular growth, attributed to a metabolic shift from aerobic glycolysis to OXPHOS. Notably, the combined administration of the OXPHOS inhibitor IACS-010759 with mdivi-1 significantly attenuated tumor progression in sorafenib-resistant liver cancer, affecting both proliferation and metastasis. Conclusion: The results of this study collectively indicate that mitochondrial dynamics regulate metabolism in sorafenib-resistant liver cancer, which displays an aggressive hybrid metabolic phenotype. Accordingly, the combined targeting of mitochondrial dynamics and metabolism may represent an effective strategy to overcome sorafenib resistance in liver cancer.

Keywords:  IACS-010759; Sorafenib-resistant hepatocellular carcinoma; glucose metabolism; mdivi-1; mitochondrial dynamics

DOI:  https://doi.org/10.32604/or.2026.067443
Adv Sci (Weinh). 2026 Jun 26. e76293

REGγ Suppresses Ferroptosis and Induces Drug Resistance by Degrading WDR6 in Chondrosarcoma.

Fanrong Liu, Shihui Shen, Dongxia Li, Peilin Shi, Jiaming Xu, Tongxin Lv, Yingying Du, Jingwei Zhang, Bo Yang, Hansen Chen, Zhuoya Peng, Wenjie Ren, Lu Zhang, Sheng Cheng, Tongjin Yin, Wencai Sheng, Lei Li, Juan Wu, Qingcheng Yang, Shuogui Xu, Wei Zheng.

  Chondrosarcoma (CS) is a malignant bone tumor for which treatment efficacy remains clinically challenging owing to chemotherapy resistance. Ferroptosis, an iron-dependent form of regulated cell death initiated by lipid peroxidation, has emerged as a promising strategy for addressing drug resistance. However, the potential of targeting ferroptosis to overcome drug resistance in CS has not been systematically elucidated. Our study identifies REGγ as a critical driver of malignant progression in chondrosarcoma, with its elevated expression correlating with unfavorable patient outcomes. Loss of REGγ potentiates lipid peroxidation and modulates the activation of ferroptosis-associated genes by enhancing WDR6 protein stability. Mechanistically, REGγ degrades WDR6 through a ubiquitin-independent mechanism, inhibiting the ferroptosis pathway governed by the STK11/AMPK axis and consequently promoting tumor drug resistance. Additionally, RLY01, an inhibitor of the REGγ-20S proteasome, effectively suppresses chondrosarcoma growth and sensitizes chondrosarcoma cells to cisplatin. Collectively, REGγ emerges as a highly promising therapeutic target for improving the efficacy of cisplatin and other chemotherapies in CS.

Keywords:  REGγ; chondrosarcoma; combination therapy; drug resistance; ferroptosis

DOI:  https://doi.org/10.1002/advs.76293
Cancer Res. 2026 Jun 22.

EGFR N-Glycosylation Catalyzed by NDST2 Promotes Lenvatinib Resistance in Hepatocellular Carcinoma.

Huiying Gu, Fan Li, Yuyan Chen, Mengling Zhang, Qiumin Wu, Haibei Zhao, Chongyang Zhou, Li Yan, Ruixi Xie, Xinchang Huang, Jihua Ren, Shengtao Cheng, Haibo Yu, Yong Chen, Zhenzhen Zhang, Juan Chen.

The clinical efficacy of lenvatinib, a multitarget tyrosine kinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), is frequently compromised by the development of drug resistance. Elucidating the molecular mechanisms underlying this resistance is essential to improving therapeutic outcomes. Using patient-derived organoids (PDOs) and orthotopic HCC xenograft models, we uncovered a role for EGFR in lenvatinib resistance. Most PDOs recapitulated the limited clinical response to lenvatinib and displayed significant resistance. Notably, resistant organoids exhibited enhanced N-glycosylation of EGFR, which correlated with increased EGFR protein expression. Functional studies demonstrated that inhibiting either global N-glycosylation or EGFR signaling restored lenvatinib sensitivity in cellular and in vivo models. Integrated proteomic and N-glycoproteomic analyses identified NDST2 as the key enzyme mediating site-specific N-glycosylation of EGFR at four conserved asparagine residues (N175, N196, N413, and N623). NDST2-catalyzed glycosylation enhanced EGFR stability by suppressing ubiquitin-proteasomal degradation and promoted its membrane localization, thereby activating multiple pro-survival pathways, including MAPK, PI3K/AKT, and JAK/STAT. Clinically, NDST2 was upregulated in lenvatinib-resistant HCC specimens and positively correlated with EGFR expression. Importantly, targeting NDST2 via genetic ablation or inhibition using a CaCO₃-nanoparticle-based siRNA delivery system effectively reversed lenvatinib resistance in HCC tumor models. These findings establish NDST2-driven EGFR N-glycosylation as a critical mechanism of lenvatinib resistance in HCC and highlight NDST2 as a promising therapeutic target for restoring drug sensitivity.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4582
Sci Adv. 2026 Jun 26. 12(26): eaed8866

PMVK drives hepatocarcinogenesis via SP1 phosphorylation-mediated lipid metabolic reprogramming.

