Jiali Wang, Hongli Li, Yuhan She, Chongli Xu, Kun Peng, Wenqiao Ding
Lipid peroxidation is a critical oxidative stress response implicated in the pathogenesis of numerous metabolic diseases, including cardiovascular diseases, diabetes, and non-alcoholic fatty liver disease (NAFLD). While its role in damaging cellular components such as membranes, proteins, and DNA is well-documented, a significant translational gap persists between our mechanistic understanding and the development of effective clinical interventions. This review critically examines this disconnect by proposing and applying a three-tiered analytical framework. First, we identify and compare the hierarchy of initial molecular targets (e.g., mitochondrial cardiolipin, LDL phospholipids, specific protein thiols) across diseases, arguing that this hierarchy dictates pathological specificity. Second, we trace how these initial insults propagate through shared yet context-dependent mechanistic themes-metabolic dysregulation, inflammatory amplification, and cell death decisions-to drive organ-specific pathology. Third, we synthesize and critically evaluate current and emerging therapeutic strategies (e.g., antioxidants, ferroptosis inhibitors, nutritional modulation) against this mechanistic backdrop, highlighting their potential, limitations, and the need for mechanism-informed, personalized approaches. By moving beyond a descriptive catalog of effects, this review aims to provide a dynamic, intervention-oriented perspective essential for bridging basic science discoveries with translational innovation in combating lipid peroxidation-associated metabolic disorders.