Multi-omic Data Integration Reveals Drug Targets of Skin Fibrosis.

Abstract

Introduction: Scar heterogeneity, encompassing normal scar (NS) and pathological scars [hypertrophic scar (HS) and keloids], emerges from the dynamic interplay between systemic immune responses and local tissue microenvironment, highlighting the urgent need for drugs targeting different types of scars through both dimensions.

Methods: Data from DECODE and EQTLGen databases were used as exposure variables at the protein and mRNA levels in the blood, and data from GTEx and ScQTLbase as exposure variables at the tissue and single-cell levels. Two sample Mendelian Randomization (MR) studies were conducted at the systemic, local, and single-cell levels. The outcome variables were based on the NS, HS, and keloid cohorts in the authoritative FinnGen database. The results were ascertained using seven MR methods, including inverse-variance weighting (IVW), Wald ratio, weighted median, weighted mode, simple median, MR-Egger, and Summary-data-based Mendelian Randomization (SMR). Single-cell RNA-seq data were leveraged to validate the expression profiles and functions of the drug targets.

Results: NUDT2, ATXN3, OGN, UROS, and TSG101 were significantly associated with keloids, while PARK7 and MZT2A showed a significant correlation with HSs, and CDCP1 was significantly linked to NSs. Among them, RNA and protein expression levels of NUDT2 and PARK7 demonstrated significant positive associations with keloids and HSs, respectively, at the blood, skin, and single-cell levels. Functional analysis revealed that the higher expression of NUDT2 was associated with angiogenesis and the cellular response to hormone stimuli, whereas PARK7 was involved in the organization of collagen fibrils and the extracellular matrix structure. Moreover, single-cell sequencing confirmed the high expression of NUDT2 and PARK7 in keloids and HSs. These findings highlight their potential roles in both systemic and local scar pathogenesis and underscore their promise as therapeutic targets.

Discussion: This study identifies scar subtype-specific targets, particularly NUDT2 and PARK7, expanding therapeutic candidates for scar management. Multi-ethnic cohort studies are warranted to validate target universality.

Conclusion: Collectively, we have identified eight drug targets, with NUDT2 and PARK7 in particular showing potential therapeutic value for keloids and HSs. Additionally, our results suggest the feasibility of both local and systemic drug administrations.