Table 1.

Ginsenosides tested in animal or cellular studies for human fibrosis-related diseases

	Ginsenosides	Model	Animal/cell type	Therapeutic target	Output (except fibrosis)	Refs
Liver fibrosis	Rb1	CCl4	Sprague–Dawley rats	The inhibition of hepatic prostaglandin E2 and TIMP-1	Decreased plasma and hepatic triglyceride, hepatic cholesterol; inhibited IL-1β concentrations	[40]
	Compound K and/or Rh1	Non-alcoholic fatty liver	Sprague–Dawley rats	The inhibition of HSCs proliferation and activation; the induction of HSCs apoptosis	Improved hepatic function and abnormal lipid metabolism; alleviated HFD-induced insulin resistance	[50]
	Rg1	Thioacetamide	Sprague–Dawley rats	The inhibition of PDGF-induced proliferation, activation of HSCs, and ROS formation, and NF-κB binding activity	Decreased hepatic hydroxyproline content and lipid peroxidation	[46]
	25-OCH3-PPD	Thioacetamide	C57BL/6 mice; rats HSC-T6 cells	The inhibition of LXRs-P2X7R-mediated NLPR3 inflammasome	Improved hepatic function; inhibited HSCs activation and hepatocyte apoptosis, and proinflammatory cytokines	[43]
	Rg1	Alcohol- and CCl4	Wistar rats; Primary HSCs of rats	The activation of Nrf2 pathway	Improved liver function; inhibited liver inflammation and HSCs activation; decreased lipid peroxidation and modified antioxidant enzyme activity	[47]
	Rb1	H2O2	Rats HSC-T6 cells	The inhibition of collagen, TGF-β1, MMP-2, and TIMP-1	Decreased HSCs proliferation and activation	[48]
	20S-Protopanaxadiol	10% FBS (primary HSCs)	Human LX-2 cells Primary HSCs of mice	The activation of LKB1-AMPK pathway	Induced HSCs apoptosis and promoted oxidative stress	[52]
	25-OCH3-PPD	Thioacetamide	Kunming mice	The inhibition of JNK and p38-ERK pathway	Decreased the release of inflammatory cytokines	[44]
	Rg1	CCl4	Kunming mice; rats HSC-T6 cells	The inhibition of the TGF-β/Smad pathway and the activation of Nrf2	Induced HSCs apoptosis and inhibited intracellular ROS level	[51]
Cardiac fibrosis	Rg1	TAC	Sprague-Dawley rats	The inhibition of p38 MAPK and the activation of phospho-Akt pathway	Decreased left ventricular hypertrophy; enhanced myocardial angiogenesis	[58]
	Rb1	Abdominal aortic coarctation	Sprague-Dawley rats	The inhibition of TGF-β/Smad and ERK signaling pathway and the activation of Akt pathway	Improved cardiac function; decreased cardiac hypertrophy; decreased mitochondrial membrane potential; enhanced the translocation of GLUT4	[63]
	Rg1	CTEPH	Sprague-Dawley rats	The regulation of MMP-2 and -9	Decreased right ventricular hypertrophy and immune cell infiltration	[59]
	Rh2	STZ	Sprague-Dawley rats; rat H9C2 cells	The regulation of PPARδ-STAT3 pathway	Improved cardiac function; decreased superoxide ions produced by high glucose	[65]
	Rb1	STZ	Wistar rats; rats primary fibroblast	The inhibition of TGF-β/Smad pathway and the promotion of Smad7	Improved cardiac function; inhibited cardiac fibroblast to myofibroblast differentiation	[70]
	Re	Isoproterenol	Wistar rats	The inhibition of TGF-β/Smad3 pathway	Decreased heart failure; improved cardiac function	[66]
	Rg1	Doxorubicin	C57BL/6J mice	The inhibition of ER stress and autophagy	Improved cardiac function; inhibited cardiac autophagy	[60]
	Rb3	CVB3	Primary CMVECs of rats	The regulation of Pyk2-PI3K-Akt pathway	Attenuated oxidative stress and preserved endothelial function	[68]
	Rd	Pressure overload	C57BL/6 mice; primary cardiac myocytes of rats	The inhibition of ERK and TGF-β1 pathways and the activation of Akt pathway	Improved cardiac function; decreased cardiac hypertrophy; decreased inflammation and oxidative stress	[67]
Renal fibrosis	Rg1	UUO	Sprague-Dawley rats	The regulation of the Klotho/TGF-β1/Smad pathway	Improved kidney function; prevented EMT	[76]
	Rb1 and Rc	Cyclosporine A	C57BL/6J mice; human HK-2 cell line	The regulation of oxidative stress pathway	Improved kidney function; inhibited inflammation and the production of proinflammatory cytokines; prevented tubular epithelial cell apoptosis	[81]
	Rg1	DN	Wistar rats	The inhibition of TGF-β1/Smads pathway and oxidative stress	Decreased BUN and SCr; increased anti-oxidative capacity	[78]
	Rg1	UUO	Sprague-Dawley rats	The inhibition of ER stress and unfolded protein response-related apoptotic pathway	Improved renal function; activated ER stress response	[75]
	Rg1	Cyclosporine A	Sprague-Dawley rats	The inhibition of ER stress-triggered tubular cell apoptosis	Decreased tubular epithelial cell apoptosis	[79]
	Rg1	UUO	Sprague-Dawley rats	The regulation of thrombospondin-1 and VEGF expression	Decreased microvessel density; improved tubular atrophy	[74]
	Rb1	UUO	Sprague-Dawley rats	The regulation of oxidative damage and TGF-β1 expression	Increased urinary heme oxygenase-1 level; decreased p47phox expression	[73]
	Rg1	TGF-β1	Rats NRK-52E cells	The inhibition of ERK pathway	Inhibited the process of EMT	[82]
	Rg1	UUO	Sprague-Dawley rats	The inhibition of TGF-β1/Smads pathway and thrombospondin-1 expression	Inhibited tubular EMT	[72]
Lung fibrosis	Rg1	Bleomycin	Sprague-Dawley rats	The regulation of TGF-β1 and Caveolin-1	Decreased lung injury, inflammatory cell infiltration	[87]
	Rg1	COPD	Sprague-Dawley rats; human MRC5 fibroblasts	The inhibition of TGF-β1/Smads pathway	Decreased emphysema; inhibited immune cell infiltration; prevented lung fibroblast transdifferentiation	[88]
	Total ginsenoside	Bleomycin	BALB/c mice	The inhibition of TGF-β/Smad pathway and the promotion of Smad7	Reduced the pulmonary coefficient; regulated the MMPs system	[89]
Other fibrotic diseases	Rg3	Rabbit-ear HS	Primary human HSFs; rabbits	The regulation of collagen fibers accumulation and VEGF expression	Inhibited HS fibroblasts proliferation and induced apoptosis; limited inflammation	[[90], [91], [92], [93]]
	Rg3	Keloid scar	Primary human keloid fibroblasts	The inhibition of TGF-β1/Smads and ERK pathway	Inhibited the proliferation, migration, invasion and angiogenesis of keloid fibroblasts	[94]
	Rb1	Rabbit-ear HS	Rabbits	The inhibition of profibrotic proteins and growth factors	Inhibited immune cell infiltration	[95]
	Rg3	Endometriosis	C57BL/6 mice; Primary human HESCs and Ishikawa Cells	The modulation of miR-27b-3p expression	Inhibited cell proliferation and invasion; regulated MMPs expression	[97]

