Jie Chen # 1, Zhuohang Liu # 1, Jian Gu # 2, Yishen Jiang # 1, Kexin Cao 1, Nannan Zhou 1, Yabo Zhou 1, Zhenfeng Wang 1, Li Zhou 1, Jin Yu 1, Xu Sun 1, Tao Li 3, Lu Zhang 4, Tianning Huang 2, Dianheng Wang 1, Chaoqi Zhang 1 5, Ke Tang 6, Jingwei Ma 7, Huafeng Zhang 8, Jiadi Lv 1, Bo Huang 9 10

Nat Metab. 2026 Apr 2.

PMID: 41927796 DOI: 10.1038/s42255-026-01507-x

Abstract

The role of hepatic insulin resistance (HIR) in the development of fatty liver, diabetes and cardiovascular diseases is well known, yet the molecular basis of HIR remains unclear, limiting targeted therapeutic strategies. Here we show that insulin signalling-inactivated phosphorylated GSK-3β (p-GSK-3β) is revitalized via reactive oxygen species-mediated sulfenylation, leading to glycogenesis termination and gluconeogenesis initiation, two hallmarks of HIR. Mechanistically, sulfenylated or 'oxidatively activated' p-GSK-3β regains the enzymatic activity to phosphorylate liver glycogen synthase, thereby blocking glucose storage. This activated p-GSK-3β can further phosphorylate insulin-suppressed Forkhead box O1, thus liberating its transcriptional activity to promote the expression of gluconeogenic enzymes. Notably, this dual-pathway mechanism is conserved in clinically relevant human liver samples and organoids. These findings elucidate the molecular mechanism by which HIR is formed and provide potential strategies against HIR by targeting sulfenylated or 'oxidatively activated' p-GSK-3β.

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