Agrimonolide

Agrimonolide is a phenethyl isocoumarin compound discovered from Agrimonia pilosa, exhibiting anti-inflammatory, antioxidant, and anticancer activities. Agrimonolide inhibits NF-κB, MAPK, and TLR4-mediated neuroinflammatory signaling, suppresses Notch and JAK2/STAT3 signaling to modulate Th17/Treg balance and maintain the intestinal barrier. Agrimonolide decreases HIF1A expression, inhibits glycolysis, and induces ferroptosis and cell cycle arrest via the mTOR pathway in tumor models, thereby suppressing cancer cell viability, proliferation, and metastasis. Agrimonolide exerts hepatoprotective and anti-fibrotic effects by regulating bile acid transporter expression and reducing hepatic bile acid accumulation. Agrimonolide is used for research on ulcerative colitis, ovarian cancer, non-small cell lung cancer, cholestatic liver injury, and neuroinflammation^{[1][2][3][4][5][6]}. In Vitro:Agrimonolide (10-20 μM; 4 days) inhibits Th17 cell differentiation from naïve CD4⁺ T cells isolated from C57BL/6J mice, as shown by reduced CD4⁺IL-17A⁺ cell frequency and lower RORγt mRNA expression^[1].
Agrimonolide (10-20 μM; 4 days) promotes Treg cell differentiation from naïve CD4⁺ T cells isolated from C57BL/6J mice, as shown by increased CD4⁺CD25⁺Foxp3⁺ cell frequency and higher Foxp3 mRNA expression^[1].
Network pharmacology analysis identifies HIF1A as a key core target of Agrimonolide in ovarian cancer, with significant enrichment of the HIF-1 signaling pathway^[2].
Agrimonolide (10-40 μM; 0-3 days) inhibits viability of SKOV3 and A2780 ovarian cancer cells^[2].
Agrimonolide (10-40 μM; 14 days) suppresses colony formation of SKOV3 and A2780 ovarian cancer cells^[2].
Agrimonolide (10-100 μM; 24 h) exhibits no significant cytotoxicity in BV2 microglial and Neuro-2a neuronal cells at concentrations below 100 μM^[6].
Agrimonolide (10-40 μM; 48 h) reduces glucose uptake and lactate production in SKOV3 and A2780 ovarian cancer cells^[2].
Agrimonolide (20-40 μM) decreases extracellular acidification rate, indicating reduced glycolytic activity, in SKOV3 and A2780 ovarian cancer cells^[2].
Agrimonolide (10-40 μM) decreases protein expression of HIF1A, HK2, and LDHA in SKOV3 and A2780 ovarian cancer cells^[2].
Agrimonolide (40 μM) has inhibitory effects on glycolysis and HK2 expression in A2780 ovarian cancer cells that are reversed by overexpression of HIF1A, confirming that Agrimonolide attenuates glycolysis through modulation of HIF1A^[2].
Agrimonolide (10-40 μM) inhibits malignant progression and induces ferroptosis in A549 non-small cell lung cancer cells by blocking the mTOR signaling pathway^[3].
Agrimonolide does not show significant inhibitory activity against LPS-induced NO production in BV2 microglial cells at the tested concentrations, as it is not among the five active compounds identified in the assay^[5].
Agrimonolide (10-50 μM; 2 h pre-incubation before LPS stimulation) dose-dependently inhibits LPS-induced P65 phosphorylation in BV2 cells with an IC₅₀ of 20.3 μM^[6].
Agrimonolide (10-50 μM; 2 h pre-incubation before LPS stimulation) dose-dependently inhibits LPS-induced phosphorylation of JNK and P38 in BV2 microglial cells^[6].
Agrimonolide (10-50 μM; 2.5 h pre-incubation before LPS stimulation) dose-dependently inhibits LPS-induced nuclear translocation of the NF-κB subunit P50 in BV2 cells^[6].
Agrimonolide (10-50 μM; pre-incubated before LPS stimulation) inhibits LPS-induced activation of NF-κB and MAPK signaling pathways in primary mouse astrocytes^[6].
In silico molecular docking predicts that agrimonolide binds with high affinity to TLR4, IRAK1, and TRAF6 (binding energies ≤ −6.53 kcal/mol) and with moderate affinity to MyD88, supporting a multi-target mechanism of action on the TLR4 signaling pathway^[6].
Agrimonolide reduces IL-1β secretion from LPS-stimulated BV2 microglial cells^[6].
Agrimonolide (10-50 μM; 6 h LPS stimulation) significantly reduces mRNA expression of IL-1β, IL-6, TNF-α, and IL-18 in LPS-stimulated BV2 cells^[6].
Agrimonolide (10-50 μM; 6 h LPS stimulation) reduces LPS-induced mRNA expression of TLR4, MyD88, IRAK1, and TRAF6 in BV2 microglial cells^[6].
Agrimonolide (10-50 μM; pre-incubated before LPS stimulation) inhibits LPS-induced activation of primary mouse microglia, as evidenced by reduced CD68 expression and preserved ramified morphology^[6].
Agrimonolide (10-50 μM; pre-incubated before LPS stimulation) significantly reduces mRNA expression of IL-1β, IL-6, TNF-α, and IL-18 in LPS-stimulated primary mouse astrocytes^[6].
Agrimonolide (10-50 μM; pre-incubated before LPS stimulation) dose-dependently inhibits LPS-induced GFAP upregulation and activation of primary mouse astrocytes^[6].
Agrimonolide (10-50 μM; 2 h pre-incubation before LPS stimulation) dose-dependently reduces LPS-induced expression of NLRP3, iNOS, and COX-2 proteins in BV2 microglial cells^[6].
Agrimonolide (10-50 μM; 2 h pre-incubation before LPS stimulation) dose-dependently reduces LPS-induced expression of TLR4, IRAK1, and TRAF6 proteins in BV2 microglial cells, while MyD88 protein levels were not notably altered under these conditions^[6]. In Vivo:Agrimonolide (25-50 mg/kg/day; i.g.; daily; starting before DSS exposure) alleviates DSS-induced colitis in mice by reducing inflammation, preserving intestinal barrier integrity, and rebalancing Th17/Treg cells through suppression of the Notch and JAK2/STAT3 signaling pathways^[1].
Agrimonolide (10-90 mg/kg; i.p.; daily; 28 days) exerts dose-dependent hepatoprotective, antifibrotic, and anti-inflammatory effects in DDC-induced chronic cholestatic liver injury in mice, reducing hepatic bile acid accumulation and normalizing bile acid homeostasis via modulation of bile acid transporters and metabolic enzymes^[4].
Agrimonolide (90 mg/kg; i.p.; daily; 28 days) reduces hepatic hydroxyproline by 60.3%, decreases myeloid cell and macrophage infiltration, and modulates bile acid transporter expression to promote bile acid efflux and reduce hepatic bile acid accumulation in DDC-induced chronic cholestatic liver injury in mice, and these hepatoprotective, antifibrotic, and anti-inflammatory effects are diminished by the bile acid transport inhibitor BMS-986020^[4].
Agrimonolide (25-50 mg/kg; i.p.; daily; 5 days) pretreatment mitigates LPS-driven neuroinflammation in ICR mice by decreasing glial activation and expression of inflammatory mediators^[6].