Cysteine-S-sulfate promotes arteriosclerosis obliterans by inducing TH17 differentiation and promoting pyroptosis.

Arteriosclerotic obliterans (ASO) is a peripheral vascular disease with a high rate of amputation, the mechanism of which remains unclear and markers for early diagnosis are seriously lacking. Therefore, we first used untargeted metabolomics analysis to reveal significant differences in metabolites between the ASO cohort and the healthy volunteer cohort. Combined with targeted analysis, it was confirmed that cysteine-S-sulfate could be identified as a potential biomarker for ASO, with good diagnostic performance. In addition, we analyzed the distribution of helper T cells (TH1, TH2, TH9, TH17 and TH22), and the results showed that TH17 was highly expressed in the ASO cohort, and IL-17 was also elevated. Through in vitro experiments, we found that cysteine-S-sulfate can promote IL-17 secretion and induce HUVCEs pyroptosis. To further clarify the pathogenicity of cysteine-S-sulfate, we used an acute lower limb ischemia model and gave a high methionine diet to simulate the high cysteine-S-sulfate state in vivo. What was shocking was that the high methionine diet group mice had lower blood flow than the control group, as well as higher levels of cysteine-S-sulfate, higher levels of TH17, and higher levels of pyroptosis. This also confirms that cysteine-S-sulfate promotes the differentiation of TH17, the secretion of cytokines, and the occurrence of pyroptosis, promoting the progression of ASO. This study is valuable in providing a diagnostic marker for ASO and elucidating its pathogenesis. This suggests that blocking IL-17 may be a new strategy to treat ASO, offering clinicians a therapeutic possibility.