bims-meract Biomed News
on Metabolic reprogramming and anti-cancer therapy
Issue of 2026–07–12
thirteen papers selected by
Andrea Morandi, Università degli Studi di Firenze
  1. Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.
  2. Polyvinyl chloride promotes radioresistance in hepatocellular carcinoma by inhibiting radiotherapy-induced CD8⁺ T cell differentiation.
  3. A succinylation-based classifier predicts chemotherapy response in prostate cancer and reveals KAT2A as a therapeutic target.
  4. Inhibition of ferroptosis via SLC25A39-NRF2 axis drives Osimertinib resistance in lung adenocarcinoma.
  5. PRMT5-Dependent Stabilization of VPS34 Orchestrates Copper Trafficking to Shield Cancer Cells from Cuproptosis and Radiotherapy.
  6. BET inhibition unmasks a targetable glycolytic dependency through a HIF1α stabilization and driven transcriptional program in a defined subset of triple-negative breast Cancer.
  7. PFKFB4 Deubiquitination by USP10 Enhances Fumarate Metabolism to Orchestrate the KDM1A/Rad51 Axis and Confer Radioresistance in Lung Cancer.
  8. Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.
  9. Unlocking the ferroptotic window: Lipidomic rewiring and metabolic addiction in EMT-driven breast cancer resistance.
  10. LD-associated signatures identified by perilipin-based proximity labeling proteomics reveal GNA14 as a therapeutic and prognostic target in renal cell carcinoma.
  11. Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer.
  12. USP20-mediated PGAM1 stabilization promotes glycolysis and confers osimertinib resistance in non-small cell lung carcinoma.
  13. LMAN2 promotes breast cancer progression and deduces cell sensitivity to doxorubicin through stearoyl-CoA desaturase.
  1. Cell Death Dis. 2026 Jul 07.
    Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.
    Marta Iozzo, Luigi Ippolito, Erica Pranzini, Simone Romagnoli, Giulia Gangarossa, Caterina Grillo, Sara Roccabianca, Giada Sandrini, Matteo Benelli, Giuseppina Comito, Elisa Giannoni, Paola Chiarugi.
      Prostate cancer (PCa) progression is strongly influenced by the metabolites available in the tumor microenvironment (TME), including lactic acid (LA), which is actively imported by PCa cells to boost mitochondrial metabolism and drive de novo collagen synthesis, sustaining increased malignancy. LA exploitation promotes the unbalance of tricarboxylic acid (TCA) cycle intermediates, particularly succinate and fumarate, well-known epigenetic modifiers for histone (de)methylation. Here, we show that the LA-induced increase in succinate levels affects the activating H3K4me3 methylation mark in PCa cells, promoting a pro-invasive phenotype. Notably, pharmacological targeting of H3K4me3 using OICR-9429 reduces LA-enhanced PCa cell invasiveness. Moreover, LA-induced H3K4me3 enrichment regulates the expression of procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 1 (PLOD1), a key enzyme involved in collagen maturation. Genetic impairment of PLOD1 reduces the LA-driven invasive potential of PCa cells, thereby highlighting PLOD1 as a crucial epigenetically regulated mediator of tumor invasion. Overall, our findings uncover a novel LA-fuelled metabolic-epigenetic axis that promotes the H3K4me3-mediated PLOD1 upregulation, consequently fostering PCa aggressiveness and unveiling a potential therapeutic vulnerability.
    DOI:  https://doi.org/10.1038/s41419-026-09091-4
  2. Nat Commun. 2026 Jul 10.
    Polyvinyl chloride promotes radioresistance in hepatocellular carcinoma by inhibiting radiotherapy-induced CD8⁺ T cell differentiation.
    Haibo Zhang, Yanwei Lu, Hao Xiong, Lei Shi, Hongen Xu, Yongshi Jia, Jun Zhao, Hailong Sheng.
