bims-meract 2025-09-14 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–09–14
twelve papers selected by
Andrea Morandi, Università degli Studi di Firenze

Loss of PTDSS1 in tumor cells improves immunogenicity and response to anti-PD-1 therapy.
Metabolic Reprogramming: A Crucial Contributor to Anticancer Drug Resistance.
Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma.
EMC2 promotes triple negative breast cancer growth by protecting FDFT1 from endoplasmic reticulum associated degradation to impair ferroptosis susceptibility.
Inhibition of dipeptidyl peptidase 9 improves sorafenib sensitivity by inducing ferroptosis in hepatocellular carcinoma.
Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.
Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer.
NNMT-driven metabolic reprogramming creates a NAMPT druggable vulnerability and reveals liquid biopsy biomarkers for TKI resistance in EGFR-mutant NSCLC.
Verteporfin inhibits the cGAS-STING pathway and improves the tumor microenvironment during cisplatin treatment in hepatocellular carcinoma.
Targeting peroxiredoxin 2 prevents hepatocarcinogenesis in metabolic liver disease.
Molecular Profiling of Belumosudil-Treated IOMM-Lee Meningioma Cells Reveals Repurposing Potential via Enhanced Oxidative Phosphorylation and ROS-Mediated Cell Death.
Disrupting the interaction between androgen receptor and its coregulator WDR77 delays the growth of treatment-resistant prostate cancer.

Sci Adv. 2025 Sep 12. 11(37): eadx8134

Loss of PTDSS1 in tumor cells improves immunogenicity and response to anti-PD-1 therapy.

Jielin Liu, Shelley Herbrich, Sreyashi Basu, Yulong Chen, Ashwat Nagarajan, Swetha Anandhan, Sangeeta Goswami, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma.

PTDSS1 (phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of Ptdss1 in tumor cells increased expression of interferon-γ (IFN-γ)-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFN-γ stimulation in vitro. Loss of Ptdss1 in tumor cells also led to increased expression of MHC-I, enhanced cytotoxicity of CD8+ T cells, and increased frequency of an iNOS+ myeloid subset. A gene signature derived from the iNOS+ myeloid cell subset correlated with clinical benefit in patients treated with anti-PD-1 therapy. Moreover, genetic and pharmacological inhibition of Ptdss1 in different tumor models improved anti-PD-1 therapy. Together, our results provide insights on a therapeutic strategy for overcoming immunosuppression by inhibiting PTDSS1 and provide rationale for development of a combination immunotherapy strategy composed of PTDSS1 inhibition plus PD-1 blockade.

DOI: https://doi.org/10.1126/sciadv.adx8134
MedComm (2020). 2025 Sep;6(9): e70358

Metabolic Reprogramming: A Crucial Contributor to Anticancer Drug Resistance.

Yunhan Zhu, Weijie Yan, Lingfeng Tong, Jie Yang, Shengfang Ge, Jiayan Fan, Renbing Jia, Xuyang Wen.

  Cancer metabolic reprogramming is a fundamental hallmark that enables tumor cells to sustain their malignant behaviors. Beyond its role in supporting growth, invasion, and migration, metabolic rewiring actively contributes to anticancer drug resistance. Cancer cells not only reshape their own metabolism but also engage in aberrant metabolic crosstalk with nonmalignant components within the tumor microenvironment (TME). These metabolic alterations create multiple barriers to the efficacy of drug therapies, including chemotherapy, targeted therapy, and immunotherapy. Despite growing evidence, an integrated understanding of how metabolic reprogramming contributes to the development of drug resistance and how it may be therapeutically targeted to overcome the resistance remains incomplete. This review summarizes recent progresses in tumor-intrinsic and TME-associated metabolic alterations that contribute to drug resistance by sustaining metabolic needs and modulating nonmetabolic processes and explores the upstream regulatory mechanisms driving these changes, focusing particularly on glucose, lipid, and amino acid metabolism. We also discuss the current advances in the integration of small molecule inhibitors targeting cancer metabolism to address drug resistance. By consolidating mechanistic insights and therapeutic opportunities, this review highlights metabolic reprogramming as a promising intervention point to overcome anticancer drug resistance.

