Piglet diarrhea is an intestinal disease caused by Clostridium perfringens(C.perfrin-gens)toxin.This study aims to reveal the damage mechanism of piglet diarrhea to IPEC-J2 cells by studying key genes and pathways related to piglet diarrhea.IPEC-J2 cells were treated with C.per-fringens toxin and transcriptome sequencing was performed.By analyzing GO function,KEGG pathway and protein interaction network of differentially expressed genes,key genes and pathways in cell damage were identified.Compared with the control group,460 genes were detected in the in-jury group,of which 419 genes were up-regulated and 41 genes were down-regulated.KEGG analy-sis further revealed that influenza A and NOD-like receptor signaling pathways were significant.Protein interaction network analysis screened out 8 core gene subnetworks,which were positively correlated with each other.These genes were mainly annotated on influenza A and NF-kappa B sig-naling pathways.qRT-PCR further confirmed the reliability of RNA-seq sequencing results.In con-clusion,influenza A,NOD-like receptor signaling pathway,and NF-kappa B pathway are involved in the damage of porcine IPEC-J2 cells caused by C.perfringens toxin.MX2,MX1,DDX58,IFI44,ISG15 genes may play an important role in the process of resistance to C.perfringens toxin in por-cine small intestine through key signaling pathways.This provides new insights into the mecha-nism of diarrhea induced by C.perfringens toxin.