SaaS sRNA promotes the interfering effect of Salmonella on hepatic iron metabolism via modulating ferroportin 1

Iron limitation plays a fundamental role in host immunity against <i>Salmonella</i> infection. The mechanisms by which <i>Salmonella</i> antagonizes nutritional immunity, particularly those regulated by small non-coding RNAs (sRNAs), remain incompletely understood. In this study, we investigated the role of a previously identified sRNA, <i>Salmonella</i> adhesive-associated sRNA (SaaS), in host iron metabolism. Utilizing a combined BALB/c mouse model and HepG2 cell model, we demonstrated that SaaS enhances hepcidin synthesis via the bone morphogenetic protein (BMP)-SMAD pathway, leading to decreased ferroportin 1 level. This suppression of ferroportin 1 results in reduced serum iron and increased hepatic iron accumulation, ultimately causing iron-deficiency anemia. The accumulation of iron triggers hepatic oxidative stress, exacerbating liver damage. Concurrently, SaaS activates the signal transducer and activator of transcription 3 (STAT3) pathway in a triggering receptor expressed on myeloid cells-1 (TREM1)-interleukin (IL)-6-dependent manner, intensifying the inflammatory response. Collectively, these results provide evidence that sRNAs serve as crucial regulators of <i>Salmonella</i> pathogenesis and underscore the potential of targeting sRNAs for the prevention of salmonellosis.