Serum valeric acid stimulates lung epithelial cilia assembly and improves prognosis in patients with severe respiratory infections

Introduction: Globally, respiratory infections remain a leading cause of mortality, with treatment efficacy increasingly challenged by antimicrobial resistance. This study aimed to investigate the role of serum metabolites in the prognosis of severe human pneumonia. Methods: Untargeted and targeted serum metabolomics were performed on intensive care unit (ICU) patients. Experimental validation was conducted in a murine bacterial infection model and cellular models. RNA sequencing was used for mechanistic exploration to identify the signaling pathways regulated by the key metabolite. Results: model, valeric acid treatment alleviated infection severity, reduced body weight loss, lung inflammation, and bacterial load. Mechanistically, RNA sequencing revealed that valeric acid suppresses IL-17-associated inflammation and upregulates pathways related to mucociliary clearance. We further delineated the underlying mechanism, finding that valeric acid acts as a histone deacetylase (HDAC) inhibitor, specifically targeting HDAC3. This inhibition activates the canonical Wnt/β-catenin signaling pathway, leading to the upregulation of the master transcriptional regulator Foxj1 and subsequent promotion of cilia assembly and function in airway epithelia. Discussion: The findings establish a protective role for the gut microbiome-derived valeric acid in respiratory infections via the novel HDAC-Wnt-FOXJ1 axis, revealing its potential as a therapeutic agent to improve clinical outcomes.