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Current anti-scar therapies have variable efficacy and are limited by recurrence, tissue damage and pain, so new strategies are needed. In this study, we examined the efficacy of tomentosenol A, a meroterpenoid compound isolated from Australian stingless bee propolis, to intervene in the development of the cellular hallmarks of scar tissue. The effects of tomentosenol A were compared to two structural analogues (4\n                    <jats:italic>S<\/jats:italic>\n                    )- and (4\n                    <jats:italic>R<\/jats:italic>\n                    )-ficifolidione, using cultured HEK293 cells expressing a SMAD binding element\/secreted embryonic alkaline phosphatase reporter and cultured normal adult human dermal fibroblasts. Cell cycle progression was assessed by CDK2 (Tyr15) and Histone H3 (Ser10) phosphorylation, apoptotic signalling by caspase-3\/7 activity, and fibroblast wound closure by live-cell scratch-wound assay. The findings revealed that all compounds inhibited TGF-\u03b21-stimulated fibroblast activation, as evidenced by prevention of \u03b1-smooth muscle actin assembly in cytoskeletal microfilaments, but only tomentosenol A prevented TGF-\u03b21-stimulated SMAD signalling and fibronectin secretion. Tomentosenol A stimulated G1\/S transition and arrested cells at G2\/M; (4\n                    <jats:italic>S<\/jats:italic>\n                    )-ficifolidione was without effect on cell cycle progression while (4\n                    <jats:italic>R<\/jats:italic>\n                    )-ficifolidione arrested cells at G1\/S. Only tomentosenol A stimulated caspase-3\/7 activity, and this effect was attenuated by TGF-\u03b21. Tomentosenol A also concentration-dependently slowed fibroblast wound closure. The findings establish tomentosenol A as a lead compound to test for anti-scarring activity. The structure in the vicinity of the free syncarpic acid conjugated with a pinene moiety appears critical to the anti-scarring potential of tomentosenol A.\n                  <\/jats:p>","DOI":"10.1007\/s11010-026-05771-z","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:25:25Z","timestamp":1791919525000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SMAD3 phosphorylation inhibitor, tomentosenol A arrests cell cycle progression and induces apoptotic signalling in cultured fibroblasts: implications for anti-scarring activity"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9236-970X","authenticated-orcid":false,"given":"Lisa J.","family":"Randall","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-6259","authenticated-orcid":false,"given":"Trong D.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Siddals","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5956-6664","authenticated-orcid":false,"given":"Robert J.","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle","family":"Greensill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate E.","family":"Woodhill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8396-4558","authenticated-orcid":false,"given":"Fraser D.","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"issue":"21","key":"5771_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms252111579","volume":"25","author":"M Kohlhauser","year":"2024","unstructured":"Kohlhauser M, Mayrhofer M, Kamolz LP, Smolle C (2024) An update on molecular mechanisms of scarring-A narrative review. 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