{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:26:12Z","timestamp":1791930372149,"version":"4.3.4"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Preeclampsia (PE) is a severe obstetric syndrome linked to impaired maternal-fetal immune tolerance, placental insufficiency, and systemic inflammatory activation. Emerging studies suggest that gut microbiota and its metabolites, especially short-chain fatty acids (SCFAs), play a pivotal role in the pathogenesis of PE. However, the precise molecular mechanisms through which SCFAs influence maternal-fetal immune interactions remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study combined clinical data and experimental models to explore the role of SCFAs in regulating cathepsin C expression, a key protease involved in immune modulation, and its impact on immune disturbances in PE. We analyzed the gut microbiota composition and serum SCFA levels in PE patients, and used an L-NAME-induced rat model of PE to assess the effects of SCFA supplementation. Additionally, forced cathepsin C overexpression in rats was performed to establish causality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our findings revealed significant gut microbiota alterations in PE patients, with a reduction in SCFA-producing bacteria and an increase in inflammatory microbes. Clinically, SCFA levels were inversely correlated with cathepsin C expression, which was associated with hypertension and proteinuria. In rats, SCFA supplementation significantly reduced cathepsin C levels and alleviated PE symptoms, including hypertension, proteinuria, and fetal growth restriction. Furthermore, overexpression of cathepsin C negated the beneficial effects of SCFAs, exacerbating PE progression. Mechanistically, SCFAs modulated macrophage polarization by inhibiting cathepsin C, promoting the shift to an anti-inflammatory M2 phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study elucidates the \"gut microbiota\u2013SCFAs\u2013cathepsin C\u2013macrophage polarization\" pathway as a crucial mechanism in the development of PE. SCFAs promote immune tolerance at the maternal-fetal interface by downregulating cathepsin C and driving M2 macrophage polarization. These findings offer new insights into potential therapeutic strategies for PE, including interventions aimed at modulating the gut microbiota to prevent or mitigate the disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1700781","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T06:26:23Z","timestamp":1763360783000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Unraveling the gut microbiota\u2013SCFAs\u2013cathepsin C pathway in preeclampsia: a novel therapeutic 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