Keywords:  cancer metabolism; drug resistance; metabolic targeted strategies; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.70358
JCI Insight. 2025 Sep 09. pii: e186703. [Epub ahead of print]10(17):

Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma.

Alyona Ivanova, Taylor M Wilson, Kimia Ghannad-Zadeh, Esmond Tse, Robert Flick, Megan Wu, Sunit Das.

  More than a third of patients with glioblastoma experience tumor progression during adjuvant therapy. In this study, we performed a high-throughput drug repurposing screen of FDA-approved agents capable of crossing the blood-brain barrier in order to find agents to counteract acquired or inherent glioma cell resistance to temozolomide-associated cytotoxicity. We identified the cholesterol processing inhibitor, lomitapide, as a potential chemosensitizer in glioblastoma. In vitro treatment of temozolomide-resistant glioblastoma cells with lomitapide resulted in decreased intracellular ubiquinone levels and sensitized cells to temozolomide-induced ferroptosis. Concomitant treatment with lomitapide and temozolomide (TMZ) prolonged survival and delayed tumor recurrence in a mouse glioblastoma model, compared with treatment xwith TMZ alone. Our data identified lomitapide as a potential adjunct for treatment of temozolomide-resistant glioblastoma.

Keywords:  Brain cancer; Cell biology; Clinical practice; Drug therapy; Oncology

DOI:  https://doi.org/10.1172/jci.insight.186703
Oncogene. 2025 Sep 10.

EMC2 promotes triple negative breast cancer growth by protecting FDFT1 from endoplasmic reticulum associated degradation to impair ferroptosis susceptibility.

Xinrui Dong, Huijuan Dai, Linli Yao, Yanping Lin, Yaohui Wang, Ye Li, Xueli Zhang, Liheng Zhou, Jinsong Lu, Wenjin Yin.

Cholesterol biosynthesis is more activated in triple negative breast cancer (TNBC) than in other subtype breast cancer and plays essential role in facilitating TNBC. However, the regulatory network and how cholesterol biosynthesis contribute to TNBC development and progression are not well elucidated. Here, we found that reticulum membrane protein complex 2 (EMC2) is highly expressed in TNBC and predicts short survival of patients. In vitro and in vivo experiments displayed that EMC2 could promote TNBC growth. We also displayed that EMC2 could increase intracellular cholesterol biosynthesis by regulating Farnesyltransferase 1 (FDFT1) expression. Mechanistically, we validated that EMC2 interacted with heat shock protein 90(HSP90) to sustain FDFT1 protein quality and correctly located in the ER membrane through protecting it from endoplasmic reticulum associated degradation (ERAD). Furthermore, EMC2 decreased TNBC cell ferroptosis susceptibility through elevating intracellular cholesterol contents. Collectively, our findings shed a new insight that EMC2 is critical for boosting cholesterol biosynthesis and ferroptosis resistance. Targeting EMC2 could be a promising novel therapeutic target for TNBC treatment.

DOI: https://doi.org/10.1038/s41388-025-03545-3
J Cancer Res Clin Oncol. 2025 Sep 09. 151(9): 243

Inhibition of dipeptidyl peptidase 9 improves sorafenib sensitivity by inducing ferroptosis in hepatocellular carcinoma.

Qing Li, Yang Wang, Jun Zou.

