{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:03:03Z","timestamp":1789718583573,"version":"4.0.1"},"reference-count":85,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Diabetic cardiomyopathy (DCM) is a multidimensional myocardial remodeling disorder driven by interconnected metabolic, inflammatory, ferroptotic, autophagic and fibrotic programs, yet the post-translational mechanisms that convert diabetic stress into persistent injury remain incompletely integrated. Ubiquitin-specific proteases (USPs) regulate substrate stability, ubiquitin-chain architecture and signaling-complex dynamics and therefore represent an important proteostatic layer in DCM. Rather than assigning fixed protective or maladaptive identities to individual enzymes, this review organizes current evidence according to specific USP-substrate axes and their cellular and disease contexts. Predominantly protective axes include USP28-PPAR\u03b1\/Mfn2, USP8-Parkin, USP13-NLRP3, USP20-p62\/STING, USP18-dependent stabilization of Notch1 or FOXC2, and the endothelial USP33-ATG7\/FIS1 pathway. Predominantly injurious axes include USP38-ACAD11, USP14-VDAC1 and USP24-associated ferroptotic and autophagy-disruptive signaling. USP7 exemplifies substrate-dependent bidirectionality: USP7-PGC1\u03b2 promotes metabolic dysfunction, whereas USP7-NRF2 supports GPX4-dependent ferroptosis resistance during empagliflozin treatment. By integrating these axes across pathological modules and cardiac cell types, this review reframes DCM as a disorder of context-dependent proteostatic maladaptation and highlights substrate-resolved USP regulation as a priority for future mechanistic and translational investigation.<\/jats:p>","DOI":"10.3389\/fcell.2026.1910665","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:22:23Z","timestamp":1789716143000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Diabetic cardiomyopathy as a disorder of proteostatic maladaptation: context-dependent ubiquitin-specific protease networks"],"prefix":"10.3389","volume":"14","author":[{"given":"Xiangyun","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Science, Gansu Provincial Hospital of Traditional Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuming","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, Gansu Provincial Hospital of Traditional Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center, Shaoxing People\u2019s Hospital, Zhejiang University Shaoxing Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"School of Medicine, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center, Shaoxing People\u2019s Hospital, Zhejiang University Shaoxing Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"School of Medicine, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center, Shaoxing People\u2019s Hospital, Zhejiang University Shaoxing Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"School of Medicine, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center, Shaoxing People\u2019s Hospital, Zhejiang University Shaoxing Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"School of Medicine, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Gansu Provincial Hospital of Traditional Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixia","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center, Shaoxing People\u2019s Hospital, Zhejiang University Shaoxing Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"School of Medicine, Shaoxing University","place":["Shaoxing, Zhejiang, China"]},{"name":"Gansu Academy of Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1038\/s41418-020-00697-5","article-title":"Deubiquitylases in developmental ubiquitin signaling and congenital diseases","volume":"28","author":"Basar","year":"2021","journal-title":"Cell Death Differ."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1111\/dom.16242","article-title":"Mechanisms of diabetic cardiomyopathy: focus on inflammation","volume":"27","author":"Bellemare","year":"2025","journal-title":"Diabetes Obes. 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