Targeting p38α promotes Parkin-mediated mitophagy to attenuate severe acute pancreatitis via suppressing the mtDNA/cGAS-STING signaling pathway
Abstract
Severe acute pancreatitis (SAP) is a life-threatening acute inflammatory disorder characterized by systemic inflammation and high mortality, for which specific targeted therapeutic strategies are still severely lacking in clinical practice. Mitochondrial dysfunction and impaired mitophagy have been validated as critical pathological drivers of SAP; nevertheless, the precise molecular targets governing the dysregulation of mitochondrial quality control remain poorly defined. Herein, we identify p38α (MAPK14) as a central regulator of mitophagy during SAP progression. Combining bioinformatic screening with an experimental SAP model, we demonstrate aberrantly hyperactivated p38α in pancreatic acinar cells. Mechanistically, activated p38α phosphorylates the S131 site of the E3 ubiquitin ligase Parkin. This site-specific phosphorylation triggers a “ubiquitination switch”, which selectively accelerates K48-linked polyubiquitination-dependent degradation of Parkin while impairing its K63-linked autoubiquitination and functional activity. Consequently, blockade of Parkin-dependent mitophagy results in accumulation of damaged mitochondria and massive leakage of mitochondrial DNA (mtDNA) into the cytoplasm, which further activates the cGAS-STING signaling cascade and exacerbates the sterile inflammatory storm. Pharmacological inhibition of p38α or genetic overexpression of the phosphorylation-deficient Parkin mutant (S131A) effectively restores mitophagic flux, eliminates cytoplasmic mtDNA accumulation, and suppresses cGAS-STING-mediated pro-inflammatory cytokine release, thereby markedly alleviating pathological injury in SAP. Our study illuminates a novel role of the p38α/Parkin/mtDNA/cGAS-STING signaling axis in the pathogenesis of SAP, and highlights targeting the p38α-mediated Parkin S131 phosphorylation switch as a promising therapeutic strategy for clinical intervention against SAP.