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The H2S–persulfidation axis as a critical regulator of redox homeostasis in chronic metabolic liver disease

par Shen, Tzu-Keng
Président du jury Loris, Remy
Promoteur Gurzov, Esteban Nicolas ;Messens, Joris
Co-Promoteur Ezeriņa, Daria
Publication Non publié, 2026-06-19

Thèse de doctorat

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Résumé :

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a prevalent andprogressive chronic liver disorder characterized by metabolic dysregulation,inflammation, and oxidative stress. Although disturbances in redox balance are centralto MASLD pathogenesis, the contribution of sulfur-based signaling pathways, whichconstitute the core cellular redox-regulatory mechanism, remains poorly understood.Cysteine persulfidation (PSSH), a reversible post-translational modification mediatedby hydrogen sulfide (H₂S), has recently emerged as an important regulator of proteinfunction and cellular redox homeostasis. However, how this modification is regulatedduring MASLD development and progression remains largely unknown.In this thesis, I systematically characterize the hepatic H₂S–persulfidation axis acrossthe MASLD spectrum. By integrating proteomics, persulfidomics, and biochemicalapproaches, I demonstrate that MASLD is associated with a pronounced reduction inhepatic H₂S production capacity and global persulfidation levels, accompanied by aselective remodeling of the hepatic persulfidome. These findings indicate that PSSH isnot merely a passive by-product of oxidative stress but rather a dynamically regulatedredox modification.To investigate the functional contribution of endogenous H₂S production, I studied liver-specific cystathionine β-synthase (CBS) knockout mice in a dietary model thatrecapitulates human metabolic dysfunction–associated steatohepatitis (MASH).Despite substantial loss of CBS, global hepatic persulfidation remained preserved,while a selective, protein-specific reprogramming of the persulfidome was observed.This suggests the presence of compensatory sulfur metabolic pathways and reveals apreviously underappreciated layer of redox adaptation.Furthermore, non-targeted pharmacological supplementation with the slow-releasingH₂S donor GYY4137 failed to improve metabolic or hepatic outcomes in a diet rich infat, fructose, and cholesterol, highlighting the context-dependent and limited efficacy ofnon-targeted H₂S donor strategies. Finally, this work validates PersIc, a geneticallyencoded fluorescent biosensor, for real-time monitoring of intracellular persulfidedynamics in hepatocytes.Collectively, this work establishes the H₂S–persulfidation axis as a critical regulator ofredox homeostasis in chronic metabolic liver disease.