Association between SQSTM1 dysregulation and risk in alopecia areata: a Mendelian randomization study

Background Alopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss. It manifests as a heterogeneous disorder with diverse clinical presentations and variable treatment responses, underscoring the significance of identifying novel biomarkers for precision management. Objective This study aims to explore the relationship between metabolic reprogramming-related genes (MRRGs) and the risk of developing AA. Methods MRRGs were identified through the GeneCards database and existing literature. Genetic instruments were obtained from the eQTLGen database, and AA-related data were retrieved from the OpenGWAS database. The TwoSampleMR R package was applied for statistical analysis. Additionally, RT-qPCR and immunofluorescence assays were performed to validate the expression of target genes in AA-affected hair follicles and healthy controls. Results Six MRRGs (DLD, NFE2L2, SDHB, SLC2A1, PSAT1, and SQSTM1) showed significant causal associations with AA. RT-qPCR analysis revealed markedly elevated SQSTM1 mRNA levels in AA-affected hair follicles compared with healthy controls. Immunofluorescence confirmed increased SQSTM1 protein accumulation alongside reduced LC3B-II expression in AA-affected hair follicles. Conclusions This study underscores the significant association between SQSTM1 and AA, advancing our understanding of AA pathophysiology.