PPARβ/δ Activation Improves Corticosterone‐Induced Oxidative Stress Damage in Astrocytes by Targeting UBR5/ATM Signaling

Oxidative stress-mediated astrocytic damage contributes to nerve injury and the development of depression, especially under stress conditions. Peroxisomes and pexophagy are essential for balancing oxidative stress and protein degradation products. Our previous findings suggest that peroxisome proliferators-activated receptor β/δ (PPARβ/δ) 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, PPARβ/δ agonists and antagonists were applied to determine the effects of PPARβ/δ on balancing peroxisomes and pexophagy in astrocytes. The PPARβ/δ agonist (GW0742) significantly improved cell viability and decreased intracellular reactive oxygen species (ROS) production induced by corticosterone, while pretreatment with the PPARβ/δ, antagonist GSK3787 reversed the effects of GW0742. Moreover, activating PPARβ/δ promoted peroxisomal biogenesis factor 5 (PEX5)-mediated pexophagy by enhancing the phosphorylation of ataxia-telangiectasia mutated (ATM) kinase. Conversely, blocking PPARβ/δ with GSK3787 partially abolished the effects of GW0742. Further investigations demonstrated that activation of PPARβ/δ not only induced transcription of the ubiquitin protein ligase E3 component n-recognin 5 (UBR5) but also enhanced the interaction between PPARβ/δ and UBR5, contributing to ATM interactor (ATMIN) degradation, and increased phosphorylated ATM kinase levels. Therefore, this study revealed that activating PPARβ/δ improves corticosterone-induced oxidative damage in astrocytes by enhancing pexophagy. PPARβ/δ directly interacts with UBR5 to facilitate ATMIN degradation and promotes ATM phosphorylation, thereby maintaining the balance between peroxisomes and pexophagy. These findings suggest that PPARβ/δ is a potential target for promoting pexophagy in astrocytes upon stress.