Fibrotic lung-derived sphingosine-1-phosphate drives emotion-like disorders by regulating hippocampal neuroinflammation and cell death

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 multiomics study, we demonstrated that sphingosine-1-phosphate (S1P) derived from the lungs of bleomycin-treated mice 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 synaptic damage, microglial and astrocytic activation, neuroinflammation and cell death in the hippocampus. Pharmacological inhibition of Sphk1, a key enzyme involved in S1P synthesis, reduced serum S1P levels and alleviated anxiety and depressive-like behaviors in bleomycin-treated mice. Similarly, selective inhibition of hippocampal S1P receptor signaling using fingolimod also attenuated neuroinflammation and cell death and ameliorated mood disorders in bleomycin-treated mice. Collectively, these findings demonstrate that metabolite S1P from fibrotic lungs serves as a mediator of lung-to-brain functional influence, providing new insights into mood disorders comorbid with IPF and highlighting potential therapeutic targets. S1P derived from fibrotic lungs drives emotional disorders and the underlying mechanism. S1P originating from the fibrotic lungs enters the bloodstream. This supraphysiological level of circulating S1P binds to hippocampal S1PR1, which triggers the PI3K/PKA/CREB signaling pathway, leading to microglial and astrocytic activation, synaptic dysfunction, neuroinflammation, and ferroptosis, thereby driving the onset of mood disorders. Pharmacological inhibition of pulmonary Sphk1 reduces serum S1P levels and alleviates mood disorders in BLM-treated mice. Similarly, functional inhibition of hippocampal S1PR1 with Fingolimod ameliorates neuroinflammation and ferroptosis, thereby alleviating emotion disorders. The graphical abstract was made in Biorender (https://app.biorender.com/)