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Recent studies have revealed that dysregulated mitochondrial dynamics contributes to the development of cardiac microvascular dysfunction. Fission-1 (FIS1), a key effector of mitochondrial fission, functions as an outer mitochondrial membrane adapter that recruits dynamin-related protein-1 (Drp1) from the cytosol to the outer mitochondrial membrane for activating mitochondrial fission. The present study screened a library targeting deubiquitinases, and identified the regulatory role of USP33 on FIS1-dependent mitochondrial fission. We found USP33 silencing elevated FIS1 protein expression and resulted in excessive mitochondrial fission in endothelial cells, which in turn impaired mitochondrial function and worsen endothelial and cardiovascular dysfunction in DCM. Mechanistically, USP33 interacted with FIS1 at the TPR2 domain and promoted FIS1 degradation via lysosomal degradation. Further studies revealed that USP33 stabilized autophagy-related 7 (ATG7) at protein level by blocking K63-linked ubiquitination of human ATG7 at K48 (mouse K44) site. This process led to lysosomal degradation of FIS1 via ATG7-mediated autophagy. In summary, our findings reveal that USP33 plays a critical role in endothelial dysfunction in DCM and demonstrate that ATG7-FIS1 pathway acts as one of the potential downstream mechanisms.<\/jats:p>","DOI":"10.1038\/s41419-026-08930-8","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T11:24:57Z","timestamp":1780140297000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["USP33 alleviates FIS1-dependent mitochondrial fission and cardiac microvascular injury in diabetic cardiomyopathy via deubiquitinating and stabilizing ATG7"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7592-5989","authenticated-orcid":false,"given":"Yuqiong","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopei","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"8930_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107057","volume":"200","author":"Z Chen","year":"2024","unstructured":"Chen Z, Li S, Liu M, Yin M, Chen J, Li Y, et al. 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