Desulfinylation of the deubiquitinase USP7 by SRXN1 attenuates oxidative acute liver injury.

Authors

Mengyun Ke, Jong-Won Kim, Meishu Xu, Jingyuan Wang, Lingyi Liu, Syamprasad N P, Bin Yang, Xiaofei Wang, Huatian Li, Songrong Ren, Kate S Carroll, Song Li, Wen Xie

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 40. Pages e2620180123. Oct 06, 2026. Epub Sep 29, 2026.

Abstract

Protein S-sulfinylation is a reversible oxidative cysteine modification, but its contribution to acute liver injury such as those induced by acetaminophen (APAP) overdose has not been reported. Sulfiredoxin-1 (SRXN1) is the only oxidoreductase known to reduce the sulfinylated proteins, yet the substrates and mechanisms through which it protects against acute liver injury are unclear. Here, we show that hepatic protein S-sulfinylation was markedly upregulated in APAP-overdose patients and mice. Hepatocyte-specific knockout or pharmacological inhibition of Srxn1 sensitized mice to APAP-induced acute liver injury. In contrast, overexpression of SRXN1, but not its oxidoreductase-dead C99S mutant, protected mice from APAP-induced liver injury. Mechanistically, we identified the deubiquitinase ubiquitin-specific protease 7 (USP7) as an SRXN1 substrate required for hepatoprotection. USP7 inhibition worsened APAP-induced liver injury, whereas its overexpression alleviated injury by stabilizing its deubiquitinase substrate heme oxygenase-1 (HO-1). Loss of SRXN1 enhanced S-sulfinylation of USP7 at Cys315, promoting its ubiquitination and degradation. SRXN1 expression correlated with USP7 levels in human liver samples. Delayed lipid nanoparticle (LNP) delivery of SRXN1 messenger RNA (mRNA) mitigated established APAP-induced liver injury beyond the therapeutic window of N-acetylcysteine. These findings define an SRXN1-USP7-HO-1 axis as a promising therapeutic target for oxidative liver injury and highlight LNP-mediated SRXN1 mRNA delivery as a potential treatment approach.

PMID:
42809400
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.