SIRT7 facilitates ferroptosis resistance of melanocytes via activating the SMAD3-ATF3-GPX4 signaling pathway in vitiligo.

INTRODUCTION: Vitiligo is a hypopigmentation disorder characterized by epidermal melanocyte loss. Endogenous and exogenous oxidative stress causes the regulated cell death (RCD) of melanocytes in vitiligo. Recent studies have indicated that ferroptosis participates in vitiligo pathogenesis. Nevertheless, the underlying regulatory mechanisms remain elusive. Sirtuins (SIRT1-7) are nicotinamide adenine dinucleotide (NAD)(+)-dependent histone deacetylases, which are involved in a diverse array of cellular and physiological processes, including the inhibition of stress-induced ferroptosis. OBJECTIVE: To investigate the potential regulatory mechanisms of SIRT7 in ferroptosis of vitiligo melanocytes. METHODS: The protein levels of ferroptosis-related molecules were detected in perilesional skin from vitiligo patients and healthy donors. Genetic intervention targeting SIRT7 and biochemical assays were utilized to study the critical role and regulatory mechanisms of SIRT7 against oxidative stress-induced ferroptosis in melanocytes. The establishment of a vitiligo mouse model with melanocyte-specific Sirt7 knockout mice (Sirt7 MCKO) was engaged to verify the role of SIRT7 in vitiligo. RESULTS: We found that anti-ferroptosis molecule expressions were significantly downregulated in melanocytes localized in vitiligo perilesional skin. Vitiligo melanocytes exhibited increased susceptibility to ferroptosis induced by oxidative stress compared to normal melanocytes. Furthermore, the expression and activity of SIRT7 were severely impaired in vitiligo melanocytes, as verified by publicly-available single-cell RNA sequencing (scRNA-seq) data. Mechanistically, SIRT7 promoted the expression of glutathione peroxidase 4 (GPX4) to protect melanocytes against ferroptosis via drosophila mothers against decapentaplegic protein 3 (SMAD3)-activating transcription factor 3 (ATF3) signaling pathway. What's more important, the melanocyte-specific Sirt7 knockout could exacerbate the progression of vitiligo in mice, accompanied by reduced expression of GPX4 and increased levels of ATF3. CONCLUSION: Our study demonstrates that SIRT7 deficiency exacerbated ferroptosis of melanocytes induced by oxidative stress and contributed to vitiligo pathogenesis. The activation of SIRT7 could serve as a potential therapeutic strategy for preserving melanocyte survival in vitiligo.