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The role of 4\u2010Octyl itaconate (4\u2010OI) in age\u2010related parotid gland dysfunction remains unclear. Thirteen\u2010month\u2010old male mice were administered 4\u2010OI (25\u2009mg\/kg) or vehicle once daily for 4\u2009weeks. The salivary flow rate was calculated to assess gland secretion function. Hematoxylin and eosin staining was used to analyze morphological alterations. Masson staining was used to quantify collagen deposition. Oil Red O staining was used to evaluate lipid droplet accumulation. Western blotting was used to detect protein expression levels. Metabolomics, transcriptome, and molecular docking analyses were performed to identify potential mechanisms of action. Functional assays revealed that 4\u2010OI increased the salivary flow rate. AMPK\u03b1 has been identified as a direct target of 4\u2010OI by molecular docking. 4\u2010OI upregulates AMPK\u03b1 phosphorylation, decreases lipid droplet deposition, and relieves fibrosis to restore the aging characteristics of the gland. 4\u2010OI regulates fatty acid oxidation (FAO) in the parotid gland through AMPK\u03b1\/PPAR\u03b1 signaling pathways. The protective effects of 4\u2010OI in aged mice were abolished by Compound C and GW6471, which inhibit AMPK\u03b1 and PPAR\u03b1, respectively. In addition, we found that 4\u2010OI treatment ameliorated parotid gland aging\u2010induced oxidative reactions, enhanced mitochondrial biogenesis, and activated the Nrf2 pathway. Moreover, the Nrf2 inhibitor ML385 was used to validate this mechanism. Treatment with 4\u2010OI improved the aging of the parotid gland by increasing gland FAO, decreasing gland fibrosis, and preventing oxidative reactions. This was achieved by upregulating the AMPK\u03b1\/Nrf2 and AMPK\u03b1\/PPAR\u03b1 signaling pathways.<\/jats:p>","DOI":"10.1096\/fj.202602956rr","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:27:28Z","timestamp":1790749648000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["4\u2010Octyl Itaconate Attenuates Age\u2010Induced Parotid Gland Dysfunction Through the Suppression of Fibrosis and Lipid Deposition by AMPK\u03b1\/PPAR\u03b1 and the Inhibition of Oxidative Stress via the AMPK\u03b1\/Nrf2 Signaling Pathway"],"prefix":"10.1096","volume":"40","author":[{"given":"Yun","family":"Chen","sequence":"first","affiliation":[{"name":"Changsha Stomatological Hospital, School of Stomatology Hunan University of Chinese Medicine  Changsha Hunan 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