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In obesity, hypertrophied adipose tissue release high levels of pro-inflammatory cytokines, including TNF-\u03b1, IL-6, and IL-1\u03b2, and elevates circulating free fatty acids. These changes promote systemic insulin resistance and ectopic lipid deposition. Mitochondrial dysfunction, including reduced oxidative phosphorylation, excess reactive oxygen species (ROS) production, and mitochondrial DNA damage, further stimulate inflammatory pathways such as the NLRP3 inflammasome, creating a feedback loop that worsens metabolic stress. Ultimately, this interaction disrupts energy balance, weakens insulin signaling, and accelerates \u03b2-cell dysfunction and hepatic steatosis. In both T2DM and MASLD, oxidative stress, defective mitochondrial quality control, and dysregulated immunometabolic responses are consistently observed pathophysiological features. Interventions aimed at reducing inflammation and restoring mitochondrial function\u2014including lifestyle modification, mitochondria-targeted therapies, inflammasome regulation, and enhancement of mitochondrial biogenesis or mitophagy\u2014may retard disease progression.<\/jats:p>","DOI":"10.3390\/ijms26199715","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:05:06Z","timestamp":1759763106000},"page":"9715","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8389-4526","authenticated-orcid":false,"given":"Wooyoung","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gun Ha","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1561-6508","authenticated-orcid":false,"given":"Tae-Hwan","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9217-968X","authenticated-orcid":false,"given":"Jae-Han","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/obr.12229","article-title":"Metabolic syndrome: A closer look at the growing epidemic and its associated pathologies","volume":"16","year":"2015","journal-title":"Obes. 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