Integrating network toxicology and transcriptomics reveals the potential targets of chlorfenapyr-induced myocardial injury

BACKGROUND: Chlorfenapyr, a novel pyrrole-class insecticide, can induce acute myocardial injury and cardiotoxicity. This study aimed to investigate its potential targets through network toxicology and transcriptomic profiling. METHODS: The toxicological profiles of chlorfenapyr and its active metabolite tralopyril were predicted using the ADMETlab 3.0 platform. Rats were administered 230 mg/kg chlorfenapyr via oral gavage based on the literature. Network toxicology and transcriptomics were performed to identify potential targets associated with chlorfenapyr, tralopyril, and myocardial injury. Their expressions were validated using in vivo and in vitro models. RESULTS: In chlorfenapyr-exposed rats, thermal imaging revealed elevated body temperatures, suggesting increased blood flow or metabolic activity. Furthermore, abnormal cardiac functional parameters, myocardial injury and ultrastructural damage in cardiomyocytes were also observed. Immunohistochemistry showed that the levels of cardiac troponin I, brain natriuretic peptide and heat shock 70 kDa protein 1 A were significantly increased in cardiac tissues post-exposure. Five targets (KCNA5, ICAM1, KCNJ6, PTGS2, and PIM1) were identified as being linked to chlorfenapyr, tralopyril, and myocardial injury, potentially mediating pathways involving inflammatory responses, apoptosis, ion homeostasis, TNF, and NF-kappa B signaling pathways. Molecular docking confirmed stable binding interactions. Chlorfenapyr and tralopyril significantly reduced cell viability, increased apoptosis, and induced mitochondrial dysfunction in H9c2 cells. The significant differential expression of Icam1, Ptgs2, and Kcna5 in H9c2 cells and rat heart tissue induced by chlorfenapyr exposure was verified, in agreement with the transcriptomic data. CONCLUSION: This study identifies potential targets and mechanisms potentially involved in chlorfenapyr-induced myocardial injury, warranting further investigation into their roles in cardiotoxicity.