{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:59:51Z","timestamp":1785405591396,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["NSTC 112-2635-B-039-004"],"award-info":[{"award-number":["NSTC 112-2635-B-039-004"]}]},{"award":["NSTC 112-2635-B-039-004"],"award-info":[{"award-number":["NSTC 112-2635-B-039-004"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012544","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU112-MF-104"],"award-info":[{"award-number":["CMU112-MF-104"]}],"id":[{"id":"10.13039\/501100012544","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CMU112-MF-104"],"award-info":[{"award-number":["CMU112-MF-104"]}],"id":[{"id":"https:\/\/ror.org\/00v408z34","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Plerixafor is a clinically approved CXCR4 antagonist that mobilizes hematopoietic stem cells by disrupting CXCL12\/CXCR4 retention signaling. However, its biochemical effects on melanocytes and pigmentation remain unexplored. We investigated how Plerixafor modulates CXCR4 signaling in melanocytes and evaluated its potential as a pro-melanogenic agent using in vitro and in vivo approaches. Human PIG1 melanocytes were treated with 10 nM Plerixafor with or without hydroquinone (HQ), followed by qPCR for MITF and tyrosinase expression, flow cytometry for CXCR4\/CXCR7 and integrin profiling, transwell migration assays, \u03b2-arrestin siRNA knockdown, Western blotting, subcellular fractionation, and ChIP-qPCR for \u03b2-catenin binding to MITF regulatory regions. A murine HQ-induced depigmentation model was used to test topical Plerixafor on pigmentation, hair follicles, melanogenic gene expression, and systemic safety markers. Plerixafor significantly increased MITF and tyrosinase mRNA and enhanced melanocyte migration while counteracting HQ-induced suppression of melanogenic genes. In addition, it reduced cell-surface CXCR4 (consistent with \u03b2-arrestin-mediated receptor internalization) without altering CXCR7, c-KIT, or N-cadherin. \u03b2-Arrestin knockdown abolished Plerixafor-induced ERK phosphorylation and melanogenic responses, confirming \u03b2-arrestin dependence. Plerixafor promoted \u03b2-catenin nuclear translocation and direct \u03b2-catenin occupancy at MITF promoter\/enhancer TCF\/LEF motifs. In vivo, topical Plerixafor restored HQ-induced depigmentation, increased hair follicle number and melanin content, and upregulated cutaneous MITF and tyrosinase without hepatic, renal, or inflammatory toxicity. Plerixafor functions as a biased CXCR4 ligand in melanocytes, influencing the \u03b2-arrestin\u2013\u03b2-catenin\u2013MITF signaling axis to drive melanogenesis and re-pigmentation. These findings identify \u03b2-arrestin-dependent CXCR4 signaling as a tractable pharmacologic mechanism for therapeutic re-pigmentation in pigmentary disorders.<\/jats:p>","DOI":"10.3390\/cimb48070730","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:00:52Z","timestamp":1784278852000},"page":"730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plerixafor Engages \u03b2-Arrestin-Dependent CXCR4 Signaling to Promote Melanogenesis via \u03b2-Catenin-MITF Activation"],"prefix":"10.3390","volume":"48","author":[{"given":"Tsong-Min","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Applied Cosmetology, HungKuang University, Taichung City 433304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Ya","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, College of Medicine, China Medical University, Taichung City 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3300-5946","authenticated-orcid":false,"given":"Huey-Chun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, College of Medicine, China Medical University, Taichung City 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1111\/pcmr.13165","article-title":"The metabolism of melanin synthesis\u2014From melanocytes to melanoma","volume":"37","author":"Snyman","year":"2024","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/s41586-023-05960-6","article-title":"Dedifferentiation maintains melanocyte stem cells in a dynamic niche","volume":"616","author":"Sun","year":"2023","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s13287-023-03479-1","article-title":"Functional and long-lived melanocytes from human pluripotent stem cells with transient ectopic expression of JMJD3","volume":"14","author":"Kobori","year":"2023","journal-title":"Stem Cell Res. 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