Quercetin attenuates emamectin benzoate-induced myocardial PANoptosis in chickens: Critical role of the MAPK/NF-κB signaling pathway and mitochondrial dynamics.

Emamectin benzoate (EMB) is a highly effective and widely detected environmental insecticide whose potential to induce severe cardiotoxicity and localized myocardial inflammation has raised substantial biomedical concerns. Quercetin (Que), a ubiquitous plant-derived natural antioxidant, has shown promise in mitigating exogenous chemical-induced toxicities, yet its precise immunopharmacological mechanism against EMB-induced cardiotoxicity remains to be fully elucidated. This study investigated the protective effects and mechanisms of Que. against EMB-induced cardiotoxicity by integrating network toxicology, transcriptomics, and in vivo/in vitro experimental validation. Multi-omics analysis identified MAPK8, MAPK3, and CASP3 as key responsive targets conserved across species. Functional enrichment revealed that these targets are predominantly involved in the MAPK/NF-κB signaling pathway and mitochondrial organization. Molecular docking and targeted intervention experiments confirmed that Que. potentially targets and binds to JNK (encoded by MAPK8), thereby blocking the EMB-activated signaling axis. This molecular interaction effectively restored mitochondrial dynamics and prevented mitochondrial DNA leakage into the cytoplasm, ultimately alleviating myocardial PANoptosis. Collectively, our findings demonstrate that Que. serves as a natural antagonist against chemical-induced cardiotoxicity by modulating the MAPK/NF-κB axis, offering a promising therapeutic strategy for mitigating pesticide-related immunotoxicological risks.