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SENP3, a\u00a0SUMO2\/3\u2010specific 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\u2010specific SENP3 knockout inhibited AAA formation in both AngII\u2010 and CaCl<jats:sub>2<\/jats:sub>\u2010induced mouse models. SENP3 deficiency repressed AAA lesion macrophage infiltration and inflammatory response. Mechanistic studies identified Cystathionine Gamma\u2013Lyase (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\u20103 modification at Lysine 361 promoted CTH protein stability, whereas de\u2010SUMOylation by SENP3 facilitated its proteasome\u2010dependent 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<jats:sub>2<\/jats:sub>S\u2010donating naproxen derivative, prevented AAA development in mice. These studies suggest that SENP3\u2010mediated CTH deSUMOylation regulates macrophage ferroptosis and AAA development. The SENP3\/CTH axis is therefore an important therapeutic\u00a0target for aortic aneurysmal diseases.<\/jats:p>","DOI":"10.1002\/advs.202414500","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:40:28Z","timestamp":1741758028000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["SENP3 Drives Abdominal Aortic Aneurysm Development by Regulating Ferroptosis via De\u2010SUMOylation of CTH"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3475-1641","authenticated-orcid":false,"given":"Long","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Cardiology Shanghai Chest Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohua","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Chest 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