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A rabbit\u2010ear HS model was established in\u00a0vivo. Hematoxylin\u2013eosin (H&amp;E) staining, Masson staining, immunofluorescence (IF), Western blot (WB), and quantitative real\u2010time PCR (RT\u2010qPCR) were used to assess the effects of Res on scar hyperplasia, collagen deposition, FB activation, and macrophage polarization. In\u00a0vitro, FB activation was stimulated by combined treatment with TGF\u2010\u03b21 and lactic acid, and a Transwell co\u2010culture system comprising FB and human monocyte\u2010derived M0 macrophages was established. Scratch assay, FCM, IF, and WB were performed to assess the impacts of Res on FB activation, migration, and macrophage polarization. Additionally, ASIC3 gene knockout experiments were conducted both in\u00a0vivo and in\u00a0vitro to confirm the mechanism underlying Res\u2010mediated HS improvement. In\u00a0vitro, Res significantly inhibited FB migration in a dose\u2010dependent manner and downregulated the protein expression of \u03b1\u2010SMA, COL1A1, COL3A1, reduced M\u2010CSF secretion, suppressed macrophage polarization toward the M2 phenotype, and decreased TGF\u2010\u03b21 mRNA expression. It also blocked activation of the PI3K\/Akt signaling pathway downstream of ASIC3. These effects were completely abolished after ASIC3 gene knockdown. In\u00a0vivo, Res significantly reduced the scar elevation index (SEI) in rabbit\u2010ear HS. It improved collagen fiber arrangement and decreased collagen deposition. It markedly inhibited M2 macrophage polarization and TGF\u2010\u03b21 mRNA expression. After ASIC3 knockout, the anti\u2010HS effects of Res, as well as its regulatory effects on macrophage polarization and fibrotic factors, were abrogated. Res ameliorates HS by inhibiting ASIC3 expression. This disrupts the ASIC3\u2013M\u2010CSF\u2013TGF\u2010\u03b21 positive feedback loop. It restores the balance of macrophage polarization, inhibits FB activation, reduces abnormal collagen deposition, and ultimately attenuates HS formation.<\/jats:p>","DOI":"10.1002\/ptr.70397","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:54:45Z","timestamp":1780980885000},"page":"5389-5404","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Resveratrol Ameliorates Hypertrophic Scar Formation by Regulating\n                    <scp>ASIC3<\/scp>\n                    \u2010Mediated Fibroblast\u2013Macrophage Crosstalk: A Mechanistic Study"],"prefix":"10.1002","volume":"40","author":[{"given":"Zili","family":"Sun","sequence":"first","affiliation":[{"name":"Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine  Jiangyin 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