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Endocrinol."],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance, progressive pancreatic \u03b2-cell dysfunction, and multi-organ metabolic dysregulation. Among various post-translational modifications, ubiquitination has emerged as a central regulator of cellular homeostasis, with E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) governing the stability and activity of key signaling proteins. This review systematically elucidates the pivotal role of ubiquitination in the pathogenesis of T2DM. We first outline the fundamental principles of the ubiquitin system, followed by an in-depth discussion of its regulatory mechanisms in insulin-sensitive tissues (liver, skeletal muscle, and adipose tissue) and pancreatic \u03b2-cells. We then explore the potential and challenges of targeting specific E3 ligases or DUBs as innovative therapeutic strategies for T2DM. Notably, this review provides three novel perspectives. First, we move from generalized description to enzyme-specific resolution, systematically profiling E3 ligases and DUBs with defined pathological functions in T2DM. Second, we adopt a multi-organ integration approach, highlighting the differential and sometimes heterogeneous roles of the same enzyme across distinct tissues. Third, we shift from a mechanism description a translational orientation, critically evaluating the current status of human evidence, identifying knowledge gaps, and discussing emerging strategies including single-cell omics, spatial transcriptomics, proteomics-based ubiquitination mapping, and artificial intelligence-assisted drug discovery. Collectively, our core conclusion is that E3 ligases and DUBs form tissue-specific regulatory networks governing T2DM pathology. Targeting the ubiquitination system offers new precision therapeutic strategies. Future directions should prioritize integrating multi-omics approaches and AI platforms to accelerate translational applications. This review provides a theoretical foundation for understanding the molecular basis of T2DM and facilitates the development of novel therapeutic interventions.<\/jats:p>","DOI":"10.3389\/fendo.2026.1802982","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:23:28Z","timestamp":1783571008000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ubiquitination modifications as central regulators of metabolic dysfunction in type 2 diabetes mellitus"],"prefix":"10.3389","volume":"17","author":[{"given":"Wen-tao","family":"Wang","sequence":"first","affiliation":[{"name":"Laboratory Animal Center, Shanxi Key Laboratory of Experimental Animal Science and Animal Model of Human Disease, Shanxi Medical University","place":["Jinzhong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-ya","family":"Shi","sequence":"additional","affiliation":[{"name":"Laboratory Animal 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