IRS-1 phase separation bridges IGF-1R signaling and the MITF/TYR axis to control melanogenesis

Melanogenesis is well known to be activated by the α-MSH/MITF signaling pathway. Recent studies have further revealed that the IGF-1/IGF-1R metabolic signaling axis can also induce melanin synthesis. Here, we demonstrate that IRS-1, a key downstream adaptor of both IGF-1R and the insulin receptor (IR), acts as a bridge by connecting the upstream IGF-1R signaling with the downstream MITF/TYR axis to promote melanogenesis. Importantly, this function of IRS-1 may be tissue-specific, as insulin alone fails to stimulate melanogenesis. Deletion of the self-interaction region (SAR) abolishes the phase separation of IRS-1, thereby preventing the activation of melanogenesis. Taken together, our findings reveal a novel function of IRS-1 phase separation in melanogenesis. This work not only sheds light on understanding the regulatory mechanism of melanin homeostasis but also provides a potential strategy for cosmetics companies to develop more effective whitening products.