Dihydromyricetin Regulates PANoptosis to Protect <i>Salmonella Typhimurium</i> ‐Infected Weaned Piglets

ABSTRACT Salmonella Typhimurium (S.Tm) infection disrupts intestinal epithelial cells (IECs) and compromises gut integrity in weaned piglets. Piglets that were fed 1% DHM for 17 days before infection showed increased average daily gain (ADG) and feed efficiency (F:G ratio) versus controls ( p &lt; 0.05). Post‐S.Tm challenge, the DHM + S.Tm group exhibited a tendency for higher ADG (0.05 ≤ p &lt; 0.1) and improved ileal villus:crypt ratios ( p &lt; 0.05), indicating mitigated intestinal damage. PANoptosis is a type of programmed cell death that integrates pyroptosis, apoptosis, and necroptosis. DHM reduced the abundance of Salmonella in the colon ( p &lt; 0.05) and enhanced PANoptosis in both the ileum and colon tissues ( p &lt; 0.05). In the ileum and colon, PANoptosis‐related signaling was broadly upregulated: phosphorylation of RIPK3 ( p &lt; 0.0001) and MLKL ( p &lt; 0.05) increased, Caspase‐3 cleavage was enhanced ( p &lt; 0.05), and GSDME activation was markedly elevated ( p &lt; 0.0001). Inflammasome activation was also enhanced, evidenced by elevated Caspase‐1 and NLRP3 levels, while the proportion of TUNEL‐positive cells decreased, indicating selective clearance of infected IECs without harming normal cells. Metabolomic profiling revealed reduced serum glutamic acid and glyceraldehyde 3‐phosphate levels, with sphingolipid metabolism identified as a key DHM‐regulated pathway. In vitro, DHM promoted PANoptosis‐mediated clearance of Salmonella Typhimurium ‐infected IECs. Overall, DHM alleviates Salmonella infection by inducing PANoptosis to eliminate infected intestinal cells, providing a potential nutritional approach for controlling pathogen dissemination in piglets.