   OBJECTIVE: Dipeptidyl peptidase 9 (DPP9) not only regulates tumor progression and drug sensitivity, but also modifies oxidative stress mediated ferroptosis. This study aimed to investigate the effect of DPP9 inhibition on sorafenib sensitivity and its interaction with ferroptosis in hepatocellular carcinoma (HCC).
METHODS: Two HCC cell lines (Huh7 and MHCC-97H) were transfected with DPP9 siRNA, followed by detection of reactive oxygen species (ROS), ferrous iron (Fe2+), malondialdehyde (MDA), and ferroptosis-related proteins, and treated by 0-16 μM sorafenib to calculate half-maximal inhibitory concentration (IC50) for sensitivity assessment. Moreover, ferrostatin-1 (Fer-1) was added with or without DPP9 siRNA, followed by the above detections.
RESULTS: Inhibition of DPP9 improved sorafenib sensitivity reflected by a lower sorafenib IC50 value, and it increased ROS fluorescence intensity, Fe2+ level, and MDA level, which also upregulated ACSL4 expression but downregulated NRF2 and SLC7A11 expressions. Fer-1 treatment decreased ROS fluorescence intensity, Fe2+ level, MDA level, and reduced sorafenib sensitivity reflected by a higher sorafenib IC50 value. Moreover, Fer-1 treatment weakened the effect of DPP9 inhibition on ROS fluorescence intensity, Fe2+ level, MDA level, most of the ferroptosis-related proteins, and sorafenib sensitivity reflected by sorafenib IC50 value.
CONCLUSION: Inhibition of DPP9 improves sorafenib sensitivity by promoting ferroptosis in HCC, which provides novel evidence for DPP9 as an HCC treatment target synergizing with sorafenib.

Keywords:  Dipeptidyl peptidase 9; Ferroptosis; Hepatocellular carcinoma; Oxidative stress; Sorafenib sensitivity

DOI:  https://doi.org/10.1007/s00432-025-06300-z
Int J Mol Sci. 2025 Aug 25. pii: 8241. [Epub ahead of print]26(17):

Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.

Laura Soumoy, Aline Genbauffe, Dorianne Sant'Angelo, Maude Everaert, Léa Mukeba-Harchies, Jean-Emmanuel Sarry, Anne-Emilie Declèves, Fabrice Journe.

  Targeted therapy with BRAFi has significantly improved outcomes for patients with BRAF-mutated metastatic melanoma. However, resistance mechanisms, particularly metabolic adaptations, such as increased glutaminolysis, present substantial clinical challenges. This study investigated the metabolic changes underlying BRAFi resistance in melanoma cells. Using pharmacological agents, including dabrafenib (BRAFi), pimasertib (MEKi), dasatinib (cKITi), and CB-839 (glutaminase inhibitor), we explored metabolic adaptations in melanoma cell lines harboring various mutations. Our methodologies included cell culture, qPCR, polysome profiling, animal studies in nude mice, and analyses of patient samples to evaluate the therapeutic potential of targeting glutaminolysis. Our findings confirmed that melanoma cells, with resistance to targeted therapies, exhibit metabolic adaptations, including enhanced glutaminolysis, increased mitochondrial content, and elevated antioxidative capacities. We evaluated the efficacy of CB-839 and demonstrated its ability to reduce the proliferation of resistant melanoma cells both in vitro and in vivo. Mechanistic studies revealed that CB-839 suppressed ATP production and TCA cycle intermediates in resistant cells while inducing oxidative stress in sensitive cells, thereby inhibiting their proliferation. High glutaminase expression in primary patient tumor samples was associated with poor prognosis. We identified a metabolic signature in tumors from patients responsive or unresponsive to BRAFi prior to treatment, which could serve as a predictive factor for BRAFi response. This study underscores the metabolic alterations driving resistance to BRAFi in melanoma cells and highlights the therapeutic potential of targeting glutaminolysis with CB-839. The identification of metabolic signatures in patient samples provides valuable insights for personalized treatment strategies, aiming to overcome resistance mechanisms and improve patient outcomes in melanoma management.

Keywords:  BRAF inhibitors; CB-839; glutaminase inhibition; melanoma resistance; metabolic adaptations; personalized therapy

DOI:  https://doi.org/10.3390/ijms26178241
Biochem Biophys Res Commun. 2025 Sep 06. pii: S0006-291X(25)01325-7. [Epub ahead of print]782 152609

Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer.

Zhiheng Zhang, Liye Fang, Hiroki Furukawa, Andy Huang, Joshua Kranrod, John M Seubert, Kousei Ito, Shigeki Aoki.

