Sphinganine‐phosphate prevents influenza infection via promoting CD8 ⁺ T cells proliferation and activation

Abstract Despite the availability of antiviral drugs and vaccines, respiratory viral infections remain a serious global health burden. To identify novel therapeutic candidates, we performed metabolomic profiling comparing serum from patients infected with influenza or SARS‐CoV‐2 with healthy individuals. This analysis identified sphinganine‐phosphate (SA) as a potential protective metabolite. In a murine model of influenza infection, SA treatment significantly reduced viral load and attenuated inflammatory responses. Further mechanistic studies, including both in vivo and in vitro experiments, demonstrated that SA enhances antiviral immunity by promoting the proliferation and activation of CD8 + T cells and boosting the production of interferon‐γ and tumor necrosis factor‐α. This effect is mediated through the inhibition of suppressor of cytokine signaling 1 and subsequent activation of the Janus kinase 1/signal transducer and activator of transcription 1 signaling pathway. Our study reveals, for the first time, that SA promotes CD8 + T cell‐mediated immunity against influenza infection, providing important insights for the development of novel therapeutic strategies.