The TNFRSF1B Connection: Implications for Androgenetic Alopecia Pathogenesis and Treatment

Androgenetic alopecia (AGA) is a prevalent form of hair loss with poorly understood mechanisms. This study investigates the association between the tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) gene and AGA, aiming to validate its potential causal relationship. Transcriptomic data from AGA patients were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, along with Weighted Gene Co-expression Network Analysis (WGCNA), were employed to determine AGA-related key genes. We then performed Mendelian randomization (MR) analysis with genome-wide association study (GWAS) data to assess the causal relationship between key genes and AGA, employing methods such as weighted median and MR-Egger regression for sensitivity analysis. Meta-analysis of AGA-related datasets from GEO was conducted, followed by in vitro and in vivo experiments on TNFRSF1B to evaluate its impact on hair dermal papilla cells (HDPCs) and AGA models. RNA-seq data revealed significant upregulation of TNFRSF1B, PIK3CD, and THEMIS2 in AGA patient hair follicles. ROC analysis indicated their diagnostic potential, with WGCNA and gene intersection analysis identifying TNFRSF1B as closely associated with AGA. MR confirmed a causal relationship between TNFRSF1B and AGA. Meta-analysis further validated TNFRSF1B upregulation across multiple AGA datasets. In vitro experiments demonstrated that TNFRSF1B knockdown enhanced HDPC proliferation and migration, reduced apoptosis, and upregulated β-catenin and CyclinD1 expression. Additionally, TNFRSF1B knockdown reduced ROS levels and increased Catalase and SOD2 expression under oxidative stress. In vivo, TNFRSF1B knockdown promoted hair regeneration and reduced oxidative stress in an AGA mice model. The findings suggest that TNFRSF1B is a potential pathogenic factor in AGA, providing a novel therapeutic target for intervention.