Medicinal Plant Research 2025, Vol.15, No.5, 233-243 http://hortherbpublisher.com/index.php/mpr 237 5 Molecular Pathway Mechanisms of Salvia miltiorrhiza 5.1 PI3K/Akt pathway S. miltiorrhiza and its active components, like tanshinone and salvianolic acids, can significantly activate the PI3K/Akt pathway, which is a core regulatory axis for cell survival and cardiac protection. Network pharmacology and experimental studies have identified AKT1 as a key target. Pathway enrichment analysis further confirmed that, PI3K/Akt is an important pathway for S. miltiorrhiza to exert its effect (Liu et al., 2023; Wei et al., 2023; Hou et al., 2025). The activation of Akt, can promote the phosphorylation of downstream effector molecules, thereby enhancing cell survival, improving metabolic adaptation, and supporting tissue repair in ischemic heart models (Zhang et al., 2021; Hou et al., 2025). Through PI3K/Akt signaling, S. miltiorrhiza can up-regulate the expression of anti-apoptotic proteins (like Bcl-2) and down-regulate pro-apoptotic factors (Bax), thereby inhibiting cardiomyocyte apoptosis, reducing ischemia-induced cell death and improving cardiac function (Liu et al., 2023). This anti-apoptotic effect is one of the key mechanisms, by which Salvia miltiorrhiza exerts its protective effect on the heart. 5.2 Nrf2/HO-1 pathway The components of S. miltiorrhiza can promote the nuclear translocation of Nrf2. Nrf2, as the core transcription factor of antioxidant defense, can bind to the antioxidant response element (AREs) in the genome after activation, and up-regulate the expression of antioxidant enzymes, like HO-1, SOD and CAT (Meng et al., 2022; Fu et al., 2023; Wei et al., 2023). This mechanism enhances the cells' defense ability against oxidative stress, which is an important factor in myocardial ischemic injury. HO-1 induced by Nrf2 activation, plays a dual role in antioxidation and anti-inflammation. It enhances the overall cardioprotective effect of S. miltiorrhiza, by degrading pro-oxidative hemoglobin, generating molecules with cytoprotective effects, such as bilivermin and carbon monoxide, and inhibiting inflammatory responses (Meng et al., 2022; Fu et al., 2023). Studies have shown that, polysaccharides and phenolic acid components in S. miltiorrhiza can activate the Nrf2/HO-1 pathway, thereby reducing ferroptosis and oxidative damage, and exhibit significant protective effects in cardiac and vascular models (Fu et al., 2023). 5.3 MAPK and TLR4 pathways S. miltiorrhiza can regulate the MAPK pathway, containing ERK, JNK and p38, influencing cell survival, apoptosis and stress response. By regulating the MAPK signal, S. miltiorrhiza helps balance pro-survival and pro-apoptotic signals, thereby further protecting cardiomyocytes in ischemic injury (Wei et al., 2023; Hou et al., 2025). KEGG pathway analysis and experimental data indicate that, MAPK1 and MAPK14 are one of the core targets of S. miltiorrhiza (Zhang et al., 2021; Wei et al., 2023). In addition, S. miltiorrhiza also can inhibit the TLR4-mediated signaling pathway, which is a key link in the inflammatory response of ischemic injury. By down-regulating TLR4 and its downstream effector molecules (like NF-κB), S. miltiorrhiza reduces cytokine production and inflammatory cell infiltration, thereby alleviating myocardial injury (Meng et al., 2022; Wei et al., 2023). The TLR4/MyD88/NF-κB axis is a common target of salvianolic acid and tanshinone, which provides a molecular basis for the anti-inflammatory and anti-apoptotic effects, exhibited byS. miltiorrhiza in cardiovascular models (Wei et al., 2023). 6 Experimental Evidence of Salvia miltiorrhizaExtracts 6.1 Cell-based studies Cell models of hypoxia/reoxygenation (H/R) injury, have been widely used to simulate in vitro ischemic heart disease studies. Studies have shown that extracts of S. miltiorrhiza, especially tanshinone IIA and salvianolic acid B, can significantly reduce myocardial cell death, maintain mitochondrial function, and enhance cell survival under oxidative stress conditions. These effects are attributed to the upregulation of antioxidant enzymes, the reduction of ROS, and the regulation of survival pathways such as PI3K/Akt and Nrf2/HO-1 (Ren et al., 2019; Jung et al., 2020; Mu et al., 2024).
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