      Radiotherapy is standard-of-care treatment for intermediate and advanced hepatocellular carcinoma (HCC); however, resistance remains widespread. Microplastics are detectable in various tumors and may disrupt immune responses, but evidence regarding the role of microplastics in radiotherapy is scarce. Here we show that various types of microplastics are detectable in 52 of the 72 HCC samples we examine, but only polyvinyl chloride (PVC) impairs radiotherapy efficacy. Mechanistically, irradiation enhances histone lactylation, which promotes transcription of HMG-CoA reductase in HCC cells, thereby facilitating cholesterol synthesis and reinforcing CD8+ T cell stemness. PVC alters cholesterol localization and affects CD8⁺ T cell differentiation, which results in the maintenance of an immunologically cold tumor immune microenvironment. A high-cholesterol diet restores CD8+ T-cell stemness and improves therapeutic response to radiotherapy in PVC-infiltrated HCC. Targeting cholesterol metabolism may represent a potential combinatorial strategy to enhance the efficacy of radiotherapy in PVC-infiltrated HCC.
    DOI:  https://doi.org/10.1038/s41467-026-75415-9
  3. Clin Transl Med. 2026 Jul;16(7): e70737
    A succinylation-based classifier predicts chemotherapy response in prostate cancer and reveals KAT2A as a therapeutic target.
    Antao Dong, Wei Hu, Zhihui Lu, Liangliang Li, Kun Liu, Shiyao Feng, Dongdong Xie.
       BACKGROUND: Chemotherapy resistance remains a critical hurdle in advanced prostate cancer (PCa). Succinylation, an essential post-translational modification linking cellular metabolism with epigenetic regulation, has been implicated in tumour progression; however, its contribution to PCa chemoresistance remains poorly defined.
    OBJECTIVE: This study aimed to evaluate the prognostic significance of succinylation in PCa, develop a succinylation-based biomarker, and elucidate the mechanisms driving chemotherapy resistance.
    METHODS: We generated a succinylation score (SS) by applying single-sample gene set enrichment analysis (ssGSEA) to transcriptomic profiles from the TCGA-PRAD cohort. Its relationships with survival, the tumour microenvironment (TME), and treatment susceptibility were examined using CIBERSORT, GSEA, TIDE, oncoPredict, and single-cell RNA sequencing (scRNA-seq). Findings were functionally validated in patient-derived organoids, PCa cell lines, and xenograft models through genetic manipulation, chemosensitivity assays, and mechanistic studies.
    RESULTS: High SS correlated with favourable prognosis, lower Gleason scores, absent lymph node metastasis, and an immune-active TME enriched in CD8+ precursor exhausted T cells. High-SS tumours showed enhanced sensitivity to docetaxel and cisplatin. scRNA‑seq identified KAT2A as a key driver in low‑SS malignant clusters with chemoresistance features. KAT2A was elevated in chemoresistant tissues, cell lines, and organoids. KAT2A knockout sensitised cells to chemotherapy, while ectopic expression promoted resistance in vitro and in vivo. Mechanistically, KAT2A-mediated succinylation of PIK3R2 at K477 and K564 inhibited its ubiquitination and proteasomal degradation, stabilising PIK3R2 to drive chemoresistance. The KAT2A inhibitor Butyrolactone 3 synergised with standard chemotherapy to suppress tumour growth.
    CONCLUSION: The succinylation score serves as a robust prognostic biomarker integrating metabolic and immunological features in PCa. The KAT2A-PIK3R2 succinylation pathway represents a newly defined driver of chemoresistance and points to MB-3-based combination therapy as a potential strategy for resistant advanced disease.
    KEY POINTS: A transcriptome-based succinylation score (SS) stratifies prostate cancer by prognosis, immune contexture, and chemotherapy sensitivity. KAT2A is enriched in low-SS, chemoresistant tumours and promotes resistance by succinylating PIK3R2. KAT2A-mediated succinylation competitively inhibits PIK3R2 ubiquitination, stabilising PIK3R2 and driving chemoresistance. The KAT2A inhibitor MB-3 synergises with chemotherapy to suppress tumour growth in both chemoresistant and chemosensitive models.
    Keywords:  KAT2A; chemoresistance; prostate cancer; succinylation; tumour microenvironment
    DOI:  https://doi.org/10.1002/ctm2.70737
  4. Cell Mol Life Sci. 2026 Jul 06.
    Inhibition of ferroptosis via SLC25A39-NRF2 axis drives Osimertinib resistance in lung adenocarcinoma.
