PGAM5 is a mitochondrial serine/threonine phosphatase that regulates multiple cellular processes through selective dephosphorylation of key substrates. Primary functions include mitochondrial dynamics regulation, quality control through selective autophagy, and modulation of stress responses. Mechanistically, PGAM5 dephosphorylates DRP1 to promote mitochondrial fission 1 and dephosphorylates FUNDC1 to regulate mitophagy independent of PARKIN 2. PGAM5 participates in the KEAP1-NRF2 antioxidant pathway 3 and regulates a ROS-induced cell death pathway termed oxeiptosis through KEAP1 and AIFM1 interactions 4. Additionally, PGAM5 dephosphorylates the pro-apoptotic protein Bax, initiating mitochondrial DNA release and inflammatory signaling via the cGAS-STING pathway 5. In macrophages, PGAM5 promotes pro-inflammatory M1 polarization by dephosphorylating DVL2 and inhibiting the β-catenin-STAT6-PPARγ axis 6. Disease relevance spans age-related conditions, as PGAM5 deletion accelerates cellular senescence in retinal pigment epithelium 1, and inflammatory pathologies including acute kidney injury and osteoarthritis where PGAM5 knockdown provides protection 5, 6. Clinically, PGAM5 represents a therapeutic target for anti-inflammatory strategies and potential cancer treatment through stabilization of the Keap1-PGAM5 complex 3.