Cystathionine γ-Lyase Protects Against Choline-Deficient High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Cysteine-Glutathione Axis in Mice.

Abstract

Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease, yet its pathogenesis remains incompletely understood. Oxidative stress is thought to play a key role in MASLD progression. This study aimed to investigate the role of cystathionine γ-lyase (CSE), an enzyme essential for cysteine and glutathione (GSH) biosynthesis, in MASLD development. Results: Choline-deficient high-fat diet (CDHFD) feeding led to elevated aspartate aminotransferase, alanine aminotransferase, hepatic triglyceride accumulation, vacuolization, macrophage infiltration, and cell death in both genotypes, with significantly greater changes observed in Cse^-/- mice. CDHFD also reduced hepatic CSE expression in Cse^+/+ mice and decreased cysteine/GSH levels in both genotypes, with more pronounced reductions in Cse^-/- mice. Furthermore, Cse deletion was associated with increased oxidized glutathione/total GSH ratios and elevated levels of 4-hydroxynonenal and malondialdehyde. Expression of glutathione synthetase and γ-glutamyl transpeptidase was increased by CDHFD in Cse^+/+ mice but blunted in Cse^-/- mice. Furthermore, CSE deficiency exacerbated CDHFD-induced hepatic iron accumulation. Innovation: Our findings suggest that the CSE-cysteine-GSH axis may serve as a potential therapeutic target for MASLD, providing new intervention strategies beyond traditional approaches. This study provides new insights into the molecular mechanisms of MASLD and supports the development of antioxidant-based therapies. Conclusions: CSE deficiency exacerbates CDHFD-induced impairments of cysteine-GSH antioxidant axis, leading to hepatic oxidative stress and cell death. This indicates that CSE plays a protective role against MASLD development and progression. Antioxid. Redox Signal. 00, 000-000.