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

Summary

Using large-scale European GWAS datasets, this two-sample Mendelian randomization identified 30 metabolites causally associated with hypertrophic scars and 49 with keloids. Telomere length positively correlated with both scar types, whereas PhenoAge showed negative correlations, and metabolites such as eugenol sulfate and phenylacetylglutamate exerted effects via dual telomere and PhenoAge-mediated pathways.

Key Findings

• Identified 30 metabolites associated with hypertrophic scars and 49 with keloids via two-sample MR.
• Telomere length showed positive correlations with both hypertrophic scars and keloids; PhenoAge showed negative correlations.
• Eugenol sulfate and phenylacetylglutamate influenced scar formation through dual mediation by telomere length and PhenoAge.
• Sensitivity analyses (Steiger's, Cochrane's Q, MR-Egger) supported directionality and minimized pleiotropy/heterogeneity.

Clinical Implications

Supports development of metabolite-centered interventions or biomarker strategies for hypertrophic scars and keloids; informs risk stratification via telomere/epigenetic ageing metrics.

Limitations

• Predominantly European ancestry may limit generalizability to other populations.
• Findings require biological validation and clinical translation; MR assumptions may be violated by residual pleiotropy.

Future Directions

Validate metabolite targets in experimental scar models; test whether modulating telomere dynamics or implicated metabolites alters scar risk or severity in prospective trials.