Ning Cui

Introduction: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major clinical challenge, with early metabolic reprogramming acting as a potential pathogenic driver. This study investigates the early lipid metabolic disturbances in DIC and evaluates the cardioprotective potential of the natural metabolic modulator, chlorogenic acid (CGA). Methods: Transcriptomic analysis was utilized to identify initial metabolic alterations. Lipidomics and spatial metabolomics were performed to map lipid distributions in DOX-treated H9c2 cardiomyocytes and C57BL/6J mouse hearts. The therapeutic mechanisms of CGA were assessed in vivo through echocardiography and histopathology, and in vitro using pharmacological interventions targeting the PPAR-FAO axis. Results: Transcriptomics and lipidomics revealed that DOX significantly suppresses the PPAR signaling pathway and fatty acid oxidation (FAO), resulting in the accumulation of ceramides and long-chain acylcarnitines. Spatial metabolomics confirmed in situ myocardial acylcarnitine accumulation. CGA treatment effectively improved cardiac function, mitigated oxidative stress, and inhibited apoptosis. Mechanistically, CGA reduced mitochondrial ROS and acylcarnitine levels by restoring PPAR expression and promoting FAO. Pharmacological blockade of PPARα or exogenous addition of acylcarnitines completely abolished CGA’s protective effects. Discussion: Impaired FAO and the subsequent accumulation of toxic acylcarnitines serve as early drivers of DOX-induced metabolic dysfunction. Targeting this lipid metabolic dysregulation with CGA represents a promising therapeutic strategy for mitigating anthracycline-induced cardiotoxicity.