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Peroxisomes and pexophagy are essential for balancing oxidative stress and protein degradation products. Our previous findings suggest that peroxisome proliferators\u2010activated receptor \u03b2\/\u03b4 (PPAR\u03b2\/\u03b4) activation significantly alleviates depressive behaviors by preventing astrocytic injury. However, the underlying mechanisms remain unclear. In the present study, we established oxidative injury by treating astrocytes with corticosterone. Subsequently, PPAR\u03b2\/\u03b4 agonists and antagonists were applied to determine the effects of PPAR\u03b2\/\u03b4 on balancing peroxisomes and pexophagy in astrocytes. The PPAR\u03b2\/\u03b4 agonist (GW0742) significantly improved cell viability and decreased intracellular reactive oxygen species (ROS) production induced by corticosterone, while pretreatment with the PPAR\u03b2\/\u03b4, antagonist GSK3787 reversed the effects of GW0742. Moreover, activating PPAR\u03b2\/\u03b4 promoted peroxisomal biogenesis factor 5 (PEX5)\u2010mediated pexophagy by enhancing the phosphorylation of ataxia\u2010telangiectasia mutated (ATM) kinase. Conversely, blocking PPAR\u03b2\/\u03b4 with GSK3787 partially abolished the effects of GW0742. Further investigations demonstrated that activation of PPAR\u03b2\/\u03b4 not only induced transcription of the ubiquitin protein ligase E3 component n\u2010recognin 5 (UBR5) but also enhanced the interaction between PPAR\u03b2\/\u03b4 and UBR5, contributing to ATM interactor (ATMIN) degradation, and increased phosphorylated ATM kinase levels. Therefore, this study revealed that activating PPAR\u03b2\/\u03b4 improves corticosterone\u2010induced oxidative damage in astrocytes by enhancing pexophagy. PPAR\u03b2\/\u03b4 directly interacts with UBR5 to facilitate ATMIN degradation and promotes ATM phosphorylation, thereby maintaining the balance between peroxisomes and pexophagy. These findings suggest that PPAR\u03b2\/\u03b4 is a potential target for promoting pexophagy in astrocytes upon stress.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70013-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70013","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T03:32:11Z","timestamp":1739244731000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["PPAR\u03b2\/\u03b4 Activation Improves Corticosterone\u2010Induced Oxidative Stress Damage in Astrocytes by Targeting UBR5\/ATM 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