{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:31:05Z","timestamp":1792452665064,"version":"4.5.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Valeric acid, a short-chain fatty acid, was significantly elevated in survivors compared with non-survivors of severe pneumonia. In the murine\n                      <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                      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\/\u03b2-catenin signaling pathway, leading to the upregulation of the master transcriptional regulator Foxj1 and subsequent promotion of cilia assembly and function in airway epithelia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1761517","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:12:34Z","timestamp":1768205554000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Serum valeric acid stimulates lung epithelial cilia assembly and improves prognosis in patients with severe respiratory infections"],"prefix":"10.3389","volume":"16","author":[{"given":"Yabin","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiabao","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1016\/j.jiph.2020.04.016","article-title":"Preparedness and response to COVID-19 in Saudi Arabia: building on MERS experience","volume":"13","author":"Algaissi","year":"2020","journal-title":"J. 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