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

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