Targeting mitochondrial phosphatase PGAM5 alleviates ferroptosis and acute pancreatitis by upregulating NRF2-mediated FSP1 expression

Ferroptosis is a regulated necrosis that is driven by iron-dependent lipid peroxidation. Phosphoglycerate mutase 5 (PGAM5), as a mitochondrial signaling hub, modulates mitochondrial dynamics, senses mitochondrial stress, and regulates the anti-oxidative response. However, the function of PGAM5 in ferroptosis remains elusive. Here, we discovered that PGAM5 emerges as a critical regulator of ferroptosis, with both genetic deletion and overexpression conferring protection against ferroptosis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) mediated ferroptosis suppressor protein 1 (FSP1) expression. On the one hand, dyregulation of PGAM5 upregulates NRF2 expression transcriptionally and inhibits its polyubiquitination. On the other hand, modulating the expression of PGAM5 results in energy stress ([AMP + ADP]/[ATP] ratio increase) and AMP-activated protein kinase (AMPK) activation. AMPK-dependent phosphorylation of NRF2 drives its nuclear accumulation, where it transcriptionally upregulates FSP1 to promote cell survival. Furthermore, pharmacological inhibition of PGAM5 attenuates arginine-induced acute pancreatitis, highlighting its therapeutic potential. Our findings establish PGAM5 as a central node in ferroptosis regulation and implicate its pathogenic role in acute pancreatitis.