ArticleMolecular biology reports2026
Targeting the USP7-PGAM5 axis overcomes oxaliplatin resistance in colorectal cancer.
Article in Molecular biology reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveChemoresistance remains a principal challenge in colorectal cancer (CRC) management, with mitochondrial dysfunction emerging as a key contributor. This study aims to elucidate the molecular mechanism by which the deubiquitinase USP7 regulates mitochondrial homeostasis to drive oxaliplatin resistance in CRC.
methodsWe comprehensively analyzed USP7 expression patterns in a cohort of 200 CRC clinical specimens and established isogenic oxaliplatin-resistant cell models. The association between USP7 and the mitochondrial phosphatase PGAM5 was systematically investigated through co-immunoprecipitation, in vitro ubiquitination assays, and molecular dynamics simulations. Functional validation was performed using genetic approaches including shRNA-mediated knockdown and overexpression, with comprehensive assessment through cell viability, apoptosis, colony formation, migration, and invasion assays.
resultsUSP7 demonstrates significant upregulation in CRC tissues and resistant cell lines, showing strong correlation with advanced TNM stage, lymph node metastasis, and reduced overall survival. Mechanistic studies support a physical association between USP7 and PGAM5, and ubiquitination assays suggest that USP7 promotes PGAM5 deubiquitination to enhance protein stability. USP7 silencing substantially sensitized CRC cells to oxaliplatin, suppressed proliferative capacity, impaired metastatic potential, and reversed epithelial-mesenchymal transition. Critically, PGAM5 overexpression effectively rescued the chemosensitive phenotype induced by USP7 deficiency.
conclusionOur findings establish the USP7-PGAM5 axis as a pivotal mitochondrial regulatory pathway that drives chemoresistance in CRC. This newly identified USP7–PGAM5 axis represents a promising therapeutic target. Pharmacological inhibition of USP7, in combination with oxaliplatin, could be a novel strategy to overcome chemoresistance in CRC patients. CLINICAL
trial registrationNot applicable (this study did not involve prospective enrollment of human participants requiring trial registration).
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