Significance: Hydrogen sulfide (H 2 S), a vital gasotransmitter in liver physiology and pathology, is produced by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MPST). Although CSE and CBS have been extensively studied in liver diseases, the role of MPST has received less attention, despite its significant and complex regulatory functions in hepatic biology and metabolism. Recent Advances: The involvement of MPST in antioxidant processes, mitochondrial function, and protein persulfidation highlights its multifaceted role in various liver diseases, where it can act either as a protective factor or as a contributor to disease progression, primarily through H 2 S metabolism. Notably, MPST also participates in crosstalk between various organs, including adipose–liver, gut–liver, skeletal muscle–liver, and pancreas–liver interactions. We also summarize current genetic models and pharmacological modulators targeting MPST. This review highlights the importance of advancing our understanding of the MPST/H 2 S pathway to develop promising therapeutic strategies for liver diseases. Critical Issues: Current research focuses mainly on changes in the expression of MPST in liver diseases, but its underlying mechanisms require further elucidation. The available genetic and pharmacological tools are still limited, underscoring the need for specific modulators and tissue- or cell-specific conditional MPST knockout or knock-in models to advance future investigations. Future Directions: Future research should focus on delineating stage-specific and cell type-dependent mechanisms of MPST in liver diseases, identifying upstream regulators, and elucidating detailed downstream molecular pathways mediating the effects of MPST. Ultimately, these efforts should aim to establish the clinical significance of MPST as a translational target. Antioxid. Redox Signal. 00, 000–000.
Xia et al. (Thu,) studied this question.