FPR1 drives sepsis-associated cognitive impairment through region-specific transcriptional and splicing dysregulation in the brain.

Sepsis-associated encephalopathy (SAE) usually causes long-term cognitive impairment, which seriously compromises the quality of life of patients, but the precise molecular mechanisms have not been elucidated. Formyl peptide receptor 1 (FPR1), a G protein-coupled receptor, plays a pivotal role in systemic and neuroinflammatory responses, but its function in SAE is unclear. Here, we employed Fpr1 knockout mice subjected to cecal ligation puncture (CLP) to model sepsis, integrating behavioral tests, flow cytometry, and transcriptomic and alternative splicing analyses of the hippocampus and prefrontal cortex. Sepsis markedly induced the expansion of reactive myeloid cells and upregulated FPR1 expression. Fpr1 deletion improved cognitive function, attenuated neuroinflammation, enhanced survival, and reversed sepsis-induced downregulation of neuroprotective genes in the hippocampus and myelin-related genes in the prefrontal cortex. Moreover, Fpr1 loss corrected aberrant transcription and splicing events in a brain region-specific manner. Our findings demonstrate that FPR1 drives SAE by orchestrating region-specific transcriptional and splicing networks, providing a rationale for targeting FPR1 to treat post-sepsis cognitive dysfunction.