    Kai Fu, Zhilin Zeng, Wenfeng Wang, Wei Wu, Yijie Gong, Xiangning Fu, Yixin Cai, Changyu Liu.
       OBJECTIVE: Overcoming resistance to Osimertinib remains a major clinical challenge in lung adenocarcinoma (LUAD). The molecular mechanisms driving this resistance are still not fully understood.
    METHODS: Integrated bioinformatics analysis and functional assays were performed to investigate the role of SLC25A39 in LUAD progression and drug resistance. Mechanistic studies were conducted using co-immunoprecipitation and rescue experiments. Osimertinib-resistant cell models and xenograft assays were used to evaluate therapeutic responses.
    RESULTS: SLC25A39 was significantly upregulated in LUAD and correlated with unfavorable patient outcomes. Functional studies showed that SLC25A39 depletion suppressed malignant phenotypes and enhanced ferroptosis, whereas its overexpression produced the opposite effects. Mechanistically, SLC25A39 was found to interact with NRF2 and was associated with increased NRF2 stability and transcriptional activity, leading to enhanced glutathione synthesis and attenuation of lipid peroxidation. Importantly, silencing SLC25A39 sensitized LUAD cells to Osimertinib. Consistent with this, pharmacological induction of ferroptosis using RSL3 markedly enhanced the antitumor effects of Osimertinib in both parental and resistant models, resulting in reduced tumor growth in vitro and in vivo, particularly in SLC25A39-high contexts.
    CONCLUSION: SLC25A39 promotes LUAD progression and Osimertinib resistance by suppressing ferroptosis via NRF2. Targeting ferroptosis may represent a promising strategy to overcome Osimertinib resistance.
    Keywords:  Chemotherapy resistance; Ferroptosis; Lung adenocarcinoma; Osimertinib; SLC25A39
    DOI:  https://doi.org/10.1007/s00018-026-06313-y
  5. Adv Sci (Weinh). 2026 Jul 08. e76350
    PRMT5-Dependent Stabilization of VPS34 Orchestrates Copper Trafficking to Shield Cancer Cells from Cuproptosis and Radiotherapy.
    Wei Chen, Ming-Ying Xiao, Lan-Lan Guo, Hao-Yue Hu, Sui-Xian Zhang, Bai-Qiang Dong, Chen-Fei Wu, Xia-Hang Huang, Li Li, Run-Zhe Chen, Yuan-Yang Huang, Ying Jin, Hai Song, Ying Wang, Qi-Wen Li, Ming Chen, Xuan Li, Yuan-Yuan Chen.
      Targeting cuproptosis for cancer therapy is hindered by an incomplete understanding of the intrinsic defense networks through which tumor cells mobilize to evade this fate, particularly under therapeutic stress such as radiotherapy. Here, we identify VPS34-mediated copper homeostasis as a critical anticuproptotic process through a genome-wide CRISPR activation screen. PRMT5 directly methylated VPS34 at Arg174 and inhibited K48-linked polyubiquitination and proteasomal degradation of VPS34 by recruiting the deubiquitinase USP10. This stabilization increased the cuproptotic defense of tumor cells by promoting autophagic degradation of the copper importer SLC31A1 and plasma membrane translocation of the exporter ATP7A, thereby reducing the intracellular copper load. Functional analysis and clinical correlation revealed that the PRMT5-VPS34 axis is robustly activated by radiation stress and is necessary for adaptive radioresistance. The inhibition of PRMT5 or VPS34 expression suppressed tumor growth and enhanced the sensitivity of tumors to radiotherapy by unleashing latent copper cytotoxicity both in vitro and in vivo. Together, our findings identify the PRMT5-VPS34 axis as a therapeutic target for sensitizing refractory cancers to radiotherapy.
    Keywords:  PRMT5; VPS34; copper homeostasis; cuproptosis; radiotherapy; resistance
    DOI:  https://doi.org/10.1002/advs.76350
  6. Cell Death Discov. 2026 Jul 08.
    BET inhibition unmasks a targetable glycolytic dependency through a HIF1α stabilization and driven transcriptional program in a defined subset of triple-negative breast Cancer.
