{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T15:10:54Z","timestamp":1772637054013,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Safety concerns surrounding skin-lightening agents have intensified following chemical leukoderma linked to rhododendrol. Here, we performed an in vitro safety and hazard profiling comparison of raspberry ketone (RK) and a total anthraquinone fraction from Fallopia multiflora var. cillinerve (Polygonum cillinerve) using an immortalized keratinocyte\u2013melanocyte co-culture model (human HaCaT keratinocytes and murine B10.BR melanocytes, 3:1). Rhododendrol and arbutin were included as contextual references. Following viability-guided range finding, cells were exposed for 48 h and evaluated for melanocyte stress and injury, including ROS generation, UPR\/ER-stress activation (PERK\/eIF2\u03b1\u2013ATF4-associated readouts: ATF4, Hmox1, GADD45a; and IRE1 phosphorylation), IL-8-related chemokine output (CXCL1\/KC, a murine functional homolog of IL-8), cell-cycle perturbation, and Caspase-3-associated apoptosis. In parallel, targeted LC\u2013MS metabolomics was performed to resolve pathway-level perturbations. High-dose RK elicited a rhododendrol-like in vitro stress\/toxicity signature, characterized by elevated ROS, robust UPR engagement, inflammatory chemokine induction, cell-cycle dysregulation, and pro-apoptotic responses; under viability-adjusted conditions, these effects remained more evident than with arbutin. Metabolomics revealed convergent disturbances between RK and rhododendrol, highlighting purine metabolism as a prominent perturbed pathway and suggesting purine-related metabolites as candidate indicators associated with leukoderma-relevant cellular stress in vitro. In contrast, the anthraquinone fraction did not trigger oxidative or ER stress within the tested range and exhibited a more favorable in vitro safety profile, including reduced ROS.<\/jats:p>","DOI":"10.3390\/molecules31050822","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T08:51:33Z","timestamp":1772614293000},"page":"822","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro Safety Profiling and Leukoderma-Relevant Hazard Assessment of Raspberry Ketone Versus Polygonum cillinerve Total Anthraquinones in a Keratinocyte\u2013Melanocyte Co-Culture Model"],"prefix":"10.3390","volume":"31","author":[{"given":"Manyi","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Cosmetics, School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China"},{"name":"Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cosmetics, School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China"},{"name":"Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Nong","sequence":"additional","affiliation":[{"name":"Department of Cosmetics, School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China"},{"name":"Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congfen","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cosmetics, School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China"},{"name":"Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Kinesiology and Health, Capital University of Physical Education and Sports, No. 11 Beisanhuanxi Road, Beijing 100191, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3943-6381","authenticated-orcid":false,"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cosmetics, School of Light Industry Science and Engineering, Beijing Technology and Business University, Beijing 100048, China"},{"name":"Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1111\/1346-8138.15878","article-title":"Rhododendrol-induced leukoderma update II: Pathophysiology, mechanisms, risk evaluation, and possible mechanism-based treatments in comparison with vitiligo","volume":"48","author":"Inoue","year":"2021","journal-title":"J. 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