  Pancreatic ductal adenocarcinoma (PDAC) cells exhibit high metabolic flexibility, enabling survival under glucose limitation by using alternative fuels such as fatty acids. Lipophagy, a selective form of autophagy targeting lipid droplets (LDs), supports mitochondrial respiration during such nutrient stress. Our previous study demonstrated that the LSD1 inhibitor SP-2509 disrupts lipophagy independently of LSD1 inhibition, leading to LD accumulation and ATP depletion in glycolysis-suppressed PDAC cells. However, the effects of disrupted lipid homeostasis on mitochondrial function remained unclear. Here, the effects of lipid overload on mitochondrial morphology and activity were investigated under glucose-restricted conditions. SP-2509 treatment caused substantial LD accumulation with mitochondrial fragmentation and closer LD-mitochondrion spatial proximity, forming peridroplet mitochondria (PDM)-like structures. These structures were not associated with increased fatty acid oxidation; instead, they correlated with impaired mitochondrial respiration, shown by a reduced complex II/IV activity ratio. Forced mitochondrial fission alone did not reduce ATP production, suggesting lipid metabolic disruption, rather than morphological changes, drives mitochondrial dysfunction. Moreover, mitochondria relocated from perinuclear to peripheral regions following treatment, a shift associated with reduced cell viability and indicating a possible link between nuclear-mitochondrial proximity and survival under stress. Our findings challenge the prevailing view of PDM as inherently adaptive organelles. In PDAC, aberrant PDM formation under lipid stress may represent a maladaptive response contributing to metabolic vulnerability. This newly identified dysregulation of lipid and mitochondrial homeostasis may offer a new therapeutic target in treatment-resistant pancreatic cancer.

Keywords:  Lipid droplet; Lipophagy; Mitochondrial dysfunction; Pancreatic cancer; Peridroplet mitochondria

DOI:  https://doi.org/10.1016/j.bbrc.2025.152609
Cancer Lett. 2025 Sep 09. pii: S0304-3835(25)00602-0. [Epub ahead of print] 218032

NNMT-driven metabolic reprogramming creates a NAMPT druggable vulnerability and reveals liquid biopsy biomarkers for TKI resistance in EGFR-mutant NSCLC.

I Pulido, J C García-Cañaveras, M L Rodríguez, J H Becker, A López, M Aupí, S Aparisi, L Chuliá-Peris, E Tamayo-Torres, C Carreres-Rey, J Alcácer Fernández-Coronado, M Benet, S Montero, S Mena, J Sandoval, J Pereda, J Alcácer, S Calabuig, E Jantus, A Cremades, J M Galbis, P Martín-Martorell, A Insa, Malek G Massad, O Juan-Vidal, A Lahoz, T Shimamura, J Carretero.

  Lung cancer is the deadliest neoplasia worldwide. Despite the availability of targeted therapies like tyrosine kinase inhibitors (TKIs) for EGFR-driven tumours in Non-Small Cell Lung Cancer (NSCLC), drug resistance remains a major factor that dramatically cuts life expectancy. Here we identify how increased expression of nicotinamide N-methyltransferase (NNMT) in TKI-resistant cancer cells diverts nicotinamide to synthesise 1-Methylnicotinamide (1-MNA), lowers NAD+ levels that generates a druggable nicotinamide phosphoribosyltransferase (NAMPT) metabolic vulnerability. We also report that high blood levels of 1-MNA, the by-product of NNMT activity, are significantly associated with lower survival rates in EGFR TKI-treated NSCLC patients. Taken together, our findings describe a new and highly specific non-genetic metabolic synthetic lethality for mesenchymal-like tumours, which exposes NAMPT as an in vivo druggable target and establishes 1-MNA as a novel liquid biopsy biomarker to predict and monitor EGFR TKI resistance in NSCLC.

Keywords:  EGFR; Metabolic rewiring; NAMPT; NNMT; NSCLC; TKIs; liquid biopsy

DOI:  https://doi.org/10.1016/j.canlet.2025.218032
Front Immunol. 2025 ;16 1658042

Verteporfin inhibits the cGAS-STING pathway and improves the tumor microenvironment during cisplatin treatment in hepatocellular carcinoma.

