{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:19:23Z","timestamp":1792793963505,"version":"4.5.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003347","name":"Fudan University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>During the healing of skin wounds, excessive fibrosis and collagen remodeling disorders often lead to the formation of proliferative scars. Fisetin is a naturally occurring flavonoid compound with antioxidant and anti-fibrotic properties. However, its therapeutic effect and mechanism of action in wound healing and inhibition of scar formation are still unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study used network pharmacological methods to identify potential targets and pathways related to wound healing and proliferative scar formation. Through protein-protein interaction analysis, Gene Ontology analysis and enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG), its potential biological functions were clarified. In addition, molecular docking was also carried out to evaluate the binding affinity between fisetin and the core target. The effect of fisetin on wound closure and collagen deposition was evaluated using the full-thickness skin wound model in rats. In in vitro experiments, human dermal fibroblasts were used to study the effect of fisetin on collagen expression and the phosphatidylinositol 3-kinase (PI3K)\/Akt signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Network pharmacological analysis highlighted serine\/threonine kinase 1 (AKT1) as a central target linking fisetin to wound repair and fibrosis. Functional enrichment indicated significant involvement of the PI3K\/Akt pathway. Molecular docking further confirmed a strong binding affinity between fisetin and AKT1.\n                      <jats:italic>In vivo<\/jats:italic>\n                      experiments demonstrated that fisetin significantly accelerated wound closure, reduced inflammatory cell infiltration, and improved histological organization. Quantitative analysis showed decreased histological inflammation scores and a reduced the ratio of type I collagen (COL1A)\/type III collagen (COL3A), indicating improved collagen remodeling and attenuated scar formation. Moreover, fisetin upregulated PTEN expression while suppressing transforming growth factor-beta1 (TGF-\u03b21) and alpha-smooth muscle actin (\u03b1-SMA) expression in wound tissues.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments further confirmed that fisetin inhibited profibrotic marker expression and regulated PI3K\/Akt signaling activity in HDFs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Fisetin promotes skin wound healing and attenuates proliferative scar formation by reducing inflammation, improving collagen remodeling, and suppressing fibrotic signaling. Mechanistically, fisetin upregulates PTEN and inhibits the PI3K\/Akt\/TGF-\u03b21 axis, thereby limiting fibroblast activation and pathological extracellular matrix deposition. These findings suggest fisetin as a promising therapeutic candidate for wound management and scar prevention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1793847","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:39:58Z","timestamp":1774593598000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Fisetin promotes skin wound healing and inhibits pathological scar formation through modulation of the PI3K\/Akt\/TGF-\u03b21 signaling axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Yi","family":"Han","sequence":"first","affiliation":[{"name":"Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guixin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]},{"name":"Department of Traumatic Orthopedics and Joint, People\u2019s Hospital of Guangming District","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.2147\/dddt.S489113","article-title":"Network pharmacology, molecular docking and experimental validation on potential application of diabetic wound healing of Cinnamomum zeylanicum through matrix Metalloproteinases-8 and 9 (MMP-8 and MMP-9)","volume":"19","author":"Akter","year":"2025","journal-title":"Drug Des. 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