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Objective <p>Chemoresistance 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.</p> Methods <p>We 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.</p> Results <p>USP7 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.</p> Conclusion <p>Our 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.</p> Clinical trial registration <p>Not applicable (this study did not involve prospective enrollment of human participants requiring trial registration).</p>

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Targeting the USP7-PGAM5 axis overcomes oxaliplatin resistance in colorectal cancer

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • Chengxing Wang,
  • Canxiu He,
  • Yongfeng Ma,
  • Weijun Liang,
  • Chaorong Zhou,
  • Jinglin Zhao,
  • Yaoming He

摘要

Objective

Chemoresistance 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.

Methods

We 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.

Results

USP7 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.

Conclusion

Our 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 registration

Not applicable (this study did not involve prospective enrollment of human participants requiring trial registration).