    Teresa Rossi, Egidio Iorio, Mattea Chirico, Maria Elena Pisanu, Federica Torricelli, Alessia Ciarrocchi, Mariaelena Pistoni.
      Triple-negative breast cancer (TNBC) is characterized by transcriptional and metabolic heterogeneity, which influences its response to therapeutics. Epigenetic drugs such as Bromodomain and Extra-Terminal domain inhibitors (BETi) are no exception to this variable response. However, the determinants of BETi sensitivity and the underlying mechanisms of response remain poorly understood, particularly in the context of metabolic reprogramming. Here, we investigated the responses to the BETi JQ1 and OTX015 across a heterogeneous panel of TNBC models. We found that the susceptibility to BETi partially correlates with basal BRD4 protein levels, but only in contexts characterized by high baseline cMYC levels, where BETi treatment triggers an upregulation of glycolytic genes, an effect that is absent in models displaying an intrinsically glycolytic phenotype. While the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) is effective as a single agent in the glycolytic-prone setting, it has limited efficacy in other TNBC models. Strikingly, a notable additive effect is visible when BETi are combined with 2-DG, leading to significant apoptotic induction, specifically in the BETi-responsive cells, whereas this additive effect is not observed in the glycolysis-driven models. Mechanistically, we identified that BETi induces the HIF1α transcriptional program in cMYC-high cells, which upregulates key glycolytic enzymes. HIF1α depletion reduced this response, confirming that HIF1α is functionally required for this adaptive rewiring. In conclusion, TNBC cells adapt to BETi by undergoing HIF1α-mediated metabolic rewiring towards glycolysis. This adaptive response creates a vulnerability, rendering these tumors sensitive to the combination of BET and glycolysis inhibitors. By mapping a transcriptional-metabolic axis that dictates BETi sensitivity, this study moves beyond the identification of a resistant subset of TNBC to reveal a deeper principle: targeted inhibition can actively reprogram cellular circuitry, thereby constructing its own unique therapeutic vulnerability. Thus, the path to overcoming resistance may lie not in evading this rewiring, but in strategically exploiting the alternative dependencies it creates.
    DOI:  https://doi.org/10.1038/s41420-026-03230-8
  7. Adv Sci (Weinh). 2026 Jul 08. e76439
    PFKFB4 Deubiquitination by USP10 Enhances Fumarate Metabolism to Orchestrate the KDM1A/Rad51 Axis and Confer Radioresistance in Lung Cancer.
    Yunshang Chen, Zilong Wu, Yongqiang Yang, Ruoxin Fang, Huichan Xue, Rui Zhou, Gang Wu, Xiaohua Jie.
      Aberrant glucose metabolism reprogramming is a key driver of radioresistance, which is a major obstacle in lung cancer treatment. As a central glucose metabolic regulator, the specific function and molecular mechanisms of PFKFB4 in this process remain undefined. This study revealed that PFKFB4 is aberrantly overexpressed in lung cancer and that targeted inhibition of PFKFB4 enhances radiosensitivity both in vitro and in vivo. Mechanistically, PFKFB4 upregulates fumarate by driving the ATP-dependent urea cycle. Accumulated fumarate inhibits the histone demethylase KDM1A, leading to increased enrichment of H3K4me1 at the Rad51 promoter and the subsequent transcriptional activation of Rad51, thereby promoting radioresistance. Furthermore, a ubiquitin library screen revealed that the deubiquitinase USP10 is an upstream regulator that binds and stabilizes PFKFB4 by deubiquitinating PFKFB4 at residue K431. Consequently, USP10 depletion increases radiosensitivity by disrupting the PFKFB4/fumarate/Rad51 axis. In summary, this study elucidates the mechanism by which PFKFB4 overexpression confers radioresistance in lung cancer, providing a rationale for targeting this protein in the clinical treatment of lung cancer patients.
    Keywords:  PFKFB4; deubiquitination; fumarate; non‐small cell lung cancer; radioresistance
    DOI:  https://doi.org/10.1002/advs.76439
  8. Nat Commun. 2026 Jul 04.
    Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.
