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Cystathionine γ-Lyase-Dependent S-Sulfhydration of Smad3: A Novel Target to Alleviate Fibrosis in Systemic Sclerosis.

Jiani Liu·Yangfan Xiao·Licong Liu·Xuan Xiao·Zixin Pi·Zehong Song·Qianyu Yang·Zhuotong Zeng·Ruixuan Zhu·Yaqian Shi·Rong Xiao
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Abstract

OBJECTIVE: The cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) axis has emerged as a key regulator in tissue fibrogenesis. This study aimed to explore the role of the CSE/H2S axis in systemic sclerosis (SSc) and to investigate its underlying mechanisms to identify promising therapeutic targets. METHODS: CSE/H2S levels were assessed in serum samples from 25 patients with SSc and 28 healthy controls. Human dermal fibroblasts from patients with SSc and healthy controls were used for functional studies, including propargylglycine (CSE inhibitor) treatment, Gyy4137, a slow-releasing hydrogen sulfide donor, CSE silencing, and CSE overexpression, combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based S-sulfhydration proteomics. Molecular dynamics simulations were performed to study the effects of S-sulfhydration on protein structure, and an Smad3 C121S (cysteine [Cys] 121 mutated to Ser) mutant was generated to verify the function targets of S-sulfhydration. In vivo, bleomycin-induced mouse models of skin and lung fibrosis were constructed to evaluate the effects of CSE overexpression. RESULTS: In human samples, CSE/H2S levels were reduced in SSc. CSE inhibition promoted extracellular matrix deposition. S-sulfhydration proteomics showed that S-sulfhydration levels were globally reduced in SSc compared to controls. CSE overexpression increased S-sulfhydration on Smad3, suppressed transforming growth factor β 1 (TGFβ1)/Smad3 signaling, mitigating skin fibrosis. Notably, Cys121 on Smad3, identified as a pivotal target for S-sulfhydration by proteomics, was shown to fine-tune its MH1 domain, with its mutation impairing the antifibrotic effects. In mice, CSE overexpression attenuated bleomycin-induced skin and lung fibrosis. CONCLUSION: Smad3 S-sulfhydration mediates the antifibrotic effect of CSE in SSc, highlighting it as a critical mechanism and promising therapeutic target.

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HumansScleroderma, SystemicCystathionine gamma-LyaseSmad3 ProteinAnimalsMiceFibroblastsFemaleHydrogen SulfideMaleBleomycinGlycineFibrosisMiddle AgedSkinAlkynesDisease Models, AnimalAdultPulmonary FibrosisOrganothiophosphorus CompoundsMorpholinesCase-Control StudiesTandem Mass SpectrometryProteomicsJournal ArticleResearch Support, Non-U.S. Gov't

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Jiani Liu, Yangfan Xiao, Licong Liu, Xuan Xiao, Zixin Pi, Zehong Song, Qianyu Yang, Zhuotong Zeng, Ruixuan Zhu, Yaqian Shi, Rong Xiao. 2026-02-22. Cystathionine γ-Lyase-Dependent S-Sulfhydration of Smad3: A Novel Target to Alleviate Fibrosis in Systemic Sclerosis.. https://doi.org/10.1002/art.70085

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