Recently, the team led by Professor Xiao Rong from the Department of Dermatology and Venereology, the Second Xiangya Hospital of Central South University, published an original research article in Arthritis & Rheumatology (IF 10.9), the official journal of the American College of Rheumatology. The study, entitled Cystathionine γ-lyase-dependent S-sulfhydration of Smad3: A novel target to alleviate fibrosis in systemic sclerosis, reveals a new theoretical basis and potential intervention strategy for the targeted therapy of systemic sclerosis.The Second Xiangya Hospital of Central South University is the sole corresponding author institution. Professor Xiao Rong and Dr. Shi Yaqian from the Department of Dermatology and Venereology are the co-corresponding authors, and Dr. Liu Jiani is the first author.
Systemic sclerosis (SSc) is a connective tissue disease characterized by immune dysregulation, vascular injury, and progressive fibrosis of the skin and internal organs. It ranks among the rheumatic diseases with the highest disability and mortality rates, and effective approaches to reverse fibrosis are currently lacking. The TGF-β1/Smad3 signaling pathway is persistently and aberrantly activated during the pathogenesis and progression of SSc fibrosis, and is recognized as one of the core pathways driving the abnormal activation of fibroblasts and collagen deposition. However, the precise regulatory mechanisms underlying the aberrant activation of this pathway in SSc remain poorly understood, which limits the further development of targeted intervention strategies.
S-sulfhydration is a newly identified post-translational modification mediated by the cystathionine γ-lyase (CSE)/H₂S axis. It is regarded as an important mechanism for the fine regulation of cellular signaling, yet its role in systemic sclerosis (SSc) remains unclear. The present study aimed to investigate the critical function of S-sulfhydration in fibroblasts and its potential regulatory mechanism in SSc-associated fibrosis.
The research team demonstrated for the first time that CSE/H₂S levels and global S-sulfhydration were significantly decreased in patients with systemic sclerosis (SSc), and CSE/H₂S expression was negatively correlated with the severity of skin sclerosis.Functional experiments confirmed that inhibition or knockdown of CSE markedly promoted fibroblast activation and extracellular matrix deposition. In contrast, enhancement of CSE expression or exogenous supplementation with H₂S effectively suppressed the fibrotic process.Mechanistically, these interventions significantly attenuated aberrant activation of the TGF-β1/Smad3 signaling pathway by reducing Smad3 phosphorylation, blocking its nuclear translocation, and inhibiting downstream transcriptional activity at multiple key steps.In vivo experiments further validated that adeno-associated virus-mediated delivery of the CSE gene markedly alleviated cutaneous and pulmonary fibrosis in mice.Collectively, these findings indicate that the CSE/H₂S axis serves as an important endogenous protective regulator during the progression of SSc-related fibrosis.
Using S-sulfhydration proteomics combined with molecular dynamics simulation, the research team further identified Smad3 as a key target protein for CSE-mediated S-sulfhydration for the first time, and verified that its Cys121 residue serves as a critical molecular switch governing Smad3 function.This post-translational modification alters the structural properties of Smad3 binding to DNA and modulates its transcriptional activity. Conversely, mutation at the Cys121 site markedly abolished the antifibrotic effect of CSE, revealing a pivotal role of S-sulfhydration in the fine regulation of Smad3-driven profibrotic function.
Professor Xiao Rong, Director of the Department of Dermatology and Venereology, Xiangya School of Medicine, Central South University, and Director of the Institute of Dermatology, Central South University, and his team have long been committed to research on immune-mediated diseases such as scleroderma, disfiguring skin diseases, environmental medicine, and novel biomaterials.In recent years, the team has published more than 200 high-quality research articles in authoritative journals at home and abroad, including Chemical Society Reviews, Coordination Chemistry Reviews, Arthritis & Rheumatology, Journal of the American Academy of Dermatology, British Journal of Dermatology, and Chinese Journal of Dermatology. They have also led the formulation of national clinical guidelines and expert consensus statements, including the Expert Consensus on the Diagnosis and Treatment of Localized Scleroderma and the Expert Consensus on Scalp Health Management.Their research has been supported by more than 30 grants, including General Programs of the National Natural Science Foundation of China and Key Projects of the Ministry of Science and Technology, as well as other funding agencies.
In the future, the team will continue to be guided by clinical needs, further investigate the pathogenesis of immune-mediated skin diseases, and consistently provide solid scientific support for the advancement of precise clinical diagnosis and treatment.
