Integrative multiomics analysis identifies RARRES2 as a regulator of keloid pathogenesis through STAT3/HSPG2 signaling axis

The molecular regulators behind the pathogenesis of keloid have not been fully determined. Through Mendelian randomization and multiomics analyses, we identified retinoic acid receptor responder 2 (RARRES2) as a causal risk factor for keloid. We further found that RARRES2 is mainly enriched in fibroblasts in various human tissues. RARRES2 is highly expressed in keloid tissue and mainly enriched in fibroblasts of keloid. Heparan sulfate proteoglycan 2 (HSPG2) was identified as a potential downstream effector molecule of RARRES2, and p-STAT3 was proven to bind to the promoter region of HSPG2. We demonstrated that RARRES2 promotes the expression of HSPG2 by phosphorylating STAT3. Moreover, we confirmed that RARRES2 exerts the pro-scarring effect through the STAT3/HSPG2 pathway in primary fibroblasts and animal models. Overall, our results demonstrate that RARRES2 is a key regulator of keloid pathogenesis through STAT3-mediated HSPG2 activation, and RARRES2 can serve as a specific molecular target in patients with keloid.