PM2.5-induced iron homeostasis imbalance triggers cardiac hypertrophy through ferroptosis in a selective autophagy crosstalk manner

Exposure to PM_2.5 is correlated with cardiac remodeling, of which cardiac hypertrophy is one of the main clinical manifestations. Ferroptosis plays an important role in cardiac hypertrophy. However, the potential mechanism of PM_2.5-induced cardiac hypertrophy through ferroptosis remains unclear. This study aimed to explore the molecular mechanism of cardiac hypertrophy caused by PM_2.5 and the intervention role of MitoQ involved in this process. The results showed that PM_2.5 could induce cardiac hypertrophy and dysfunction in mice. Meanwhile, the characteristics of ferroptosis were observed, such as iron homeostasis imbalance, lipid peroxidation, mitochondrial damage and abnormal expression of key molecules. MitoQ treatment could effectively mitigate these alternations. After treating human cardiomyocyte AC16 with PM_2.5, ferroptosis activator (Erastin) and inhibitor (Fer-1), it was found that PM_2.5 could promote ferritinophagy and lead to lipid peroxidation, mitochondrial dysfunction as well as the accumulation of intracellular and mitochondrial labile iron. Subsequently, mitophagy was activated and provided an additional source of labile iron, enhancing the sensitivity of AC16 cells to ferroptosis. Furthermore, Fer-1 alleviated PM_2.5-induced cytotoxicity and iron overload in the cytoplasm and mitochondria of AC16 cells. It was worth noting that during the process of PM_2.5 caused ferroptosis, abnormal iron metabolism mediated the activation of ferritinophagy and mitophagy in a temporal order. In addition, NCOA4 knockdown reversed the iron homeostasis imbalance and lipid peroxidation caused by PM_2.5, thereby alleviating ferroptosis. In summary, our study found that iron homeostasis imbalance-mediated the crosstalk of ferritinophagy and mitophagy played an important role in PM_2.5-induced ferroptosis and cardiac hypertrophy.