Quercetin Alleviates TMT-Induced PANoptosis in Chicken Skeletal Muscle through Modulation of the ROS/mtDNA Axis

Abstract

Trimethyltin (TMT) is an environmental organotin contaminant with recognized systemic toxicity, but its skeletal muscle effects and the protective mechanism of quercetin (Que) remain unclear. This study integrated network toxicology, molecular docking, molecular dynamics simulations, and in vivo/in vitro validation to investigate Que-mediated protection against TMT-induced skeletal-muscle injury. Network analysis indicated the involvement of oxidative stress and cytosolic DNA-sensing pathways, while docking and dynamic simulations suggested stable interactions between Que and mitochondrial regulators and PANoptosis-associated proteins. In vivo and in vitro validation showed that TMT induced skeletal muscle injury, reactive oxygen species (ROS) accumulation, mitochondrial dynamic imbalance, respiratory chain dysfunction, mitochondrial DNA (mtDNA) leakage, and PANoptosis activation. Que markedly suppressed ROS generation, restored mitochondrial homeostasis, reduced cytosolic mtDNA leakage, and inhibited PANoptosis-related signaling. Collectively, Que alleviates TMT-induced skeletal muscle toxicity by regulating the ROS/mtDNA axis, supporting its potential as a dietary intervention or feed additive against organotin-associated muscle damage.