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Here, we identify Optineurin (OPTN) as an active regulator for maintenance of muscle homeostasis during muscle atrophy. Knockdown (KD) of\n                    <jats:italic>Optn<\/jats:italic>\n                    induces muscle atrophy, while overexpression of\n                    <jats:italic>Optn<\/jats:italic>\n                    alleviated dexamethasone-induced muscle atrophy in mice. Mechanistically, we for the first time identified Junction plakoglobin (JUP) as a novel interacting partner of OPTN. OPTN alleviates muscle atrophy in a JUP-dependent manner, corroborating JUP as the downstream effector of OPTN-mediated muscle atrophy. RNA-seq analysis revealed that PI3K-AKT pathway is markedly downregulated in\n                    <jats:italic>Optn<\/jats:italic>\n                    -KD muscle, and pharmacological activation of PI3K-AKT pathway effectively rescued muscle atrophy in\n                    <jats:italic>Optn<\/jats:italic>\n                    -KD mice. We further show that OPTN coordinates the interaction between JUP and PI3-Kinase p85 in muscle, promoting activation of the PI3K-AKT pathway. Collectively, our study proposed a conceptual novelty that OPTN-JUP axis mediated activation of the PI3K-AKT pathway during muscle atrophy. These findings offer new insights into the mechanisms of muscle atrophy and suggest potential therapeutic strategies for this condition.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003581","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T18:36:57Z","timestamp":1769107017000},"page":"e3003581","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Optineurin binding to the novel interacting partner Junction plakoglobin prevents muscle atrophy in mice"],"prefix":"10.1371","volume":"24","author":[{"given":"Xiao Chen","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun 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