    Renming Fan, Xintong Lu, Bingjie Zhang, Zhuang Hou, Ting Zhao, Yongrui Hai, Ye Chen, Wenhui Wang, Yue Chen, Qiu Sun, Lei Liang, Le Yang, Gaofei Wei.
      Colorectal cancer (CRC) often exhibits a suppressive tumor microenvironment that is associated with elevated glutamine metabolism and induction of immunosuppressive macrophages. Glutamine antagonists such as 6-diazo-5-oxo-L-norleucine (DON) and its prodrug JHU-083 can limit tumor growth, but their toxicity and immune cell selectivity remain suboptimal. Here, we conjugate DON with the macrophage-targeting moiety artesunate to develop WGF-T17 (T17), which blocks glutamine metabolism in macrophages. In vitro, T17 rewires macrophage metabolism toward glycolysis, inducing lactate buildup and histone lactylation, enhancing mitochondrial fission and phagocytic activity, and thereby reprogramming macrophages to an inflammatory state. In vivo, T17 controls tumor growth better than JHU-083 via macrophage-dependent pathways, and also increases the efficacy of immunotherapy, chemotherapy and anti-angiogenic therapy in female mice carrying subcutaneous CRC tumors. Our findings thus hint T17 as a promising treatment strategy for CRC by targeting macrophage glutamine metabolism to reverse immune suppression.
    DOI:  https://doi.org/10.1038/s41467-026-75208-0
  9. Cell Death Discov. 2026 Jul 04.
    Unlocking the ferroptotic window: Lipidomic rewiring and metabolic addiction in EMT-driven breast cancer resistance.
    Jian Lu, Chrysa Filippopoulou, Junjie Sun, Pengtao Hu, Chaoyue Pan, Xiaoyan Wu, Xidong Gu, Xiaohong Xie, Qijin Shu, Georgios Giamas.
      Breast cancer (BC) continues to pose a substantial clinical challenge due to acquired resistance induced by epithelial-mesenchymal transition (EMT). Nevertheless, this adaptive evolution, which frequently takes the form of a highly plastic, partial EMT (p-EMT) state, induces a profound lipidomic reconfiguration and iron dysregulation, thereby inadvertently revealing a targetable metabolic vulnerability: ferroptosis. In this Perspective, we outline the hierarchical molecular logic that governs this susceptibility, emphasizing the manner in which progressive p53 mutations (ranging from loss-of-function to gain-of-function) transform p-EMT cells from passive sensitization to an extreme "metabolic addiction." We argue that conventional "occupancy-driven" kinase inhibitors are unable to eliminate these resistant populations because they are unable to dismantle the essential non-catalytic scaffolding functions of core EMT-induced kinases (EIKs). As a result, we suggest a paradigm shift toward a chemical biology approach that is "event-driven." The p-EMT infrastructure can be irreversibly destroyed and resistant cells can be compelled to undergo catastrophic lipid peroxidation by deploying proteolysis targeting chimeras (PROTACs) against concealed scaffold super-hubs, particularly AXL and lemur tail kinase 3 (LMTK3), which are indispensable for stabilizing the hybrid p-EMT infrastructure. Additionally, we investigate the spatiotemporal modulation of this synthetic lethal axis by the tumor microenvironment (TME) through matrix mechanics and extracellular vesicles (EVs). Ultimately, we suggest a multimodal liquid biopsy strategy that couples specific oxidized phospholipid signatures with circulating tumor DNA (ctDNA) kinetics to precisely monitor in vivo ferroptotic events. This approach offers a transformative roadmap for eradicating minimal residual disease (MRD) and surmounting BC dormancy.
    DOI:  https://doi.org/10.1038/s41420-026-03217-5
  10. Cancer Gene Ther. 2026 Jul 11.
    LD-associated signatures identified by perilipin-based proximity labeling proteomics reveal GNA14 as a therapeutic and prognostic target in renal cell carcinoma.
    Yuankang Feng, Xinran Zhang, Shiyue Zhang, Jianqiao Li, Zhihao Bo, Jialu Ma, Xinyu Liu, Yang Liu, Shumin Yu, Rui Wang, Mingjian Lian, Yaqun Zhang, Dan Yue, Yong Wang.
