Trimethyltin chloride triggers ferroptosis in myocardial injury: mitochondria-dependent protection by luteolin.

Trimethyltin chloride (TMT), a poison from water and soil, has been linked to bradycardia. Ferroptosis, an iron-driven type of regulated cell death, is critically involved in cardiovascular diseases. However, the mechanism of TMT-induced myocardial injury remains unclear. This study aims to investigate the toxicological mechanism of TMT-induced myocardial injury and evaluate the protective effect of Lut. In this study, RNA sequencing identified Gpx4 as the key ferroptosis-related gene of TMT-induced cardiomyopathy. In vitro, TMT induced ferroptosis, which was reversed by Ferrostatin-1. Notably, TMT also suppressed mitophagy, co-treatment with chloroquine (CQ) aggravated TMT-induced ferroptosis, whereas Urolithin A reversed this effect. In vivo and in vitro, TMT caused bradycardia and myocardial ferroptosis, while Luteolin (Lut) exerted anti-ferroptosis effects. Furthermore, TMT increased DRP1 phosphorylation and reduced the expression of mitochondrial fusion and mitophagy proteins, which were restored by Lut. And the anti-ferroptosis effect of Lut was abolished by CQ. Collectively, it revealed that TMT induced ferroptosis in vitro and in vivo, while Lut alleviated TMT-induced myocardial injury by activating mitophagy, inhibiting ferroptosis, then restoring mitochondrial function.