Glucose-6-phosphatase catalytic subunit 3 enhances host resistance to porcine epidemic diarrhea virus through regulating glycolysis/gluconeogenesis

Porcine epidemic diarrhea virus (PEDV) causes a highly contagious disease in pigs, and the intricacies of its host–pathogen interactions require further elucidation. Chinese Min piglets, known for their superior resistance to stress and disease, were compared with Yorkshire piglets to investigate breed-specific resistance mechanisms. We established PEDV infection models in both breeds and analyzed differences by assessing cytokine levels, viral loads, and histological changes in jejunal tissues. Transcriptomic analysis of jejunal tissues identified 5422 differentially expressed (DE) protein-coding genes (PCGs) and 1999 DE long non-coding RNAs (lncRNAs) between the two pig breeds. Functional annotation revealed that Yorkshire piglets exhibited upregulation of inflammatory and apoptotic pathways, whereas Chinese Min piglets displayed strong inflammatory responses and enhanced mucosal immunity. Notably, glucose-6-phosphatase catalytic subunit 3 (<i>G6PC3</i>) expression was significantly higher in Chinese Min piglets than in Yorkshire piglets. Knockdown of <i>G6PC3</i> in the intestinal porcine epithelial cell line J2 (IPEC-J2) resulted in increased PEDV replication and decreased expression of immune-related genes involved in the glycolysis/gluconeogenesis metabolism pathway. These findings highlight the distinct immune responses of Chinese Min and Yorkshire piglets to PEDV infection, and identify key PCGs and lncRNAs associated with PEDV immunity.