Polystyrene nanoplastics induce cardiotoxicity by driving myocardial metabolic reprogramming via the SDHA/Succinate/HIF-1α axis.

Micro- and nano-plastics (MNPs) have emerged as ubiquitous environmental contaminants and are increasingly implicated in adverse cardiovascular outcomes, yet their induced cardiotoxicity and potential mechanisms remain poorly understood. This study integrated in vivo mouse models, AC16 cardiomyocytes and a human cardiac organoid-on-a-chip (COoC) platform to multi-dimensionally evaluate polystyrene nanoparticles (PS-NPs)-induced cardiac injury and clarify its key molecular mechanisms. We found that PS-NPs exposure induced pronounced structural and functional cardiac injury in mice and caused impaired myocardial contraction, disrupted calcium transients and increased injury biomarkers in vitro. Notably, PS-NPs exposure perturbed myocardial energy metabolism, producing a metabolic reprogramming profile characterized by suppressed fatty acid oxidation (FAO) and enhanced glycolytic activity. Metabolic interventions further showed that activation of FAO or promotion of mitochondrial pyruvate oxidation improved myocardial energy status and alleviated cardiotoxicity, whereas direct inhibition of glycolysis aggravated energy depletion and cellular injury, suggesting that enhanced glycolysis provided partial energetic compensation but was insufficient to offset impaired oxidative metabolism. Mechanistically, our findings indicated a functional role of the SDHA/succinate/HIF-1α signaling axis in this metabolic reprogramming. PS-NPs-induced SDHA downregulation promoted succinate accumulation and HIF-1α stabilization, thereby rewiring myocardial energy metabolism and contributing to cardiac dysfunction. Collectively, we revealed myocardial metabolic reprogramming as an important mechanism underlying PS-NPs-induced cardiotoxicity and identified the SDHA/succinate/HIF-1α axis as a potential molecular link between PS-NPs exposure and cardiac injury.