      Renal cell carcinoma (RCC), especially clear cell RCC (ccRCC), is characterized by metabolic reprogramming, notably disordered lipid metabolism and prominent intracellular lipid droplet accumulation. In addition to abnormal triglyceride and cholesterol ester storage, lipid droplets promote tumor proliferation, survival, and drug resistance by supplying energy, membrane components, and signaling platforms, thereby representing potential therapeutic targets. We integrated TMU-RNAseq and TCGA-KIRC datasets and performed proximity-labeling mass spectrometry targeting PLIN2/3 to identify perilipin-related genes (PRGs). Based on TCGA-KIRC, we established a lipid droplet-related model (LDM), and the LDM score (LDMS) effectively predicted ccRCC prognosis. Validation in TCGA-KIRC and three external cohorts (GSE22541, E-MTAB-1980, and E-MTAB-3267) showed superior prognostic performance over conventional clinical parameters. High LDMS was associated with increased mutation frequency and an immunosuppressive microenvironment. Drug sensitivity analysis suggested differential responses to Sorafenib, Cediranib, and Saracatinib. Functional assays demonstrated that GNA14 inhibits ccRCC progression and enhances lipid accumulation via PLIN2 upregulation. GNA14 overexpression combined with Lovastatin further strengthened antitumor effects. Overall, LDM is a robust prognostic tool, and GNA14 plus Lovastatin may offer a potential therapeutic strategy for ccRCC. On one hand, at a general level, overexpression of GNA14 in RCC significantly inhibits the proliferation, migration, and invasion of renal cancer cells, thereby exerting a suppressive effect on RCC. On the other hand, GNA14 interacts with PLIN2, leading to an increase in PLIN2 expression, which subsequently results in an enlargement of lipid droplet quantity and volume. This causes a notable rise in cholesterol and triglyceride levels within RCC cells, further facilitating RCC progression. Excitingly, lovastatin can partially block the detrimental pathway by which GNA14 promotes lipid accumulation. Therefore, combining lovastatin with GNA14 overexpression yields a more effective suppression of RCC.
    DOI:  https://doi.org/10.1038/s41417-026-01055-2
  11. Nat Commun. 2026 Jul 08.
    Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer.
    Scott Best, Daniel S Hippe, Eli Grunblatt, Jackson Fatherree, Pritha Chanana, Feinan Wu, Richard Ivey, Jacob J Kennedy, David Sokolov, Ali Ibrahim, Haodong Xu, Raymond J Monnat, Lucas B Sullivan, Patrick Paddison, Amanda G Paulovich, David MacPherson.
      Small cell lung cancer (SCLC) responds exceptionally well to cytotoxic chemotherapy. However, relapse with the emergence of chemoresistant disease is rapid and accompanied by poor treatment outcomes. To understand the genetic basis of chemoresistance in SCLC, we apply in vivo CRISPR deletion screening to patient-derived xenograft (PDX) models. Top screen hits include genes encoding components of the transcriptional co-activator SAGA (Spt-Ada-Gcn5 acetyltransferase) complex. We demonstrate that deletion of the SAGA deubiquitylase USP22 confers cisplatin-etoposide resistance in two chemosensitive PDX models, and that restoring expression in a PDX model harboring homozygous truncating mutation of USP22 re-sensitizes tumors to chemotherapy. USP22 loss increases gene body histone H2AK119 monoubiquitylation at key regulators of neuronal differentiation and suppresses neural and neuroendocrine gene expression including targets of ASCL1. Chemoresistance following USP22 loss reflects attenuated DNA damage-driven phosphorylation events and apoptosis, in conjunction with increased expression of glycolysis and hypoxia-related genes. Glycolysis program upregulation may reflect a targetable vulnerability, as inhibition of GLUT1 re-sensitizes USP22-null tumors to chemotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-75117-2
  12. Oncogene. 2026 Jul 08.
    USP20-mediated PGAM1 stabilization promotes glycolysis and confers osimertinib resistance in non-small cell lung carcinoma.
