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

Oncogene volume 45, pages 383–397 (2026)Cite this article

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Abstract

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.

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Fig. 1: USP10 is significantly overexpressed in pancreatic cancer and associated with gemcitabine resistance and poor prognosis.
Fig. 2: USP10 promotes pancreatic cancer cell proliferation and gemcitabine resistance.
Fig. 3: USP10 interaction with IGF2BP3, deubiquitinating IGF2BP3 to stabilize its protein expression.
Fig. 4: The USP10-IGF2BP3 axis is critical for pancreatic cancer progression and chemoresistance to gemcitabine.
Fig. 5: IGF2BP3 positively regulates STEAP3 expression.
Fig. 6: STEAP3 promotes cancer cell growth and facilitates gemcitabine resistance in PAAD by suppressing ferroptosis.
Fig. 7: STEAP3 overexpression counteracts the effect induced by IGF2BP3 knockdown.
Fig. 8: Clinical significance of the USP10-IGF2BP3-STEAP3 axis in gemcitabine resistance.

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Data availability

The datasets generated during or analyzed during the current study are available from the corresponding authors on reasonable request. Figshare :https://doi.org/10.6084/m9.figshare.30017347.

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Acknowledgements

We thank the Institute of Gastrointestinal Disease, the Sixth Affiliated Hospital of Sun Yat-Sen University for support with equipment and site.

Funding

This study was supported by National Natural Science Youth Foundation of China (Z201901022021121076), Discipline construction fund of the Sixth Affiliated Hospital of Sun Yat-Sen University (X202102172026091185), National Natural Science Youth Foundation of China (No. Z201901022021121076; No. 82403535) and China postdoctoral science foundation (2023M744076, 2024T171079).

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Author notes

  1. These authors contributed equally: Yong-Ling Liang, Cheng-Rui Zhong, Jia-Yan Wu.

Authors and Affiliations

  1. Department of General Surgery (Hepatobiliary Pancreatic and Splenic Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Yong-Ling Liang, Cheng-Rui Zhong, 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

  2. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    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

  3. Department of Thoracic Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Jia-Yan Wu

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Contributions

Y-lL, C-RZ, and J-YW performed most of the cellular, biochemical, and animal experiments. Z-JL and Z-L partially designed the experimental plans and contributed to the cellular and biochemical experiments. T-jY, Z-PC, H-LJ, and J-DY partially contributed to the data analysis and provided the technological support for animal experiments. G-LL, Y-LW, and Z-YL designed experiments, supervised the project analyzed results, and wrote the paper.

Corresponding authors

Correspondence to Ze-Yu Lin, Yun-Le Wan or Guo-Lin Li.

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The authors declare no competing interests.

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The study was conducted in compliance with international, national, and institutional regulations regarding animal experiments, clinical studies, and biodiversity rights. All participants signed an informed consent form and this information was submitted to the ethics committee for the assignment of an ethical approval code. The Institutional Review Board of The Sixth Affiliated Hospital of Sun Yat-Sen University approved this study. Approval number: IACUC-2022081101. The study was performed in accordance with the Declaration of Helsinki.

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Liang, YL., Zhong, CR., Wu, JY. et al. USP10 promotes cell proliferation and gemcitabine resistance in pancreatic cancer by the regulation of IGF2BP3-STEAP3. Oncogene 45, 383–397 (2026). https://doi.org/10.1038/s41388-025-03654-z

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