{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T15:53:16Z","timestamp":1789487596894,"version":"build-2803163510"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"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>\n                      Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and gut microbiota dysbiosis.\n                      <jats:italic>Gnaphalium hypoleucum<\/jats:italic>\n                      DC. total flavonoids (GHTFs) exhibit anti-inflammatory and immunomodulatory properties.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      In this study, we employed an integrated strategy combining machine learning (ML), molecular docking, and molecular dynamics simulations to identify active compounds within GHTFs. The therapeutic mechanisms of these compounds were further investigated using LPS-stimulated RAW264.7 macrophages and a collagen-induced arthritis mouse model. Differential expression analysis identified 2,676 RA-associated genes. A glmBoost + LDA model demonstrated robust diagnostic performance (AUC_train = 0.959; AUC_val \u2265 0.837) and prioritized five key genes (POLB, EGFR, MMP13, VEGFA, and KMT2D). Molecular docking and dynamics simulations confirmed the stable binding of amentoflavone (AF), a primary constituent of GHTFs, to core targets MMP9, MMP13, TOP2A, and ALOX5.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , both GHTFs and AF inhibited proliferation, migration, and nitric oxide release in LPS-stimulated RAW264.7 macrophages, and suppressed IL-17, TNF-\u03b1, and NF-\u03baB signaling pathways, with AF showing more potent effects (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;gt;0.05).\n                      <jats:italic>In vivo<\/jats:italic>\n                      , GHTFs treatment reduced clinical arthritis scores by over 40%, alleviated synovial hyperplasia, preserved collagen volume fraction, and lowered serum levels of TNF-\u03b1 and IL-1\u03b2, demonstrating superior overall efficacy compared to AF and methotrexate (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;gt;0.05). Gut microbiota analysis revealed that GHTFs enriched beneficial\n                      <jats:italic>Lactobacillus<\/jats:italic>\n                      species (e.g.,\n                      <jats:italic>L. johnsonii, L. intestinalis<\/jats:italic>\n                      ), reduced the abundance of pro-inflammatory taxa, and restored microbial metabolic functions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, our findings identify GHTFs as a promising therapeutic candidate for RA, ameliorating disease progression through modulation of inflammatory responses and microbiota-mediated immune regulation.<\/jats:p>\n                  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