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Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review)

  • Authors:
    • Shiting Jiang
    • Dan Liu
    • Tingting Wei
    • Qiwei Shi
    • Haowen Wang
    • Yidan Gao
    • Pingsu Mao
    • Wenli Yang
  • View Affiliations / Copyright

    Affiliations: Institute for Cancer Medicine, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, College of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
    Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 301
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    Published online on: August 31, 2026
       https://doi.org/10.3892/ijmm.2026.5972
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Abstract

Salvianolic acids (SAs), a water‑soluble active component extracted from the traditional Chinese herb Salvia miltiorrhiza, have attracted considerable attention as an anti‑tumor agent. Accumulating evidence demonstrates that SAs potently inhibit tumor‑cell migration, invasion and metastasis through multiple signaling pathways and molecular targets. First, SAs remodel the extracellular matrix and suppress matrix metalloproteinase activities, thereby attenuating the epithelial‑mesenchymal transition and the associated stem‑like properties of cancer cells. Second, SAs block tumor angiogenesis, depriving tumors of essential nutrients and routes for metastasis. Third, SAs reprogram the tumor microenvironment by modulating immune cells, enhancing immune cell infiltration and relieving immunosuppression, ultimately curbing tumor progression. Fourth, SAs target metastatic cellular plasticity and therapy resistance by disrupting cytoskeletal reorganization, impairing cell motility and reversing drug‑resistant phenotypes, thereby enhancing cancer treatment efficacy with reduced toxicity. At the molecular level, SAs suppress the PI3K/AKT, MAPK and TGF‑β1/Smad signaling cascades, thereby diminishing the invasive and migratory capacity of tumor cells. In this review, recent advances in understanding the anti‑metastatic effects and underlying mechanisms of SAs were systematically summarized, the challenges hindering their clinical translation were discussed and future directions that may facilitate their development as a promising anti‑metastatic therapeutic agent were outlined.
View Figures

Figure 1

Structure of the mainly SA monomers
in Salvia miltiorrhiza. 2-D chemical structures of the SAs:
Danshensu (PubChem CID, 11600642), caffeic acid (PubChem CID,
689043), 3,4-dihydroxybenzaldehyde (PubChem CID, 8768),
lithospermic acid (PubChem CID, 6441498), rosmarinic acid (PubChem
CID 5281792), SAA (PubChem CID 5281793), SAB (PubChem CID 6451084),
SAC (PubChem CID 13991590), SAD (PubChem CID 75412558), SAE
(PubChem CID 86278266), SAF (PubChem CID 10903113) and SAG (PubChem
CID 11530200) (142). SAA,
salvianolic acid A.

Figure 2

Pharmacology of SAs from Salvia
miltiorrhiza. These salvianolic acid metabolites isolated from
dried Salvia miltiorrhiza roots exhibit multiple
pharmacological effects: i) Inducing apoptosis in tumor cells. ii)
Restoring hyperactivated/aggregated platelets to a quiescent state.
iii) Normalising endothelial cells damaged by oxidative stress. iv)
Repolarization of TAMs from M2 (promote tumor growth) to M1
(anti-tumor). SAs, salvianolic acids; TAM, tumor-associated
macrophage.

Figure 3

The mechanisms of SAA and SAB in
inhibiting the EMT. SAA and SAB curb tumor-cell invasion and
migration by silencing MMP-2/9 via the STAT3, MAPK and AKT/mTOR
cascades, and by directly repressing EMT-driving transcription
factors to lower both the mRNA and protein levels of key motility
genes. SAB, salvianolic acid B; SAB@HMON-PDA,
SAB@dopamine-functionalized hollow mesoporous organosilica; FAK,
focal adhesion kinase; SRC, sarcoma; ERK, extracellular
signal-regulated kinase; c-RAF, cellular rapidly accelerated
fibrosarcoma; EZH2, enhancer of zeste homolog 2; YAP1,
yes-associated protein 1; AKT, protein kinase B; mTOR, mammalian
target of rapamycin; RECK, reversion-inducing cysteine-rich protein
with Kazal motifs; EMT, epithelial to mesenchymal transition;
N-cad, neural cadherin; E-cad, epithelial cadherin; TGF-β,
transforming growth factor-β; Smad, small mothers against
decapentaplegic; MAPK, mitogen-activated protein kinase; MMP,
matrix metalloproteinase; STAT3, signal transducer and activator of
transcription 3.

Figure 4

SAs inhibit tumor angiogenesis and
promote vascular normalization. SAs (SAA, SAB) selectively
neutralize MMP-2/9, halting collagenolysis within the tumor
extracellular matrix. The resulting vascular pruning curtails
perfusion deficits, relieves intratumoral hypoxia and ultimately
drives a phenotypic switch toward functionally normalized,
drug-permissive vasculature. MMP, matrix metalloproteinases; PI3K,
phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR,
mammalian target of rapamycin; SAA, salvianolic acid A; M1 TAM,
classically activated tumor-associated macrophage; M2 TAM,
alternatively activated TAM.

