Chronic Histamine Exposure Promotes Melanogenesis via ORAI1-STIM1-Mediated Calcium Signaling Remodeling

Abstract

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 (10–30 μM) significantly increased melanin content (2.5–2.8-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. © 2026 by the authors.