Yaqian Huang, Zongmin Li, Shuai Wang, Yuan Wang, Wei Li, Hanlin Peng, Li Wang, Lulu Zhang, Selena Chen, Jing Wang, Dingfang Bu, Heng Zhang, Changting Cui, Qinghua Cui, Bin Geng, Jichun Yang, Nan Chen, Chu Wang, Ming Chu, Chaoshu Tang, Junbao Du, Jingyuan Li, Hongfang Jin
Protein S-persulfidation, a post-translational modification mediated by hydrogen sulfide (H 2 S), plays an essential role in regulating protein function. However, current profiling methods, mainly based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), tend to detect abundant proteins and often miss low-abundance but important regulators like transcription factors (TFs). To better understand the S-persulfidation landscape, we integrated datasets from three species— Homo sapiens , Mus musculus , and Arabidopsis thaliana —and found that TFs are strikingly underrepresented. To address this gap, we applied oxidative proteomics data from the Oximouse database, which reflects age-related redox changes, and identified hepatocyte nuclear factor 1α (HNF1α) as a candidate S-persulfidated TF. We confirmed that H 2 S induces S-persulfidation at Cys241 of HNF1α, disrupting its DNA binding through structural remodeling. This modification reduced PCSK9 expression, improved lipid profiles, and alleviated atherosclerosis in mice. Our study presents a cross-species strategy to uncover functional S-persulfidation targets and reveals a redox-based transcriptional mechanism involved in lipid metabolism and cardiovascular protection.