基于双硫死亡机制的肾纤维化治疗靶点与药物筛选OA

Objective To investigate the role of disulfidptosis in renal fibrosis and to perform high-throughput screening for candidate drugs that can delay its progression by targeting common targets shared by the disease and the phenotype.Methods Genes related to renal fibrosis were obtained from the GEO database and the GeneCards platform.Common targets shared between renal fibrosis and disulfidptosis were identified via Venn analysis.Protein-protein interaction(PPI)network was constructed,followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses.The Connectivity Map(CMap)database was used to perform high-throughput drug screening for key targets.Molecular docking and molecular dynamics simulations were then applied to evaluate the binding characteristics and stability between candidate drugs and the core target(SLC7A11).Results Venn analysis showed 13 common targets shared between disulfidptosis and renal fibrosis,including GCLM,RPN1 and SLC7A11.Subse-quent CMap screening identified three drugs:floxuridine,sacubitril and cobimetinib.PPI analysis yielded 11 core targets,such as ACSL4,GCLM and HMGA2.KEGG enrichment analysis indicated that the 13 common targets were primarily involved in regulating pathways related to ferroptosis,and cancer.Ferroptosis and disulfidptosis are closely interrelated in terms of cystine metabolism and NADPH levels,suggesting a potential mechanism by which disulfidptosis regulates renal fibrosis.Molecular docking and molecular dynamics simulations demonstrated that sacubitril and cobimetinib exhibited strong and stable binding to the core target SLC7A11,which could regulate disulfidptosis and delay renal fibrosis progression by inhibiting SLC7A11 expression.Conclusion Disulfidpto-sis-related genes are associated with the progression of renal fibrosis,and SLC7A11 may serve as a key node connecting the regulatory networks of both processes.Therefore,sacubitril and cobimetinib,as candidate drugs targeting SLC7A11,have potential value for the intervention of renal fibrosis.