Abbreviations: CCl4, carbon tetrachloride; TIMP-1, tissue inhibitor of metalloproteinase-1; IL-1β, interleukin-1β; HSCs, hepatic stellate cells; HFD, high fat diet; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; NF-κB, nuclear factor-κB; LXR, liver X receptor; P2X7R, P2X7 receptor; TGF-β1, transforming growth factor-β1; MMP-2, matrix metalloproteinase; FBS, fetal bovine serum; LKB1, liver kinase B1; AMPK, AMP-activated protein kinase; JNK, c-jun N-terminal kinase; ERK, extracellular signal-regulated kinase; TAC, transverse aortic constriction; MAPK, mitogen-activated protein kinase; GLUT4, glucose transporter type 4; CTEPH, chronic thromboembolic pulmonary hypertension; STZ, streptozotocin; PPARδ, peroxisome proliferator-activated receptor δ; STAT3, signal transducer and activator of transcription 3; ER, endoplasmic reticulum; CVB3, coxsackievirus B3; UUO, unilateral ureter obstruction; EMT, epithelial–mesenchymal transition; DN, diabetic nephropathy; BUN, blood urea nitrogen; SCr, serum creatinine; VEGF, vascular endothelial growth factor; COPD, chronic obstructive pulmonary disease; MMPs, matrix metalloproteinase; HS, hypertrophic scarring; HSC: hepatic stellate cell line; LX-2: human hepatic stellate cell line; H9C2: embryonic cardiomyocytes cell line; CMVECs: cardiac microvascular endothelial cells; HK-2: human renal proximal tubular cells; NRK-52E: rat renal tubular epithelial cells; MRC5: human embryonic lung fibroblasts; HSFs: hypertrophic scar fibroblasts; HESCs: human endometrial stromal cells