Fangchinoline drives NOS2-dependent host immunity to restrict intracellular enteric pathogens

Intracellular bacterial infections remain difficult to treat due to antibiotic tolerance, immune evasion, and the emergence of multidrug resistance. Here, we identify Fangchinoline (Fcn), a natural alkaloid, as a host-directed immunomodulator that restricts intracellular Salmonella through NOS2-dependent nitric oxide (NO) signalling. Fcn enhances macrophage bactericidal activity and promotes Th1 immunity, leading to improved bacterial control in vitro and in vivo. Pharmacological inhibition of NO synthesis and loss of protection in NOS2^-/- mice establish NO as a central effector mechanism. Serum metabolomics indicate Fcn is associated with immunometabolic changes consistent with enhanced NO biosynthesis. In addition, Fcn synergizes with suboptimal-dose Ciprofloxacin to control Salmonella infection while preserving host immune responses. Notably, Fcn primes memory-like T cell responses and enhances resistance upon subsequent infection. Collectively, these findings suggest Fangchinoline as a host-directed immunotherapeutic that integrates metabolic, innate, and adaptive immune programs to restrict intracellular enteric pathogens, including multidrug-resistant strains, and augment antibiotic efficacy.