Zhihao, X.; Deshang, X.; Keqin, L.; Yijia, Y.; Xingjie, H.; Fen, Y.; Wenbin, N.; Jiang, D.; Rui, G.; Yonghai, L.; Ping, Z.; Yanli, L.; Juntang, L.

The incidence of emotional disorders in patients with idiopathic pulmonary fibrosis (IPF) is substantially higher than that in the general population, severely compromising their quality of life. However, the underlying mechanisms remain poorly understood. In this study with multi-omics, we demonstrated that sphingosine-1-phosphate (S1P) derived from IPF lungs drive anxiety and depressive-like behaviors. Mechanistically, circulating S1P in the blood bound to hippocampal S1PR1 to regulate the PI3K/PKA/CREB signaling pathway, leading to synapse damage, the activation of microglia and astrocytes, neuroinflammation and ferroptosis in the hippocampus. Pharmacological inhibition of Sphk1, a key enzyme in S1P synthesis, reduced serum S1P levels and alleviated IPF-induced anxiety and depressive-like behaviors. Similarly, selective inhibition of hippocampal S1P receptor signaling using Fingolimod also attenuated neuroinflammation and ferroptosis and ameliorated mood disorders in IPF models. Collectively, these findings demonstrate that metabolite S1P from fibrotic lungs serves as a mediator of lung-to-brain functional influence, providing new insights into the IPF comorbid mood disorders and potential therapeutic targets.