The de-sulfinylation enzyme sulfiredoxin-1 attenuates hepatic stellate cell activation and liver fibrosis by modulating the PTPN12-NLRP3 axis

Jong Won Kim, Hung Chun Tung, Mengyun Ke, Pengfei Xu, Xinran Cai, Yue Xi, Meishu Xu, Songrong Ren, Yixian Huang, Amit Bhowmik, Kate S. Carroll, Yun Soo Bae, Song Li, Wen Xie

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: Liver fibrosis is characterized by the progressive scarring of liver tissue. Oxidative stress is a critical causal factor of hepatic stellate cell (HSC) activation and the subsequent liver fibrogenesis, but the mechanism is not fully understood. Cysteine sulfinic acid (Cys-SO2H), a modification of reactive cysteine residues, is a unique form of oxidative response that alters the structure and function of proteins. Sulfiredoxin 1 (SRXN1) is responsible for ATP-dependent reduction of the Cys-SO2H to sulfenic acid (Cys-SOH). Approach & Results: We found that the expression of SRXN1 was increased in activated HSCs and in human and mouse fibrotic livers. HSC-specific ablation of Srxn1 or pharmacological inhibition of Srxn1 exacerbated HSC activation and sensitized mice to liver fibrosis. Mechanistically, SRXN1 inhibited HSC activation by de-sulfinylating the phosphatase protein tyrosine phosphatase non-receptor type 12 (PTPN12), which enhanced its phosphatase activity and protein stability, leading to decreased tyrosine phosphorylation and reduced activation of the pro-fibrotic inflammasome protein NLRP3. The anti-fibrotic effect of SRXN1 was abolished when NLRP3 was inhibited. In contrast, overexpression of PTPN12 attenuated NLRP3 activation, and this effect was further amplified by the C164A S-sulfinylation resistant mutant of PTPN12. Conclusions: Our findings have uncovered an important role of SRXN1 and protein S-sulfinylation in HSC activation and liver fibrosis. The SRXN1-PTPN12-NLRP3 axis represents potential therapeutic targets for liver fibrosis.

Original languageEnglish
JournalHepatology
DOIs
StateAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
Copyright © 2024 American Association for the Study of Liver Diseases.

Keywords

  • hepatic stellate cell
  • liver fibrosis
  • oxidative stress
  • S-sulfylation
  • SRXN1

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