帕金蛋白在代谢相关脂肪性肝病中的潜在非经典功能及治疗展望OA

Metabolic associated fatty liver disease(MAFLD),as the most prevalent chronic liver disease worldwide,features a complex and multifactorial pathogenesis,and no targeted therapeutics are currently available.This review focuses on the E3 ubiquitin ligase Parkin,providing a systematic analysis of its classical and non-classical functions during MAFLD progression.We particularly highlight Parkin's pivotal roles in multiple pathological processes,including the regulation of apoptosis and pyroptosis,mediation of endoplasmic reticulum-mitochondria crosstalk,reprogramming of lipid metabolism,and modulation of hepatic stellate cell activation.It is well established that Parkin-mediated mitophagy via the PINK1/Parkin pathway serves as a central mechanism for maintaining hepatic metabolic homeostasis and suppressing inflammatory responses.However,growing evidence from cross-disease model studies suggests that under lipotoxic stress,Parkin's functional repertoire extends far beyond mitochondrial quality control.Building on this evidence,we propose that Parkin likely participates may potentially participate in multiple MAFLD pathogenic pathways through a series of non-canonical ubiquitination events.Consequently,future therapeutic strategies in MAFLD should aim at coordinated multi-pathway intervention.This perspective opens new avenues for innovative drug discovery targeting Parkin.