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We conducted a split-face, paired longitudinal study in 22 adults treated three times with a 1940-nm non-ablative fractional laser (NAFL). Epidermal samples were collected by tape-stripping from treated and contralateral control sites at baseline, after the first treatment, and after 1, 3, and 6 months. Enzymatic methyl-sequencing profiled\u2009~\u20093.8\u00a0million CpGs per sample, alongside clinical endpoints: quantitative VISIA measurements and global aesthetic scores. No significant differentially methylated regions (DMRs) were detected immediately post-treatment; however, 635 DMRs emerged 1 month after the final session, expanded through 3 months, and stabilized by 6 months. These loci were enriched for pathways related to epidermal differentiation, collagen organization, wound response, and stem-cell maintenance, with selective modulation at Polycomb-regulated and WNT-signalling genes. NAFL reversed age-associated methylation trajectories at 83.9% of CpGs showing strong differential signal in both the aging reference and NAFL-treatment. Treatment also induced transient, treatment-specific DMRs linked to immune and stress responses. Epigenetic remodelling paralleled significant clinical improvements, indicating that 1940-nm NAFL induces durable methylation changes at loci implicated in skin aging beyond transient wound-repair responses.<\/jats:p>","DOI":"10.1038\/s41598-026-56604-4","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:20:54Z","timestamp":1782814854000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Non-ablative fractional laser 1940-nm treatment modulates epigenetic signatures associated with skin aging in a split-face investigation"],"prefix":"10.1038","volume":"16","author":[{"given":"Konika Patel","family":"Schallen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Schomacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiana","family":"Banila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Pink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolle","family":"Dest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine L. 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