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ETHNOPHARMACOLOGICAL RELEVANCE Oryeong-san (ORS) is a traditional formula that has long been used for the treatment of dysfunctions of body fluids and electrolyte homeostasis in Korea, China and Japan. Recent reports have shown that ORS may suppress hypertension by controlling the renin-angiotensin-aldosterone system (RAAS) in the kidney, but its action mechanism has not been well defined. AIM OF THE STUDY The aim of this study was to decipher the ORS mechanisms in the treatment of hypertension using a systems pharmacology approach. MATERIALS AND METHODS The compounds of ORS were obtained from the TM-MC (database of medicinal materials and chemical compounds in Northeast Asian traditional medicine), and the drug-likeness (DL) and oral bioavailability (OB) of the compounds were evaluated. The potential targets of the compounds were identified using various pharmacology databases. To analyze the mechanisms of the ORS for hypertension, a Compound-Target-Disease (C-T-D) network was established with respect to the genes related to hypertension. RESULTS A screening evaluation of the DL and OB of the ORS compounds identified a list of 232 active compounds. The pharmacological activity of the targets was investigated by exploring the interaction network between the compounds and the targets. Analysis of the interactions between the compounds and the hypertension-related targets revealed that 14 ORS compounds regulate the RAAS and vasoconstrictors in the kidney. CONCLUSIONS This study used the systems pharmacology approach to decipher the mechanisms of action of ORS for the treatment of hypertension. When hypertension drugs and ORS are used in combination for treatment, possible side effects should be considered because most hypertension drugs are related to the RAAS. The results of this study may provide clues to not only analyze the pharmacological activity of ORS for the treatment of hypertension but other diseases as well.