SENP3 Drives Abdominal Aortic Aneurysm Development by Regulating Ferroptosis via De‐SUMOylation of CTH

• DOI: 10.1002/advs.202414500
• Publication Date: 2025-03-12T09:40:28Z
• Authors: Long Chen; Zhaohua Cai; Danrui Xiao; Yiping Shi; Qingqing Xiao; Min Liang; Yangjing Jiang; Yijie Huang; Feng Liang; Guo Zhou; Fei Zhuang; Xia Wang; Huanhuan Huo; Liang Fang; Qin Shao; Ben He

Abstract Abdominal aortic aneurysm (AAA) is a high‐risk inflammatory disorder. SENP3, SUMO2/3‐specific protease, closely involved in the development of cancer. In this study, aim to explore role SENP3 macrophages AAA. It found that protein expression significantly upregulated both human and murine AAA specimens. negatively regulated by E3 ubiquitin ligase STUB1/CHIP. Furthermore, myeloid‐specific knockout inhibited formation AngII‐ CaCl 2 ‐induced mouse models. deficiency repressed lesion macrophage infiltration response. Mechanistic studies identified Cystathionine Gamma–Lyase (CTH), critical enzyme hydrogen sulfide production, as target mediated exacerbating effects on ferroptosis programs macrophages. SUMO‐3 modification at Lysine 361 promoted CTH stability, whereas de‐SUMOylation facilitated its proteasome‐dependent degradation. Most importantly, it inhibitor counteracted protective effect Additionally, supplementation with ATB346, novel H S‐donating naproxen derivative, prevented mice. These suggest SENP3‐mediated deSUMOylation regulates development. The SENP3/CTH axis therefore an important therapeutic for aneurysmal diseases.