    Yunchong Meng, Xiaojun Wang, Shihao Wu, Wei Lin, Mingliang Wang, Kuo Li, Peiyuan Mei, Quanfu Huang, Liao Yongde, Na Wang.
      Osimertinib resistance poses a significant clinical challenge in treating non-small cell lung carcinoma (NSCLC) patients harboring EGFR-activating or T790M mutations, highlighting the urgent need to elucidate the underlying molecular mechanisms. In this study, we show that elevated USP20 expression drives osimertinib resistance and is associated with poor clinical outcomes in osimertinib-resistant NSCLC. Mechanistically, USP20 specifically interacts with PGAM1 and catalyzes the removal of K225-linked ubiquitin chains through its C154 catalytic site, thereby stabilizing PGAM1 to enhance glycolysis and promote osimertinib resistance. Importantly, through extensive virtual drug screening, we identified compound 89131-02-2 as a novel and selective inhibitor that targets the USP20 C154 catalytic site. Pharmacological inhibition of USP20 by 89131-02-2 effectively suppressed glycolysis and restored osimertinib sensitivity in functional assays. Our findings not only establish the USP20-PGAM1 axis as a key mediator of osimertinib response but also offer a potential therapeutic strategy to overcome resistance in NSCLC patients.
    DOI:  https://doi.org/10.1038/s41388-026-03889-4
  13. Breast Cancer Res. 2026 Jul 08.
    LMAN2 promotes breast cancer progression and deduces cell sensitivity to doxorubicin through stearoyl-CoA desaturase.
    Changjiao Yan, Fengqiang Cui, Chutuo Liu, Rui Ling, Meiling Huang, Ting Wang.
       BACKGROUND: Dysregulated lipid metabolism and chemoresistance are key drivers of breast cancer progression. Lectin, mannose-binding 2 (LMAN2) is frequently overexpressed in human breast tumors and functions as an oncogenic driver. However, whether LMAN2 contributes to chemoresistance remains unknown.
    METHODS: We integrated multi-omics data from 1,085 primary tumors and matched normal tissues (from GEPIA and UALCAN) with functional studies in breast cancer cell lines and a doxorubicin (ADM)-treated nude mouse xenograft model. LMAN2 expression was modulated via siRNA/shRNA-mediated silencing or lentivirus-driven overexpression. Cellular phenotypes-including proliferation, migration, apoptosis, and response to ADM were systematically assessed. RNA-sequencing, untargeted lipidomics, and rescue experiments identified stearoyl-CoA desaturase (SCD) as a critical downstream effector. IC50 shifts and epistasis analysis further validated the role of the LMAN2/SCD axis in chemoresistance.
    RESULTS: LMAN2 mRNA was elevated across all molecular subtypes (luminal > HER2 > triple-negative) and predicted poorer overall survival (P = 5 × 10-4) and progression-free survival (P = 0.018). Silencing LMAN2 reduced clonogenicity by ~ 45% and migration by 37-63%, whereas overexpression increased cell viability by 1.4-1.7-fold and doubled motility. Knockdown of LMAN2 decreased the ADM IC50 by 4-5 fold, abolished macroscopic colony formation, and elevated apoptosis rates from 15 to 18% to 39-41%; these effects were reversed upon LMAN2 overexpression. In vivo, shLMAN2 combined with ADM reduced tumor volume and weight by 72% and 75%, respectively, compared to ADM alone (P < 0.001). Mechanistically, LMAN2 loss downregulated genes involved in "cholesterol homeostasis" and reduced total cellular cholesterol by 24%. SCD emerged as the most significantly downregulated enzyme and fully rescued the phenotypic and chemoresistance effects resulting from LMAN2 modulation. Epistasis experiments confirmed that LMAN2-mediated chemoresistance strictly depends on SCD function.
    CONCLUSIONS: LMAN2 is a robust prognostic biomarker that promotes breast tumor growth and anthracycline resistance by enabling SCD-dependent lipid desaturation. Therapeutic targeting of the LMAN2/SCD axis represents a promising strategy to overcome chemoresistance in breast cancer.
    Keywords:   LMAN2 ; ADM; SCD; breast cancer; cholesterol homeostasis
    DOI:  https://doi.org/10.1186/s13058-026-02343-3
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