Liu Jiachen, Zeng Dianjie, Wang Yinhuai, Deng Fei, Wu Shuiqing, Deng Zebin
Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, 410011, Hunan, China.
Xiangya Hospital, Central South University, Changsha, Hunan, China.
Biol Direct. 2025 Mar 27;20(1):38. doi: 10.1186/s13062-025-00631-0.
Acute kidney injury (AKI) remains a critical condition with limited therapeutic options, predominantly managed by renal replacement therapy. The challenge of developing targeted treatments persists.
We integrated genetic data related to druggable proteins and gene expression with AKI genome-wide association study (GWAS) findings. Based on multi-omics Mendelian randomization (MR), we identified the potential causal influence of 5,883 unique proteins and genes on AKI. We also performed using reverse MR and external cohort-based analysis to verify the robustness of this causal relationship. Expression patterns of these targets were examined using bulk transcriptome and single-cell transcriptome data. In addition, drug repurposing analyses were conducted to explore the potential of existing medications. We also constructed a molecular interaction network to explore the interplay between identified targets and known drugs.
Genetically predicted levels of seven proteins and twelve genes were associated with an increased risk of AKI. Of these, six targets (NCF1, TNFRSF1B, APEH, ACADSB, ADD1, and FAM3B) were prioritized based on robust evidence and validated in independent cohorts. Reverse MR showed a one-way causal relationship of targets. These targets are predominantly expressed in proximal tubular cells, endothelial cells, collecting duct-principal cells, and immune cells within both AKI-affected and normal tissues. Several promising drug repurposing opportunities were identified, such as telmisartan-NCF1, calcitriol-ACADSB, and ethinyl estradiol-ACADSB. The molecular interaction mapping and pathway integration analysis provided further insights, suggesting potential strategies for combinatorial therapies.
This extensive investigation identified several promising therapeutic targets for AKI and highlighted opportunities for drug repurposing. These findings offer valuable insights that could shape future research and the development of targeted treatments.
急性肾损伤（AKI）仍然是一种危急病症，治疗选择有限，主要通过肾脏替代疗法进行管理。开发针对性治疗方法的挑战依然存在。
我们将与可成药蛋白和基因表达相关的遗传数据与AKI全基因组关联研究（GWAS）结果相结合。基于多组学孟德尔随机化（MR），我们确定了5883种独特蛋白质和基因对AKI的潜在因果影响。我们还使用反向MR和基于外部队列的分析来验证这种因果关系的稳健性。使用批量转录组和单细胞转录组数据检查这些靶点的表达模式。此外，还进行了药物重新利用分析，以探索现有药物的潜力。我们还构建了一个分子相互作用网络，以探索已确定靶点与已知药物之间的相互作用。
七种蛋白质和十二个基因的遗传预测水平与AKI风险增加相关。其中，六个靶点（NCF1、TNFRSF1B、APEH、ACADSB、ADD1和FAM3B）基于有力证据被优先考虑，并在独立队列中得到验证。反向MR显示了靶点的单向因果关系。这些靶点主要在受AKI影响的组织和正常组织中的近端肾小管细胞、内皮细胞、集合管主细胞和免疫细胞中表达。确定了几个有前景的药物重新利用机会，如替米沙坦-NCF1、骨化三醇-ACADSB和炔雌醇-ACADSB。分子相互作用图谱和通路整合分析提供了进一步的见解，暗示了联合治疗的潜在策略。
这项广泛的研究确定了几个有前景的AKI治疗靶点，并突出了药物重新利用的机会。这些发现提供了有价值的见解，可能会影响未来的研究和靶向治疗的开发。
