{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T07:00:51Z","timestamp":1785308451023,"version":"3.55.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"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>Background<\/jats:title>\n                    <jats:p>Rosacea is a chronic inflammatory skin condition. Excessive LL-37 is produced when serine protease kallikrein-5 (KLK5) is hyperactivated, contributing to the inflammatory response in rosacea. Thus, inhibition of KLK5 has the potential to attenuate inflammation in this condition. Reports suggest that specnuezhenide (Spe), an isomer of oleanolic acid, is effective as an anti-inflammatory agent for the treatment of inflammatory diseases. However, little is known about the role of Spe and its mechanisms in alleviating rosacea.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Spe was identified as a potential KLK5 inhibitor through virtual screening and molecular docking, showing high-affinity binding via hydrophobic and hydrogen-bond interactions. Rosacea was induced in mice by intradermal LL-37 injection, followed by intraperitoneal administration of Spe. The severity of skin inflammation was assessed histologically. Serum cytokines, inflammatory gene expression, and protein levels of CD31, MMP-9, CD4, and KLK5 were analyzed by ELISA, RT-qPCR, and immunofluorescence, respectively. Inhibition of the TLR4\/NF-\u03baB pathway was examined by Western blot. Untargeted metabolomics was applied to characterize alterations in serum metabolites.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Spe markedly reduced LL-37-induced skin inflammation, decreased inflammatory cell and mast cell infiltration, decreased MMP-9 expression, and reduced CD31 fluorescence intensity and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell recruitment. The study demonstrated that Spe inhibited the expression of pro-inflammatory cytokines (IL-1\u03b2, IL-6, and TNF-\u03b1) in serum and suppressed activation of TLR2, MMP-9, KLK5, IL-1\u03b2, IL-6, and TNF-\u03b1 genes. Moreover, Spe inhibited KLK5 expression and blocked activation of the TLR4\/NF-\u03baB pathway. Metabolomics identified 43 dysregulated metabolites in rosacea, 26 of which were normalized by Spe treatment. Pathway enrichment analysis suggested that regulation of unsaturated fatty acid biosynthesis is a key mechanism underlying the effects of Spe.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrates for the first time that Spe, a novel KLK5 inhibitor, suppresses the inflammatory response mediated by the KLK5\/TLR4\/NF-\u03baB pathway, accompanied by metabolic remodeling, particularly involving the biosynthesis of unsaturated fatty acids, thereby ameliorating rosacea-like dermatitis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1886252","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:03:56Z","timestamp":1785305036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Virtual screening identifies specnuezhenide as a potential therapeutic agent for rosacea via KLK5\/TLR4\/NF-\u03baB pathway inhibition and metabolic modulation"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingang","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Medical Parasitology, Wannan Medical University","place":["Wuhu, Anhui, China"]},{"name":"Department of Clinical Pathology, The First Affiliated Hospital of Zhejiang University School of Medicine Suzhou Branch","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Parasitology, Wannan Medical University","place":["Wuhu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Parasitology, Wannan Medical University","place":["Wuhu, Anhui, 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