Metabolic dysfunction-associated steatohepatitis reduces hepatic H2S-producing enzymes altering persulfidome composition

Abstract

Steatohepatitis; Metabolic dysfunction; Persulfidome

Esteatohepatitis; Disfunció metabòlica; Persulfidoma

Esteatohepatitis; Disfunción metabólica; Persulfidoma

Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive disease driven by obesity-related hepatic inflammation and oxidative stress. Recently, cysteine persulfidation (PSSH), a protective post-translational modification by hydrogen sulfide (H2S), was established to play a role in redox regulation. Despite the role of the liver in H2S metabolism, the function of PSSH in MASH remains underexplored. We demonstrated that H2S-producing enzymes are downregulated in both human and mouse livers with steatosis and fibrosis, resulting in a decline in global PSSH levels. Dimedone-switch mass spectrometry in dietary mouse models of distinct obesity-associated liver disease stages revealed dysregulated PSSH on specific proteins. Surprisingly, increased hepatic PSSH levels of protein tyrosine phosphatases and redox regulators were found in advanced disease stages, suggesting a targeted adaptive response to oxidative stress. Overall, our findings demonstrated that impaired H2S production disrupts protective PSSH networks in MASH. However, selective PSSH preservation on redox-sensitive proteins may represent a compensatory mechanism, underscoring the therapeutic potential of persulfidation in restoring redox homeostasis during obesity-associated chronic liver disease.

European Research Council (ERC) Consolidator grant METAPTPs GA817940 (ENG). FNRS-WELBIO grant (35112672), FNRS-Aspirant fellowship (40010598, 40024372) and ULB Foundation (ENG). European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme Grant Agreement No. 864921 (MRF). VIB grant (JM). Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR) (WW). Biomedical Research Council (BMRC) Core Research Fund for use-inspired basic research and IAF-PP project H22J2a0043 (WW). Singapore National Medical Research Council (NMRC) project MOH-001401-00 (WW). FNRS-ASP scholarship and ENG is a Research Associate of the FNRS, Belgium (TKS).