{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T10:00:01Z","timestamp":1771840801217,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dongguk University Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Post-inflammatory hyperpigmentation (PIH) is a common pigmentary disorder characterized by excessive melanin production following skin inflammation. Histamine, a key inflammatory mediator, is known to stimulate melanogenesis via H2 receptors; however, the underlying calcium (Ca2+) signaling mechanisms remain largely unexplored. In this study, we investigated the role of the ORAI1-STIM1 complex in histamine-induced melanogenesis using B16F10 melanoma cells and normal human epidermal melanocytes (NHEMs). Histamine (10\u201330 \u03bcM) significantly increased melanin content (2.5\u20132.8-fold), an effect specifically abolished by the H2 antagonist famotidine. Notably, while acute histamine application failed to trigger immediate Ca2+ influx, chronic exposure significantly enhanced store-operated Ca2+ entry (SOCE) capacity by approximately 2.8-fold, providing evidence for a functional remodeling of the Ca2+ signaling machinery. Histamine-induced melanogenesis was significantly suppressed by intracellular Ca2+ chelation, pharmacological inhibition of ORAI1 (BTP-2 or Synta-66), and siRNA-mediated silencing of ORAI1 or STIM1, but not ORAI2, ORAI3, or STIM2. Our findings demonstrate that chronic histamine exposure drives hyperpigmentation through ORAI1-STIM1-mediated SOCE remodeling, establishing this complex as a promising therapeutic target for the treatment of PIH and related inflammatory pigmentary disorders.<\/jats:p>","DOI":"10.3390\/ijms27042055","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T08:58:21Z","timestamp":1771837101000},"page":"2055","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic Histamine Exposure Promotes Melanogenesis via ORAI1-STIM1-Mediated Calcium Signaling Remodeling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7738-8777","authenticated-orcid":false,"given":"Nhung Thi Hong","family":"Van","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea"},{"name":"Department of Physiology, College of Medicine, Dongguk University, Gyeongju 38066, Republic of Korea"},{"name":"Channelopathy Research Center (CRC), College of Medicine, Dongguk University, Goyang 10326, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9203-6489","authenticated-orcid":false,"given":"Hong Thi Lam","family":"Phan","sequence":"additional","affiliation":[{"name":"Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Institute of Regulatory Innovation through Science, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Institute of Integrated Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6215-8266","authenticated-orcid":false,"given":"Minh Tuan","family":"Nguyen","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0359-3967","authenticated-orcid":false,"given":"Woo Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Channelopathy Research Center (CRC), College of Medicine, Dongguk University, Goyang 10326, Republic of Korea"},{"name":"Department of Internal Medicine, Graduate School of Medicine, Dongguk University, Goyang 10326, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6130-7028","authenticated-orcid":false,"given":"Hyun Jong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Dongguk University, Gyeongju 38066, Republic of Korea"},{"name":"Channelopathy Research Center (CRC), College of Medicine, Dongguk University, Goyang 10326, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8300-6974","authenticated-orcid":false,"given":"Joo Hyun","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Dongguk University, Gyeongju 38066, Republic of Korea"},{"name":"Channelopathy Research Center (CRC), College of Medicine, Dongguk University, Goyang 10326, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1111\/j.1751-1097.2007.00226.x","article-title":"The protective role of melanin against UV damage in human skin","volume":"84","author":"Brenner","year":"2008","journal-title":"Photochem. 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