USP10 promotes cell proliferation and gemcitabine resistance in pancreatic cancer by the regulation of IGF2BP3-STEAP3.

Gemcitabine resistance remains a major obstacle in the treatment of pancreatic adenocarcinoma (PDAC). Through gain- and loss-of-function experiments, we identified USP10 as a positive regulator of tumor growth and gemcitabine resistance. Mechanistically, we demonstrate that USP10 stabilizes IGF2BP3 by removing its K48- and K63-linked ubiquitin chains, thereby inhibiting proteasomal degradation. The stabilized IGF2BP3 binds to and enhances the stability of STEAP3 mRNA in an m⁶A-dependent manner. Upregulation of STEAP3 suppresses ferroptosis by increasing glutathione levels and reducing lipid peroxidation, ultimately promoting tumor proliferation and gemcitabine resistance. Our study identifies the USP10-IGF2BP3-STEAP3 axis as a critical mechanism underlying chemoresistance in pancreatic cancer, suggesting that targeting USP10 may offer a promising therapeutic strategy for overcoming gemcitabine resistance.