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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年12月11日

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  • Yong-Ling Liang,
  • Cheng-Rui Zhong,
  • Jia-Yan Wu,
  • Ze-Jin Lin,
  • Zhu Lin,
  • Tai-Jun Yi,
  • Zhi-Ping Chen,
  • Hui-Lin Jin,
  • Jian-Dong Yu,
  • Ze-Yu Lin,
  • Yun-Le Wan,
  • Guo-Lin Li

摘要

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.