Ethanolamine phosphate phospholyase in NAFLD: Emerging mechanisms, pathways, and therapeutic opportunities.

Nonalcoholic fatty liver disease (NAFLD) represents a growing global health burden with limited pharmacological options. Ethanolamine Phosphate Phospholyase (ETNPPL) is a liver enzyme involved in lipid metabolism, predominantly expressed in the mitochondrial matrix. Recent studies have confirmed a potential association between ETNPPL dysregulation and insulin resistance, ferroptosis, and macrophage reprogramming. These findings partially overlap with the pathogenesis of NAFLD. However, a comprehensive synthesis of these mechanisms remains lacking. On this basis, we propose an evidence-stratification framework to distinguish direct, indirect, and speculative mechanisms underlying the relationship between ETNPPL and NAFLD. This review synthesizes current evidence regarding the molecular biochemistry of ETNPPL, its potential mechanistic roles in NAFLD pathogenesis, and the therapeutic potential of targeting ETNPPL and its associated pathways. It also critically evaluates the reliability of relevant findings and explores translational prospects, aiming to bridge the gap between preclinical research and clinical application.