Yi Gong, Yajun Xiong, Yuting Gao, Xiaoyong Song, Yanli Gong, Dan Wang, Zhihan Liu, Yanguang Yang, Junlan Lu, Isabelle Xinyue Zou, Xinli Shi.

   Background: Cisplatin (DDP) is a clinical first-line chemotherapy drug for hepatocellular carcinoma (HCC), but treatment is often ineffective due to drug resistance. Yes-associated protein 1 (YAP1) is a critical regulator/factor in HCC tumor progression. Our previous research showed that DDP promoted the expression of YAP1 in mice bearing H22 cell in situ liver tumors, which might be related to the poor therapeutic effect of DDP.
Methods and results: DDP could inhibit tumor growth and decrease tumor volume in DEN/TCPOBOP-induced HCC mice, increase the number of CD8+ T cells in the tumor, reduce the proportion of PD-1+CD8+ T cells in the peripheral blood and spleen of mice, and reduce the immune exhaustion of the tumor microenvironment in HCC. Of note, that DDP treatment activated YAP1 expression in HCC cells. In addition, using a murine model of subcutaneous transplantation of HCC cells, it was found that the combined use of the YAP1 inhibitor, verteporfin, and DDP led to significant tumor regression. Inhibition of YAP1 reduced activation of the cGAS-STING pathway by DDP treatment. Furthermore, bioinformatics analysis revealed that YAP1 was positively correlated with cGAS and STING in HCC tissues. We further confirmed the correlation of YAP1 with cGAS-STING in HCC using two models: DEN/TCPOBOP induction of HCC in hepatocyte-specific Yap1 knockout mice; and giving verteporfin treatment to mice with subcutaneously transplanted HCC tumors. Inhibiting the expression of YAP1 in HCC tissues can reduce the expression of cGAS-STING and enhance the therapeutic effect of cisplatin.
Conclusions: The combination of YAP1 inhibitor, verteporfin and DDP enhances anti-tumor immunity by regulating the interaction between YAP1 and cGAS-STING in the tumor microenvironment, providing new insights into a combined chemotherapy strategy for HCC.

Keywords:  CD8 + T cells; CGAS; PD-1; STING; Yap1; cisplatin; hepatocellular carcinoma

DOI:  https://doi.org/10.3389/fimmu.2025.1658042
J Clin Invest. 2025 Sep 11. pii: e169395. [Epub ahead of print]

Targeting peroxiredoxin 2 prevents hepatocarcinogenesis in metabolic liver disease.

Emilie Crouchet, Eugénie Schaeffer, Marine A Oudot, Julien Moehlin, Cloé Gadenne, Frank Jühling, Hussein El Saghire, Naoto Fujiwara, Shijia Zhu, Fahmida Akter Rasha, Sarah C Durand, Anouk Charlot, Clara Ponsolles, Romain Martin, Nicolas Brignon, Fabio Del Zompo, Laura Meiss Heydmann, Marie Parnot, Nourdine Hamdane, Danijela Heide, Jenny Hetzer, Mathias Heikenwälder, Emanuele Felli, Patrick Pessaux, Nathalie Pochet, Joffrey Zoll, Brian Cunniff, Yujin Hoshida, Laurent Mailly, Thomas F Baumert, Catherine Schuster.

  Treatment options for advanced liver disease and hepatocellular carcinoma (HCC) are limited and strategies to prevent HCC development are lacking. Aiming to discover novel therapeutic targets, we combined genome wide transcriptomic analysis of liver tissues from patients with advanced liver disease and HCC and a cell-based system predicting liver disease progression and HCC risk. Computational analysis predicted peroxiredoxin 2 (PRDX2) as a candidate gene mediating hepatocarcinogenesis and HCC risk. Analysis of HCC patient tissues confirmed a perturbed expression of PRDX2 in cancer. In vivo perturbation studies in mouse models for MASH driven hepatocarcinogenesis showed that specific Prdx2 knockout in hepatocytes significantly improved metabolic liver functions, restored AMPK activity and prevented HCC development by suppressing oncogenic signaling. Perturbations studies in HCC cell lines, a CDX mouse model and patient-derived HCC spheroids unraveled that PRDX2 also mediates cancer initiation, cancer cell proliferation and survival through its antioxidant activity. Targeting PRDX2 may therefore be a valuable strategy to prevent HCC development in metabolic liver disease.

