Abstract
BACKGROUND: Keloids, benign skin tumors due to connective tissue overgrowth, can be exacerbated by ubiquitin-proteasome system abnormalities through uncontrolled inflammation. This study aimed to use Mendelian randomization (MR) analysis to explore keloid pathogenesis and identify target drugs for treatment. METHODS: The single-nucleotide polymorphism identifiers of keloid were obtained from the Open Genome-Wide Association Study database, and ubiquitin-related genes from GeneCards database. Five techniques were used for MR analysis during the research, with the accuracy of MR results evaluated by sensitivity analysis. Then, the R software package coloc was used for colocalization analysis of ubiquitin-related genes and keloid. Subsequently, the Comparative Toxicogenomics Database was used to predict skin complications related to keloid-associated target genes. Also, the Drug-Gene Interaction Database was used to study potential target drugs for target genes, and the mechanism of drug inhibition of keloid formation was explored using the DrugBank, Therapeutic Target Database, and STRING databases. RESULTS: IFNGR1 and RNF187 were significant risk factors for keloid formation. A causal relationship exists between IFNGR1 and chronic skin ulcers (a keloid complication). Moreover, indole-3-carbinol, interferon gamma-1b, and pretomanid (targeting IFNGR1) are potential keloid treatments. Tretinoin can affect the IFNGR1 protein via the AKT1 pathway, inhibiting keloid proliferation. CONCLUSIONS: IFNGR1 was associated with the pathogenesis of keloids. Interferon gamma-1b targeting IFNGR1 might be a potential strategy for the treatment of keloids, and this discovery opened up a new direction for the treatment of keloids.