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This study aimed to evaluate the pharmacological effects of Shengmai Injection(SMI) on cerebral ischemia/reperfusion(I/R) injury and explore its underlying mechanisms in regulating inflammatory responses following cerebral ischemia. Male SD rats were randomly divided into a sham group, a model group, a low-dose SMI group(2 mL·kg~(-1)), a medium-dose SMI group(4 mL·kg~(-1)), a high-dose SMI group(6 mL·kg~(-1)), and a positive control group(Ginaton Injection at 4 mL·kg~(-1)), with 16 rats in each group. A rat model of middle cerebral artery occlusion/reperfusion(MCAO/R) was established using the intraluminal suture method. Drug administration began on the day of modeling and continued for three consecutive days. The therapeutic effects of SMI on brain injury in MCAO/R rats were evaluated using neurological function scoring, cerebral blood flow monitoring, cerebral infarction area determination, hematoxylin-eosin(HE) staining, and Nissl staining. The predominant therapeutic mechanisms and key signaling pathways involved in SMI treatment of cerebral ischemia in the rat model were explored using proteomic analysis. The expression of major indicators and related proteins was subsequently validated using enzyme-linked immunosorbent assay(ELISA) and Western blot. In addition, targeted metabolomics was employed to investigate downstream arachidonic acid metabolism of the related signaling pathways. RESULTS:: show that compared with the sham group, the model group showed significantly increased neurological function scores and cerebral infarction area, accompanied by significantly decreased cerebral blood flow and Nissl body density. Compared with the model group, the SMI-treated groups showed significantly decreased neurological function scores and cerebral infarction area, accompanied by significantly increased cerebral blood flow and Nissl body density. The proteomic analysis results showed that the inflammatory response was the main process involved in SMI's therapeutic effect on cerebral ischemia, with the mitogen-activated protein kinase(MAPK) signaling pathway identified as the key signaling pathway. ELISA and Western blot results showed that SMI significantly reduced the expression levels of inflammatory factors in brain tissue of MCAO/R rats, including tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and interleukin-6(IL-6), with significantly regulated expression levels of phosphorylated JNK(p-JNK)/JNK and p-p38 MAPK/p38 MAPK. Targeted metabolomics further reveals that SMI significantly reduced the levels of arachidonic acid(AA) and its metabolites, such as prostaglandin D_2(PGD_2), prostaglandin E_2(PGE_2), 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], and 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], and other pro-inflammatory mediators, accompanied by a reduced ratio of thromboxane B_2(TXB_2) to 6-keto-prostaglandin F_(1α)(6-keto-PGF_(1α)). In conclusion, SMI can effectively alleviate cerebral ischemia injury, primarily through modulation of the inflammatory response. The potential mechanism is closely related to the regulation of the MAPK signaling pathway and the downstream arachidonic acid metabolism.