ATG7 dysfunction in senescent melanocytes and hypopigmented skin: Reversal by metformin

Abstract Background Melanocyte senescence predominantly occurs in sun-exposed skin of elderly individuals and contributes to skin aging and hypopigmentary disorders. Objectives To identify early molecular events preceding melanocyte senescence and to evaluate a therapeutic strategy for preventing melanocyte aging Methods Single-cell RNA sequencing and time-course bulk transcriptome analyses were performed on UVB-induced senescent melanocytes to identify senescence-associated pathways. Autophagy impairment was validated using gene and protein assays, immunohistochemistry, and ATG7 knockdown or overexpression. The protective effects of metformin on ATG7-dependent autophagy and redox balance were assessed in senescent melanocytes. Results Autophagy dysregulation was identified as an early event preceding glycolytic reprogramming during UV-induced melanocyte senescence. ATG7 downregulation emerged as the earliest molecular alteration and was consistently observed in both senescent melanocytes and idiopathic guttate hypomelanosis skin. Metformin treatment restored autophagic activity, including ATG7 upregulation, and mitigated oxidative stress, thereby delaying melanocyte senescence. Conclusion Early autophagy dysfunction represents a key initiating event in melanocyte senescence. Autophagy preservation particularly through ATG7 maintenance offers a promising early intervention strategy to prevent melanocyte aging and related hypopigmentary disorders.