Deciphering the Causal Links Among Metabolomics, Ageing Phenotypes, and Pathological Scars: A Two-Sample Mendelian Randomization Study

Background: Hypertrophic scars (HS) and keloids represent pathological outcomes following cutaneous injury, characterized by complex pathogenesis and suboptimal therapeutic outcomes. The interplay between metabolomics and ageing may offer novel intervention targets for scar formation. Objective: This study aimed to systematically investigate the causal relationships between blood metabolites, ageing phenotypes (telomere length, epigenetic age), and HS/keloids through Two-sample Mendelian randomization (MR) and Two-step Mediation MR analysis. Methods: We integrated large-scale GWAS data from European populations, including 1400 blood metabolites (n=8299), telomere length (n=438,351), epigenetic age (n=41,000), HS (2068 cases/465,673 controls), and keloids (4086 cases/1,278,496 controls). Two-sample MR analysis was performed using inverse-variance weighted (IVW) and Wald ratio methods. Steiger’s, Cochrane’s Q, and MR-Egger tests were applied to exclude reverse causality, heterogeneity, and pleiotropy. Mediation effects of ageing phenotypes were quantified. Results: The study identified 30 metabolites significantly associated with HS and 49 with keloids. Among ageing phenotypes, telomere length showed positive correlations with both scar types, whereas PhenoAge exhibited negative correlations. Key metabolites such as Eugenol sulfate and Phenylacetylglutamate regulated scar formation through dual pathways involving telomere length and PhenoAge. Conclusion: This study elucidated the causal metabolite-ageing-scar network through genetic evidence, identifying multiple potential therapeutic targets, including Eugenol sulfate and Phenylacetylglutamate. These findings establish a robust foundation for developing targeted metabolic interventions. Keywords: ageing phenotypes, hypertrophic scars, keloids, metabolomics, mendelian randomization