Targeting mitochondrial phosphatase PGAM5 alleviates ferroptosis and acute pancreatitis by upregulating NRF2-mediated FSP1 expression
Year: 2026
Type: article
Abstract: 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. The molecular mechanism of alleviation of ferroptosis by dysregulation of PGAM5.
Source: Cell Death and Disease
Institution: Harbin Institute of Technology
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,990
Funder: Harbin Institute of Technology
OpenAlex ID: W7130845674