Functional S-persulfidation exploration reveals a novel regulatory mechanism of HNF1α
Protein S-persulfidation, a post-translational modification mediated by hydrogen sulfide (H<sub>2</sub>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<sub>2</sub>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.
Authors
- Hongfang Jin (ORCID: https://orcid.org/0000-0002-1606-8988)
- Jichun Yang (ORCID: https://orcid.org/0000-0001-8150-2923)
- Changting Cui (ORCID: https://orcid.org/0000-0002-5056-3608)
- Qinghua Cui (ORCID: https://orcid.org/0000-0003-3018-5221)
- Ming Chu (ORCID: https://orcid.org/0000-0001-8090-4197)
- Bin Geng (ORCID: https://orcid.org/0000-0001-7573-8710)
- Selena Chen (ORCID: https://orcid.org/0000-0001-5147-9507)
- Dingfang Bu (ORCID: https://orcid.org/0000-0001-9001-2133)
- Yaqian Huang (ORCID: https://orcid.org/0000-0001-8346-3809)
- Hanlin Peng
- Wei Li (ORCID: https://orcid.org/0000-0001-6694-3368)
- Shuai Wang (ORCID: https://orcid.org/0000-0001-9476-3532)
- Li Wang (ORCID: https://orcid.org/0000-0001-7415-5599)
- Heng Zhang (ORCID: https://orcid.org/0000-0002-5179-0458)
- Lulu Zhang (ORCID: https://orcid.org/0000-0002-8284-5781)
- Nan Chen (ORCID: https://orcid.org/0000-0001-6638-2193)
- Jing Wang (ORCID: https://orcid.org/0009-0007-9352-2850)
- Jingyuan Li (ORCID: https://orcid.org/0000-0003-2926-1864)
- Chu Wang (ORCID: https://orcid.org/0000-0002-6925-1268)
- Junbao Du (ORCID: https://orcid.org/0000-0001-9036-4980)
- Yuan Wang (ORCID: https://orcid.org/0000-0002-4291-3700)
- Zongmin Li (ORCID: https://orcid.org/0009-0002-6607-3045)
- Chaoshu Tang
Institutions
- Capital Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Beijing Chao-Yang Hospital, Capital Medical University (CN)
- University of California San Diego (US)
- Peking University First Hospital (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Redox Biology
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1016/j.redox.2025.103934
- Citations
- 1
- Primary Topic
- Sulfur Compounds in Biology
- Type
- article
- Field-Weighted Citation Impact
- 1.11