Keywords:  Carbohydrate metabolism; Hepatology; Oncology; Preventative medicine; Therapeutics

DOI:  https://doi.org/10.1172/JCI169395
J Proteome Res. 2025 Sep 13.

Molecular Profiling of Belumosudil-Treated IOMM-Lee Meningioma Cells Reveals Repurposing Potential via Enhanced Oxidative Phosphorylation and ROS-Mediated Cell Death.

Ankit Halder, Archisman Maitra, Diksha Attrish, Adrita Saha, Deeptarup Biswas, Bhavuk Dhamija, Rahul Purwar, Sanjeeva Srivastava.

  Meningioma is the most prevalent primary brain tumor. The aggressive forms of the tumor pose a major challenge to clinicians, as it becomes difficult to eradicate them surgically. This has necessitated a concerted effort to explore novel therapeutic candidates. A multiomics-based pathway analysis, followed by drug repurposing, was undertaken to identify a suitable drug candidate that could potentially be used to control proliferation. Multiomics analysis indicates that IOMM-Lee (high-grade meningioma) cells show enhanced oxidative phosphorylation and ROS-mediated cell-death upon treatment with belumosudil, an FDA-approved Rho kinase inhibitor. Dysregulation of key pathways, including Wnt, p53, and phosphoinositol signaling, was also observed. It suggests that the drug treatment induces a ROS-rich environment, primarily affecting the nucleus and mitochondria. The cellular metabolome also shows an increase in lipid peroxidation product in concordance to an increase in ROS production. The intracellular and mitochondrial ROS concentrations have also been found to be increased with FACS-based assays. The efficacy of belumosudil observed in the cell-line-based study opens up the possibility of advancing to the next stages of in vivo studies and clinical trials for its use in the treatment of high-grade meningioma, either as a standalone therapy or in combination with other therapeutics.

Keywords:  Drug repurposing; High grade meningioma; IOMM-Lee; Oxidative phosphorylation; ROS; Therapeutics

DOI:  https://doi.org/10.1021/acs.jproteome.5c00262
Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01006-X. [Epub ahead of print]44(9): 116235

Disrupting the interaction between androgen receptor and its coregulator WDR77 delays the growth of treatment-resistant prostate cancer.

Ujjwal R Dahiya, Sangeeta Kumari, Nidhi Singh, Chitra Rawat, Eduardo Cortes, Yara Ghanem, Eva Corey, Scott M Dehm, Belinda Willard, Mohammed Alshalalfa, Elai Davicioni, Jesse McKenney, Christopher Weight, Samuel C Haywood, Song Liu, Tao Liu, Hannelore V Heemers.

  Continued reliance on the androgen receptor (AR) after androgen deprivation therapy (ADT) fails causes 35,000 American prostate cancer (CaP) deaths annually. Targeting the AR's transcriptional activity could overcome this acquired resistance, but has been challenging. We demonstrate the therapeutic potential of disrupting interactions between the AR and its coregulator WDR77. WDR77 stimulated CaP growth, and its overexpression was associated with worse patient survival. AR and WDR77 cistromes overlapped considerably, and AR- and WDR77-bound genes correlated with aggressive CaP features. Direct WDR77-AR interaction occurred, which, when disrupted, prevented AR-WDR77 complex formation, reduced AR DNA-binding and AR-dependent gene expression, and decreased cell proliferation to the same extent as ADT. Such interference inhibited cell growth by ADT-resistant AR action and after ADT-resistance without impacting AR-negative CaP or benign cells. Blocking AR-WDR77 cooperation also delayed the growth of organoids from patient-derived xenografts and fresh CaP specimens. Disrupting coregulator control over AR action may thus improve survival from ADT-resistant CaP.

Keywords:  CP: Cancer; CP: Molecular biology; MEP50; androgen deprivation therapy; androgens; antiandrogens; castration; hormonal therapy; hormones; methylosome; transcription; treatment resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.116235