Deng Xinrui, He Sui, Long Huiyu, Xiao Jinyuan, Xie Zhengchun
Hunan University Affiliated Xiangtan Central Hospital, Clinical Laboratory, Xiangtan, Hunan, China.
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
J Cosmet Dermatol. 2025 Jul;24(7):e70334. doi: 10.1111/jocd.70334.
Rosacea is a chronic inflammatory facial disorder with limited therapeutic options, severely impacting patients' quality of life. The identification of druggable genes plays a crucial role in facilitating the development of effective therapeutic strategies.
We conducted Mendelian randomization (MR) and Summary-based Mendelian randomization (SMR) analyses by integrating data on 5883 druggable genes, cis-expressed quantitative trait loci (eQTL) from blood and skin tissue (lower leg and suprapubic), and genome-wide association study (GWAS) data on rosacea to elucidate the causal relationship between druggable genes and rosacea. Robustness was confirmed via heterogeneity/horizontal pleiotropy tests, Steiger filtering, Bayesian colocalization analysis, and the heterogeneity in dependent instruments (HEIDI) analysis. The expression levels of identified druggable genes were validated using the GSE65914 data sets. Further analyses included protein-protein interactions (PPIs), functional enrichment analysis, phenome-wide association study (PheWAS), drug prediction, and molecular docking.
MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants. GEO data sets confirmed significant upregulation of IRF1 and downregulation of SLC22A5 in rosacea patients. PPIs and functional enrichment analyses revealed that IRF1 promotes inflammation by regulating immune cell activation and interferon signaling pathways; SLC22A5 regulates membrane transport and metabolic processes, and its dysregulation may lead to lipid homeostasis imbalance. PheWAS analysis indicated no other phenotypes associated with IRF1 and SLC22A5. Drug prediction and molecular docking verified the pharmacological value of IRF1 and SLC22A5.
This study identified IRF1 and SLC22A5 as potential drug targets for the treatment of rosacea, and their significant therapeutic potential provides a critical foundation for the development of targeted therapies.
酒渣鼻是一种慢性炎症性面部疾病，治疗选择有限，严重影响患者的生活质量。可药物作用基因的鉴定在促进有效治疗策略的开发中起着关键作用。
我们通过整合5883个可药物作用基因的数据、来自血液和皮肤组织（小腿和耻骨上）的顺式表达数量性状位点（eQTL）以及酒渣鼻的全基因组关联研究（GWAS）数据，进行孟德尔随机化（MR）和基于汇总数据的孟德尔随机化（SMR）分析，以阐明可药物作用基因与酒渣鼻之间的因果关系。通过异质性/水平多效性检验、Steiger过滤、贝叶斯共定位分析和依赖工具中的异质性（HEIDI）分析来确认稳健性。使用GSE65914数据集验证已鉴定的可药物作用基因的表达水平。进一步的分析包括蛋白质-蛋白质相互作用（PPI）、功能富集分析、全表型关联研究（PheWAS）、药物预测和分子对接。
MR和SMR分析确定IRF1和SLC22A5是酒渣鼻的可药物作用基因，贝叶斯共定位强烈支持共享的因果变异。GEO数据集证实酒渣鼻患者中IRF1显著上调，SLC22A5下调。PPI和功能富集分析表明，IRF1通过调节免疫细胞活化和干扰素信号通路促进炎症；SLC22A5调节膜转运和代谢过程，其失调可能导致脂质稳态失衡。PheWAS分析表明没有其他与IRF1和SLC22A5相关的表型。药物预测和分子对接验证了IRF1和SLC22A5的药理价值。
本研究确定IRF1和SLC22A5是治疗酒渣鼻的潜在药物靶点，它们显著的治疗潜力为开发靶向治疗提供了关键基础。