Ruiyang Liu, Caini Huang, Zhijie Xu, Fuyuan Xu, Xinyi Wen, Zhiju Zhao, Fei Xiao.

Metabolic reprogramming is a hallmark of cancer, yet the critical drivers and mechanisms in hepatocellular carcinoma (HCC) remain incompletely understood. Through a metabolism-focused CRISPR screen, we identified phosphomevalonate kinase (PMVK), a mevalonate pathway enzyme, as a key regulator of HCC stemness and progression. PMVK directly phosphorylates the transcription factor SP1 at Thr355, which enhances SP1's DNA binding affinity and promotes its interaction with the master lipid regulator SREBP1/2, driving a transcriptional program essential for de novo cholesterol and fatty acid synthesis. Clinically, PMVK levels are positively correlated with phospho-SP1 (Thr355) levels and predicate poor prognosis in patients with HCC. Functionally, we demonstrate that genetic or pharmacologic inhibition of the PMVK-SP1 axis, including using the SP1 inhibitor mithramycin A (MTA), significantly suppresses HCC tumorigenesis. In conclusion, our findings uncover the PMVK-SP1 axis as a central driver of lipid metabolic reprogramming and hepatocarcinogenesis, highlighting it as a compelling therapeutic target in HCC.

DOI: https://doi.org/10.1126/sciadv.aed8866
Cell Death Differ. 2026 Jun 26.

SUMOylation-stabilized G6PD orchestrates metabolic rewiring for oxidative stress survival and chemoresistance in HCC via a PKCδ-phosphorylation trigger.

Hongliang Luo, Fenna Zhang, Yingping Li, Rui Tong, Chengchang Gao, Yueqi Wen, Xueli Bian.

The adaptive mechanisms enabling cancer cells to withstand oxidative stress through metabolic rewiring remain poorly defined. Here, we decipher a redox-operated phosphorylation-SUMOylation relay that dynamically regulates glucose-6-phosphate dehydrogenase (G6PD) to drive hepatocellular carcinoma (HCC) progression. Oxidative stress activates protein kinase C delta (PKCδ), which phosphorylates G6PD at threonine 236 (T236), creating a steric barrier that displaces the deSUMOylase SENP1 and licenses K238 SUMOylation. This dual post-translational modification orchestrates G6PD stabilization through impaired TRIM21-mediated ubiquitination and catalytic activation via dimeric structural reorganization. Functionally, stabilized G6PD amplifies pentose phosphate pathway flux, sustaining NADPH-dependent redox balance and ribose-5-phosphate-fueled nucleotide biosynthesis to promote HCC survival under oxidative duress. Genetic disruption of K238 SUMOylation or pharmacological PKCδ inhibition synergistically enhances cisplatin efficacy by overcoming chemoresistance in preclinical models. Clinically, coordinated upregulation of G6PD and phospho-T236 correlates with aggressive HCC phenotypes and predicts poor patient outcomes. Our study identifies G6PD post-translational control as a potential metabolic vulnerability and suggests that targeted disruption of this axis may represent a promising approach to subvert redox adaptation in HCC.

DOI: https://doi.org/10.1038/s41418-026-01802-w
Sci Transl Med. 2026 Jun 24. 18(855): eadu0167

Transferrin in combination with induction chemotherapy improves outcomes in mouse models of acute myeloid leukemia.

Marta Lopes, Filipa Lemos, Lídia Rocha, Carolina Pereira, Catarina Moreira-Barbosa, Joana P Reis, Tiago L Duarte, André M N Silva, Nuno Gonçalves, Laura Mosteo, Mariana Trigo Miranda, Maria J Teles, Sérgio Chacim, George S Vassiliou, Graça Porto, Maria J Oliveira, Pedro Madureira, Delfim Duarte.

