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These paracrine factors are involved in the oxidative stress, inflammatory, vascular and hormonal pathways, among others. Damage of the dermoepidermal barrier also occurs and facilitates melanin deposition in the dermis, also known as dermal or mixed melasma. We used artificial intelligence tools to define the best combination of compounds for skin pigmentation inhibition. Mathematical models suggested the combination of retinol, diosmin and ferulic acid to be the most effective one. In vitro cellular tyrosinase activity assay proved that this combination had a synergistic depigmenting effect. Further assays proved that the combination could inhibit key pathways involved in melasma by downregulating <jats:italic>ET\u20101<\/jats:italic> and <jats:italic>COX\u20102<\/jats:italic> gene expression and IBMX\u2010induced dendricity in human melanocytes, and upregulated the gene expression of <jats:italic>IL\u20101b<\/jats:italic>, <jats:italic>TIMP3<\/jats:italic> and several endogenous antioxidant enzymes. The combination also reduced melanin levels in a phototype VI 3D epidermis model. These results indicate that the combination of retinol, diosmin and ferulic acid is an effective synergistic complex for the treatment of melasma by regulating the key molecular pathways involved in skin hyperpigmentation pathophysiology.<\/jats:p>","DOI":"10.1111\/exd.14752","type":"journal-article","created":{"date-parts":[[2023,1,22]],"date-time":"2023-01-22T13:26:45Z","timestamp":1674394005000},"page":"611-619","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Depigmenting topical therapy based on a synergistic combination of compounds targeting the key pathways involved in melasma pathophysiology"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2666-2638","authenticated-orcid":false,"given":"Mart\u00ednez\u2010Guti\u00e9rrez","family":"Alfredo","sequence":"first","affiliation":[{"name":"Biotechnology Unit, Mesoestetic Pharma Group  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9rez\u2010Mart\u00ednez","family":"Maribel","sequence":"additional","affiliation":[{"name":"Biotechnology Unit, Mesoestetic Pharma Group  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pena\u2010Rodr\u00edguez","family":"Eloy","sequence":"additional","affiliation":[{"name":"Biotechnology Unit, Mesoestetic Pharma Group  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f3mez\u2010Escalante","family":"Susana","sequence":"additional","affiliation":[{"name":"Medical Unit, Mesoestetic Pharma Group  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis G. 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