Autophagy related 7 dysfunction in senescent melanocytes and hypopigmented skin: reversal by metformin.

Abstract

Melanocyte senescence predominantly occurs in the sun-exposed skin of older individuals and contributes to skin ageing and hypopigmentary disorders. To identify early molecular events preceding melanocyte senescence and to evaluate a therapeutic strategy for preventing melanocyte ageing. Single-cell RNA sequencing and time-course bulk transcriptome analyses were performed on ultraviolet (UV)B-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 autophagy related 7 (ATG7)-dependent autophagy and redox balance were assessed in senescent melanocytes. 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 found in senescent melanocytes and idiopathic guttate hypomelanosis skin. Metformin treatment restored autophagic activity, including ATG7 upregulation, and mitigated oxidative stress, delaying melanocyte senescence. 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 ageing and related hypopigmentary disorders.