Figure 5

SAs suppress tumor progression
through coordinated remodeling of the immunosuppressive metastatic
microenvironment. SAA, SAB and SAC act as 'phenotype switchers'
within the TME: They repolarize macrophages from M2 to M1, drive
platelets from a pro-coagulant to a quiescent state, convert
exhausted T cells into cytotoxic effectors and trans-differentiate
cancer-associated fibroblasts toward a non-activated phenotype.
Concurrently, the compounds silence GJB2 and α-SMA while blocking
PD-L1, dismantling physical and immune barriers that otherwise
suppress anti-tumor immunity. IL, interleukin; SAA, salvianolic
acid A; TGF-β1, transforming growth factor β1; ERK, extracellular
signal-regulated kinase; SRC, sarcoma kinase; FAK, focal adhesion
kinase; ADP, adenosine diphosphate; DOX, doxorubicin; CD41, cluster
of differentiation 41; GJB2, gap junction protein β2; PD-L1,
programmed cell death ligand 1; HIF-1α, hypoxia-inducible factor
1α; IκBα, inhibitor of nuclear factor κB α; GLUT1, glucose
transporter 1; T cell, thymus-derived lymphocyte; CD4+
T, T helper cells; CD8+T, cytotoxic T lymphocyte ; ECM,
extracellular matrix; SAB@HMON-PDA, SAB@Dopamine-functionalized
hollow mesoporous organosilica; SMA, smooth muscle actin;
PEG-SAB-Lip, nanoparticles or polyethylene glycol-modified
liposomes as drug carriers for SAB; TAM, tumor associated
macrophage; TAF, tumor-associated fibroblast; TME, tumor
microenvironment; M1 TAM, classically activated tumor-associated
macrophage; M2 TAM, alternatively activated TAM.

Figure 6

SAs suppress metastatic cellular
plasticity and therapy-resistant tumor states. Schematic of
molecular pathways activated in drug-resistant cell lines,
illustrating crosstalk between cytoplasmic and nuclear effectors.
SAA and SAB directly disrupt cytoskeletal proteins and resensitize
resistant cells to PTX, DDP and VCR by inhibiting the PI3K/AKT/mTOR
axis, boosting ROS production and driving lethal damage. SAA,
salvianolic acid A; PTX, paclitaxel; DDP, cisplatin; VCR,
vincristine; AKT, protein kinase B; Smad, small mothers against
decapentaplegic; mTOR, mammalian target of rapamycin; TAGLN2,
transgelin-2; PI3K, phosphatidylinositol 3-kinase; ERK,
extracellular signal-regulated kinase; CFL, cofilin; MDR1,
multidrug-resistance protein 1; RhoA, Ras homolog gene family,
member A; SOX2, SRY-related HMG-box 2; CD44, cluster of
differentiation 44; ABCG2, ATP-binding cassette sub-family G member
2; P-gp, P-glycoprotein; MDR1, multi-drug resistance 1; RTKs,
receptor tyrosine kinases; GPCRs, G protein-coupled receptors; ROS,
reactive oxygen species.
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Copy and paste a formatted citation
Spandidos Publications style
Jiang S, Liu D, Wei T, Shi Q, Wang H, Gao Y, Mao P and Yang W: Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review). Int J Mol Med 58: 301, 2026.
APA
Jiang, S., Liu, D., Wei, T., Shi, Q., Wang, H., Gao, Y. ... Yang, W. (2026). Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review). International Journal of Molecular Medicine, 58, 301. https://doi.org/10.3892/ijmm.2026.5972
MLA
Jiang, S., Liu, D., Wei, T., Shi, Q., Wang, H., Gao, Y., Mao, P., Yang, W."Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review)". International Journal of Molecular Medicine 58.5 (2026): 301.
Chicago
Jiang, S., Liu, D., Wei, T., Shi, Q., Wang, H., Gao, Y., Mao, P., Yang, W."Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review)". International Journal of Molecular Medicine 58, no. 5 (2026): 301. https://doi.org/10.3892/ijmm.2026.5972
Copy and paste a formatted citation
x
Spandidos Publications style
Jiang S, Liu D, Wei T, Shi Q, Wang H, Gao Y, Mao P and Yang W: Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review). Int J Mol Med 58: 301, 2026.
APA
Jiang, S., Liu, D., Wei, T., Shi, Q., Wang, H., Gao, Y. ... Yang, W. (2026). Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review). International Journal of Molecular Medicine, 58, 301. https://doi.org/10.3892/ijmm.2026.5972
MLA
Jiang, S., Liu, D., Wei, T., Shi, Q., Wang, H., Gao, Y., Mao, P., Yang, W."Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review)". International Journal of Molecular Medicine 58.5 (2026): 301.
Chicago
Jiang, S., Liu, D., Wei, T., Shi, Q., Wang, H., Gao, Y., Mao, P., Yang, W."Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review)". International Journal of Molecular Medicine 58, no. 5 (2026): 301. https://doi.org/10.3892/ijmm.2026.5972
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