Acute myeloid leukemia (AML) is an aggressive leukemia with high rates of chemoresistance and relapse. Patients with AML undergoing induction chemotherapy often have delayed erythropoietic recovery and febrile neutropenia. Infection is a leading cause of mortality in this population. There is an unmet need to improve disease-specific outcomes in patients with AML undergoing cytotoxic chemotherapy. AML, at diagnosis, is characterized by increased levels of circulating iron due to erythroid block and cell death, which is further aggravated upon intensive chemotherapy. We hypothesized that iron, particularly toxic non-transferrin-bound iron (NTBI), can be redistributed away from AML cells and bacteria into nonmalignant transferrin receptor (CD71)-expressing cells by administering exogenous iron-free apotransferrin (apoTF). Using mouse models of AML, we show that mice treated with human apoTF had decreased NTBI and increased bone marrow erythropoiesis and B cell responses. ApoTF treatment resulted in normalization of bone marrow blood vessels and reduction of lipid peroxidation in endothelial cells. Crucially, apoTF combined with chemotherapy resulted in a reduction of AML cells and in improved survival, which was dependent on adaptive immunity. We established a murine model of Escherichia coli sepsis in leukemic mice receiving chemotherapy. We show that apoTF administration increased the survival of E. coli-infected mice. Mechanistically, apoTF treatment decreased the levels of circulating C-C motif chemokine ligand 2 (CCL2) and interleukin-6 through reduced expression of CCL2 in lipopolysaccharide-polarized macrophages. Our results demonstrate an overall benefit of iron redistribution induced by transferrin in combination with cytotoxic chemotherapy in AML.

DOI: https://doi.org/10.1126/scitranslmed.adu0167
Angiogenesis. 2026 Jun 22. pii: 48. [Epub ahead of print]29(3):

Tumour endothelial cell reprogramming orchestrates angiocrine signalling to drive chemoresistance in breast cancer.

Jesus Gomez-Escudero, Eleni Maniati, Julie Holdsworth, Gordon Beattie, Maruan Hijazi, Matt Guelbert, Samar Elorbany, Pedro Cutillas, Jun Wang, Kairbaan Hodivala-Dilke, Gabriela D'Amico.

  Despite its established role in breast cancer treatment, Doxorubicin treatment remains subject to adaptive resistance mechanisms that extend beyond cancer cell intrinsic alterations ultimately reducing therapy efficacy. Our study in a MMTV-PyMT-driven mouse breast cancer model reveals that prolonged Doxorubicin (Dox) exposure triggers significant reprogramming of the tumour vasculature, substantially altering the angiocrine landscape and shaping treatment outcomes. Notably, tumours that initially respond, but later revert, display an endothelial cell subclustering with activation of proliferative and NF-κB-dependent cytokine pathways. We further identify a novel endothelial subpopulation characterised by higher expression of drug clearance and oxidative metabolism markers, suggesting an active role in mitigating Dox efficacy and angiogenesis promotion. These findings substantiate endothelial plasticity as a critical mediator of therapeutic failure. By uncovering these vascular adaptations, our work provides a new perspective on the underlying mechanisms of Dox resistance and the prolonged efficacy of chemotherapy in breast cancer.

Keywords:  Angiocrine; Breast cancer; Chemoresistance; Doxorubicin; NF-κB

DOI:  https://doi.org/10.1007/s10456-026-10063-7
Cell Death Discov. 2026 Jun 26.

Ferroptosis-induced oxidative stress in therapy-resistant glioblastoma.

Sofia Remedia, Cristina Martelli, Marcella Bonanomi, Bruno Giovanni Galuzzi, Francesca Servidio, Clarissa Gervasoni, Martina Nespoli, Chiara Pellizzer, Alessandro Giammona, Daniela Gaglio, Daniele Capitanio, Gloria Bertoli, Luisa Ottobrini, Alessia Lo Dico.

Temozolomide (TMZ) resistance remains a major obstacle in glioma treatment. Ferroptosis, an iron-dependent, lipid peroxidation-driven regulated cell death, represents a promising alternative strategy. We investigated molecular determinants of ferroptosis sensitivity in TMZ-resistant glioma, focusing on HIF-1α and oxidative stress. One TMZ-sensitive (U251) and three TMZ-resistant (T98, U118, LN18) cell lines were treated with ferroptosis inducers (Erastin, FIN56, RSL3). Viability, ROS (total and mitochondrial), lipid peroxidation, and ferroptosis-related gene/protein expression were assessed. MitoTEMPO and deferoxamine (DFX) were used to probe mitochondrial ROS and iron dependence, respectively. Integrated metabolomic-proteomic analyses and an orthotopic U118-Luc model supported in vitro findings. Ferroptosis inducers reduced viability and bypassed TMZ resistance in vitro and suppressed tumor growth in vivo with partial body-weight loss. Resistant cells displayed high HIF-1α with elevated GSH/NRF2 activity and reduced lipid peroxidation. Treatments increased oxidative stress and downregulated GPX4, xCT, FSP1, and ATF4; MitoTEMPO rescued cells, implicating mitochondrial ROS. Ferroptosis induction reduced HIF-1α expression/nuclear localization and decreased HIF-1α/VEGF/SOX2/NRF2 in tumor tissue, supporting therapeutic potential.

DOI: https://doi.org/10.1038/s41420-026-03227-3