Implications of hydrogen sulfide in liver pathophysiology: Mechanistic insights and therapeutic potential

Abstract

Background: Over the last several decades, hydrogen sulfide (H₂S) has been found to exert multiple physiological functions in mammal systems. The endogenous production of H₂S is primarily mediated by cystathione β-synthase (CBS), cystathione γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes are widely expressed in the liver tissues and regulate hepatic functions by acting on various molecular targets.

Aim of review: In the present review, we will highlight the recent advancements in the cellular events triggered by H₂S under liver diseases. The therapeutic effects of H₂S donors on hepatic diseases will also be discussed.

Key scientific concepts of review: As a critical regulator of liver functions, H₂S is critically involved in the etiology of various liver disorders, such as nonalcoholic steatohepatitis (NASH), hepatic fibrosis, hepatic ischemia/reperfusion (IR) injury, and liver cancer. Targeting H₂S-producing enzymes may be a promising strategy for managing hepatic disorders.

Keywords: 3-MP, 3-mercaptopyruvate; 3-MST, 3-mercaptopyruvate sulfurtransferase; AGTR1, angiotensin II type 1 receptor; AMPK, AMP-activated protein kinase; Akt, protein kinase B; CAT, cysteine aminotransferase; CBS, cystathione β-synthase; CO, carbon monoxide; COX-2, cyclooxygenase-2; CSE, cystathione γ-lyase; CX3CR1, chemokine CX3C motif receptor 1; Cancer; DAO, D-amino acid oxidase; DATS, Diallyl trisulfide; EGFR, epidermal growth factor receptor; ERK, extracellular regulated protein kinases; FAS, fatty acid synthase; Fibrosis; H2S, hydrogen sulfide; HFD, high fat diet; HO-1, heme oxygenase 1; Hydrogen sulfide; IR, ischemia/reperfusion; Liver disease; MMP-2, matrix metalloproteinase 2; NADH, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NAFLD, non-alcoholic fatty liver diseases; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor-kappa B; NaHS, sodium hydrosulfide; Nrf2, nuclear factor erythroid2-related factor 2; PI3K, phosphatidylinositol 3-kinase; PLP, pyridoxal 5′-phosphate; PPG, propargylglycine; PTEN, phosphatase and tensin homolog deleted on chromosome ten; SAC, S-allyl-cysteine; SPRC, S-propargyl-cysteine; STAT3, signal transducer and activator of transcription 3; Steatosis; VLDL, very low density lipoprotein; mTOR, mammalian target of rapamycin.