SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation

Yijie Tao^#^{1

2}, Shulei Yin^#¹, Kai Wei^#³, Liyuan Zhao^#¹, Yani Cui^{1

2}, Chunzhen Li¹, Yunyang Wu⁴, Panpan Hu^{1

2}, Shenhui Yin¹, Likun Cui¹, Yunyan Zhang⁵, Yixian He¹, Shu Yu¹, Jie Chen¹, Shaoteng Lu¹, Guifang Qiu¹, Mengqi Song¹, Siqi Yang¹, Qianshan Hou¹, Yiquan Xue¹, Chen Qian¹, Sheng Xu⁶, Yizhi Yu⁷, Zui Zou^{8

9

10}

Affiliations

¹ National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.
² School of Anesthesiology, Naval Medical University, Shanghai, China.
³ Department of Anesthesiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁴ School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China.
⁵ Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China.
⁶ National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. xusheng@immunol.org.
⁷ National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. yuyz@immunol.org.
⁸ National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. zouzui@smmu.edu.cn.
⁹ School of Anesthesiology, Naval Medical University, Shanghai, China. zouzui@smmu.edu.cn.
¹⁰ Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China. zouzui@smmu.edu.cn.

^# Contributed equally.

PMID: 41145774
DOI: 10.1038/s43018-025-01061-7

SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation

Yijie Tao et al. Nat Cancer. 2025.

. 2025 Oct 27.

doi: 10.1038/s43018-025-01061-7. Online ahead of print.

Authors

Affiliations

¹ National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.
² School of Anesthesiology, Naval Medical University, Shanghai, China.
³ Department of Anesthesiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁴ School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China.
⁵ Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China.
⁶ National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. xusheng@immunol.org.
⁷ National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. yuyz@immunol.org.
⁸ National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. zouzui@smmu.edu.cn.
⁹ School of Anesthesiology, Naval Medical University, Shanghai, China. zouzui@smmu.edu.cn.
¹⁰ Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China. zouzui@smmu.edu.cn.

^# Contributed equally.

PMID: 41145774
DOI: 10.1038/s43018-025-01061-7

Abstract

Systemic therapy is the optimal choice for individuals with unresectable or advanced hepatocellular carcinoma (HCC). However its effectiveness is constrained by resistance. Ferroptosis is a unique form of regulated cell death and plays an essential role in HCC systemic therapy. Here we identified that secernin-1 (SCRN1) was closely associated with ferroptosis resistance and poor prognosis in HCC. Specifically, high expression of SCRN1 enhances the interaction of phosphokinase serine/threonine kinase 38 (STK38) and glutathione peroxidase 4 (GPX4) to promote the phosphorylation of GPX4 at S45. This phosphorylation impairs heat shock protein family A member 8 (HSC70) recognition and degradation of GPX4 by chaperone-mediated autophagy, which further alleviates lipid peroxidation and ferroptosis. Our findings reveal a critical mechanism by which tumor cells antagonize ferroptosis through enhanced GPX4 phosphorylation and provide potential targets and strategies for HCC treatment.

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Conflict of interest statement

Competing interests: All authors declare no competing interests.

References

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SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation

Affiliations

SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous