TRPM2 couples cell-autonomous type-I interferon signaling to pigmentation homeostasis

Transient Receptor Potential Melastatin 2 (TRPM2), a Ca²⁺-permeable cation channel, regulates innate and adaptive immunity and has recently been implicated in vitiligo, an autoimmune pigmentary disorder. However, whether TRPM2 exerts cell-autonomous immunoregulatory functions and how such signaling intersects with pigmentation remain unknown. Here, we reveal an unexpected role for TRPM2 as an intrinsic suppressor of pigmentation through type-I interferon (IFN) signaling in melanocytes. Pharmacological inhibition, genetic silencing, and gain-of-function approaches demonstrate that TRPM2 negatively regulates melanogenesis in vitro . Notably, TRPM2-deficient zebrafish and TRPM2⁻/⁻ mice exhibit enhanced pigmentation in vivo , establishing physiological relevance. Transcriptomic profiling uncovers autonomous activation of the type-I-IFN pathway upon TRPM2 loss, leading to induction of interferon-stimulated gene 15 (ISG15). Mechanistically, ISG15 attenuates global ubiquitination and stabilizes microphthalmia-associated transcription factor (MITF), the master regulator of melanogenesis, thereby promoting pigmentation. Collectively, our findings define a previously unrecognized TRPM2–type-I-IFN–ISG15–MITF signaling axis that functionally integrates cell-autonomous immune surveillance pathways with pigmentary control. Further, it provides a conceptual framework linking type-I interferon signaling to pigmentation homeostasis and pigmentary disorders. Key highlights of the study TRPM2 negatively regulates pigmentation in vitro (mouse and primary human cells) and in vivo (zebrafish and mice). Unbiased RNA-sequencing identifies ISG15 as a positive regulator of melanogenesis downstream of TRPM2 silencing. TRPM2 knockdown generates a cell autonomous type-I-IFN response in melanocytes that induces ISG15 expression. ISG15 antagonizes global ubiquitination and regulates stability of MITF, the master regulator of pigmentation.