Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review).

Abstract

Non‑alcoholic fatty liver disease (NAFLD), characterized by excessive lipid accumulation in hepatocytes, has emerged as the leading cause of chronic liver disorders globally. As the central metabolic organ, the liver critically depends on mitochondrial integrity. Mitophagy, a selective form of autophagy, plays a pivotal role in sustaining mitochondrial homeostasis by eliminating dysfunctional mitochondria. Dysregulated mitophagy contributes to the progression of NAFLD, while its restoration mitigates disease severity. The present review outlines the tripartite axis of mitophagy, namely, the PTEN‑induced putative kinase 1/Parkin, PI3K/AKT/mTOR and AMP‑activated protein kinase pathways, in NAFLD pathogenesis across the various stages of disease development, including steatosis, nonalcoholic steatohepatitis and fibrosis, and explores their therapeutic potential. Additionally, emerging regulators, including FUN14 domain‑containing protein 1, prohibitin 2, ceramide signaling and non‑coding RNAs, which fine‑tune mitophagy in NAFLD are highlighted. By integrating evidence from pharmacological and natural agents, including traditional Chinese medicines, mitophagy‑centric strategies to promote hepatic lipid metabolism, mitigate disease progression and inform novel NAFLD therapeutics are discussed. This exploration of the mechanisms that govern mitochondrial‑autophagic crosstalk not only advances mechanistic insights but also opens new avenues for precision medicine in the treatment of metabolic liver diseases.