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.

代谢相关脂肪性肝病（MAFLD）作为全球流行率较高的慢性肝病，其发病机制错综复杂，目前仍缺乏特异性治疗药物。本篇综述围绕E3泛素连接酶帕金蛋白（Parkin），系统梳理了其在MAFLD疾病进展中的经典与非经典功能，重点探讨了Parkin在细胞凋亡与焦亡调控、内质网-线粒体交流、脂质代谢重编程以及肝星状细胞活化等多个病理环节中的关键作用。Parkin经PINK1/Parkin通路介导的选择性线粒体自噬是维持肝细胞代谢稳态、抑制炎症反应的核心机制。然而，越来越多的跨疾病模型研究证据提示，在脂毒性应激环境下，Parkin的功能并不局限于线粒体质量调控，其可能通过一系列非经典泛素化修饰，潜在参与MAFLD的多条致病通路。因此，未来针对MAFLD的治疗策略应着眼于多通路协同调控，这为靶向Parkin的创新药物研发开辟了新的方向。