Significance: Hydrogen sulfide (H₂S) is a recently recognized gasotransmitter involved in physiological and pathological conditions in mammals. It protects organs from oxidative stress, inflammation, hypertension, and cell death. With abundant expression of H₂S-production enzymes, the liver is closely linked to H₂S signaling. Recent Advances: Hepatic H₂S comes from various sources, including gut microbiota, exogenous sulfur salts, and endogenous production. Recent studies highlight the importance of hepatic H₂S in liver diseases such as nonalcoholic fatty liver disease (NAFLD), liver injury, and cancer, particularly at advanced stages. Endogenous H₂S production deficiency is associated with severe liver disease, while exogenous H₂S donors protect against liver dysfunction. Critical Issues: However, the roles of H₂S in NAFLD, liver injury, and liver cancer are still debated, and its effects depend on donor type, dosage, treatment duration, and cell type, suggesting a multifaceted role. This review aimed to critically evaluate H₂S production, metabolism, mode of action, and roles in liver function and disease. Future Direction: Understanding H₂S's precise roles and mechanisms in liver health will advance potential therapeutic applications in preclinical and clinical research. Targeting H₂S-producing enzymes and exogenous H₂S sources, alone or in combination with other drugs, could be explored. Quantifying endogenous H₂S levels may aid in diagnosing and managing liver diseases. Antioxid. Redox Signal. 40, 122-144.

Phuc L. Nguyen

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