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The mitochondrial\u2010derived peptide mitochondrial open reading frame of the 12S rRNA type\u2010C (MOTS\u2010c) has emerged as a promising regulator of metabolic and inflammatory pathways. In this study, we investigated the effects of MOTS\u2010c treatment on leucine\u2010rich repeat and pyrin domain\u2010containing receptor 3 (NLRP3) inflammasome activity in a high\u2010fat diet and streptozotocin\u2010induced T2DM rat model. MOTS\u2010c treatment significantly reduced fasting blood glucose and circulating C\u2010reactive protein levels, while selectively modulating plasma inflammatory cytokines, including interleukin (IL)\u201010 and IL\u20101\u03b2. Immunohistochemical analysis revealed reduced levels of NLRP3, apoptosis\u2010associated speck\u2010like protein containing a caspase activation and recruitment domain (ASC), and cleaved caspase\u20101 in left ventricular tissue following MOTS\u2010c administration. Correlation analyses linked IL\u201018 and IL\u20101\u03b2 with elevated markers, including low\u2010density lipoprotein and uric acid, suggesting interplay between overall health and inflammasome activity. These results indicate that MOTS\u2010c modulates both systemic and cardiac inflammation in T2DM, providing a novel therapeutic approach for reducing cardiovascular risk in diabetic patients.<\/jats:p>","DOI":"10.1113\/ep093714","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T01:40:36Z","timestamp":1781919636000},"page":"3742-3752","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial peptide MOTS\u2010c suppresses systemic and cardiac inflammasome activation in a diabetic rat model"],"prefix":"10.1113","volume":"111","author":[{"given":"Aimee R.","family":"Mills","sequence":"first","affiliation":[{"name":"Buchanan Ocular Therapeutics Unit Department of Ophthalmology, New Zealand National Eye Centre University of Auckland  Auckland New Zealand"},{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"de Souza","sequence":"additional","affiliation":[{"name":"Buchanan Ocular Therapeutics Unit Department of Ophthalmology, New Zealand National Eye Centre University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6323-9217","authenticated-orcid":false,"given":"Toan","family":"Pham","sequence":"additional","affiliation":[{"name":"Auckland Bioengineering Institute University of Auckland  Auckland New Zealand"},{"name":"Department of Engineering Science and Biomedical Engineering University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odunayo O.","family":"Mugisho","sequence":"additional","affiliation":[{"name":"Buchanan Ocular Therapeutics Unit Department of Ophthalmology, New Zealand National Eye Centre University of Auckland  Auckland New Zealand"},{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2828(92)93381-S"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.16242"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00040"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.679597"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-03526-2"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00845.2013"},{"issue":"14","key":"e_1_2_9_8_1","first-page":"3720","article-title":"Interleukin\u20101 in the pathogenesis and treatment of inflammatory diseases. 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