Free radical biology & medicine · 2025
Uncovering novel biomarkers and drug targets for androgenetic alopecia via metabolite regulation and multi-tissue validation.
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Yi Sha, Liu Aimei, Zhang Xinyue, Deng Yongqiong, Chen Yan, Huoshen Wuda
Аннотация
BACKGROUND: Androgenetic alopecia (AGA) is the most common form of hair loss globally. Despite its prevalence, only two FDA-approved drugs-minoxidil and finasteride-are currently available, underscoring the urgent need to discover novel biomarkers and therapeutic targets for AGA diagnosis, treatment, and monitoring.
OBJECTIVES: This study aimed to explore novel therapeutic targets and biomarkers for AGA and investigate the causal role of plasma metabolites mediating therapeutic targets in AGA.
METHODS: Cis-expression quantitative trait loci (cis-eQTL) data were derived from the eQTLGen Consortium (31,684 samples). Genetic associations with AGA were obtained from the FinnGen cohort (220 cases, 219,249 controls), and the UK Biobank (66,172 cases and 140,864 controls). Colocalization and summary-data-based MR (SMR) analyses were performed to rank these candidate therapeutic targets. Additionally, Transcriptome-Wide Association Study (TWAS) and Multi-marker Analysis of GenoMic Annotation (MAGMA) analyses were conducted to prioritize potential biomarkers, while Phenome-wide association study (PheWAS), and drug prediction were used to identify therapeutic targets. Lastly, mediation analysis was applied to explore the role of metabolites in AGA treatment.
RESULTS: Ten genes emerged as promising targets after multi-layer validation. Among them, SOD1 and KL were classified as tier 1 targets with strong evidence. NT5E, SQLE, and ADM were designated tier 2 with moderate support, while PAM, LAMC1, LAMC3, PRLR, and BRAF were tier 3 candidates. Polymerase Chain Reaction (qPCR) validation supported these findings.
CONCLUSIONS: Our integrative multi-omics analysis identified 10 potential therapeutic targets and biomarkers for AGA. SOD1 and KL stand out as strong candidates, offering promising directions for future AGA therapies.
OBJECTIVES: This study aimed to explore novel therapeutic targets and biomarkers for AGA and investigate the causal role of plasma metabolites mediating therapeutic targets in AGA.
METHODS: Cis-expression quantitative trait loci (cis-eQTL) data were derived from the eQTLGen Consortium (31,684 samples). Genetic associations with AGA were obtained from the FinnGen cohort (220 cases, 219,249 controls), and the UK Biobank (66,172 cases and 140,864 controls). Colocalization and summary-data-based MR (SMR) analyses were performed to rank these candidate therapeutic targets. Additionally, Transcriptome-Wide Association Study (TWAS) and Multi-marker Analysis of GenoMic Annotation (MAGMA) analyses were conducted to prioritize potential biomarkers, while Phenome-wide association study (PheWAS), and drug prediction were used to identify therapeutic targets. Lastly, mediation analysis was applied to explore the role of metabolites in AGA treatment.
RESULTS: Ten genes emerged as promising targets after multi-layer validation. Among them, SOD1 and KL were classified as tier 1 targets with strong evidence. NT5E, SQLE, and ADM were designated tier 2 with moderate support, while PAM, LAMC1, LAMC3, PRLR, and BRAF were tier 3 candidates. Polymerase Chain Reaction (qPCR) validation supported these findings.
CONCLUSIONS: Our integrative multi-omics analysis identified 10 potential therapeutic targets and biomarkers for AGA. SOD1 and KL stand out as strong candidates, offering promising directions for future AGA therapies.