Objective It is to explore the potential biomarkers and key biological pathways of resistant hypertension based on proteomics and complex network analysis.Methods Ten patients with refractory hypertension who were hospital-ized in the Affiliated Hospital of Shandong University of Traditional Chinese Medicine and Jinan Fifth People's Hospital from January to December in 2022 were recruited as the hypertension group,and another 10 healthy individuals were recrui-ted in the same period as the healthy group.The blood samples of subjects of the two groups were analyzed by proteomics technology to screen the clinical markers of resistant hypertension,and their potential clinical values were analyzed by pro-teomics technology combined with weighted gene co-expression network analysis(WGCNA).Results Proteomic analysis found that 60 differentially expressed proteins were totally identified in the hypertension group,which were mainly enriched in key signal transduction pathways such as phosphatidylinositol 3-kinase(PI3K)/protein kinase(Akt)and hypoxia induc-ible factor-1(HIF-1).Protein interaction analysis showed that COL6A3,CSF1R,HSPG2,ITGA2,PDGFB,THBS1 and vWF were the markers involved in the development of resistant hypertension,and they could participate in the pathophysio-logical process of the development of hypertension through the functional regulation of inflammation,oxidative stress,cell autophagy and other aspects.Conclusion The pathogenesis and outcome of refractory hypertension are closely related to the potential markers in PI3K/Akt and HIF-1 pathway,and induce the downstream inflammatory response.The abnormal ex-pressions of 7 proteins,such as COL6A3,HSPG2 and vWF,can be used as biomarkers for early diagnosis of refractory hy-pertension and target organ damage.