The potential therapeutic role of ginsenosides on fibrosis-associated diseases: a review on molecular mechanisms and call for further research

Abstract

Fibrosis is characterized as an aberrant reparative process involving the direct replacement of damaged or deceased cells with connective tissue, leading to progressive architectural remodeling across various tissues and organs. This condition imposes a substantial burden, resulting in considerable morbidity and mortality. Ginseng (Panax ginseng C. A. Meyer), renowned for its medicinal properties, has been incorporated as a key component in Chinese patent medicines to mitigate fibrotic diseases. Ginsenosides, the primary bioactive compounds in ginseng, have garnered significant attention. Over the past five years, extensive research has explored the pharmaceutical potential of ginsenosides in diverse organ fibrosis conditions, including liver, myocardial, renal, and pulmonary fibrosis. Studies have elucidated that ginsenosides demonstrate potential effects on inflammatory responses stemming from parenchymal cell damage, myofibroblast activation leading to extracellular matrix (ECM) production, and myofibroblast apoptosis or inactivation. Additionally, potential downstream targets and pathways associated with these pathological processes have been identified as being influenced by ginsenosides. This review presents a comprehensive overview of the efficacious treatments utilizing ginsenosides for various tissue fibrosis types and their potential anti-fibrotic mechanisms. Furthermore, it offers a reference for the development of novel candidate drugs for future organ fibrosis therapies.

Keywords

Ginsenosides / Liver fibrosis / Myocardial fibrosis / Renal fibrosis / Pulmonary fibrosis / Mechanisms

References

[1] Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012; 18(7):1028-1040. https://doi.org/10.1038/nm.2807.

[2] Gu Z, Yan Y, Yao H, et al. Targeting the LPA1 signaling pathway for fibrosis therapy: a patent review (2010-present). Expert Opin Ther Pat. 2022; 32(10):1097-1122. https://doi.org/10.1080/13543776.2022.2130753.

[3] Nanthakumar CB, Hatley RJD, Lemma S, et al. Dissecting fibrosis: therapeutic insights from the small-molecule toolbox. Nat Rev Drug Discov. 2015; 14(10):693-720. https://doi.org/10.1038/nrd4592.

[4] Henderson NC, Rieder F, Wynn TA.Fibrosis: from mechanisms to medicines. Nature. 2020; 587(7835):555-566. https://doi.org/10.1038/s41586-020-2938-9.

[5] Zhao X, Kwan JYY, Yip K, et al. Targeting metabolic dysregulation for fibrosis therapy. Nat Rev Drug Discov. 2020; 19(1):57-75. https://doi.org/10.1038/s41573-019-0040-5.

[6] Li X, Ding Z, Wu Z, et al.Targeting the TGF-β signaling pathway for fibrosis therapy: a patent review (2015-2020). Expert Opin Ther Pat. 2021; 31(8):723-743. https://doi.org/10.1080/13543776.2021.1896705.

[7] Cannito S, Novo E, Parola M. Therapeutic pro-fibrogenic signaling pathways in fibroblasts. Adv Drug Deliv Rev. 2017; 121:57-84. https://doi.org/10.1016/j.addr.2017.05.017.

[8] Habibie H, Adhyatmika A, Schaafsma D, et al. The role of osteoprotegerin (OPG) in fibrosis: its potential as a biomarker and/or biological target for the treatment of fibrotic diseases. Pharmacol Ther. 2021;228:107941. https://doi.org/10.1016/j.pharmthera.2021.107941.

[9] Rockey DC, Bell PD, Hill JA. Fibrosis-a common pathway to organ injury and failure. N Engl J Med. 2015; 372(12):1138-1149. https://doi.org/10.1056/NEJMc1504848.

[10] Afratis NA, Klepfish M, Karamanos NK, et al. The apparent competitive action of ECM proteases and cross-linking enzymes during fibrosis: applications to drug discovery. Adv Drug Deliv Rev. 2018; 129:4-15. https://doi.org/10.1016/j.addr.2018.03.004.

[11] Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005; 115(2):209-218. https://doi.org/10.1172/JCI24282.

[12] Sofias AM, De Lorenzi F, Peña Q, et al. Therapeutic and diagnostic targeting of fibrosis in metabolic, proliferative and viral disorders. Adv Drug Deliv Rev. 2021;175:113831. https://doi.org/10.1016/j.addr.2021.113831.

[13] Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007; 117(3):524-529. https://doi.org/10.1172/JCI31487.

[14] Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008; 214(2):199-210. https://doi.org/10.1002/path.2277.

[15] Hu J, Zhang L, Fu F, et al. Cardioprotective effect of ginsenoside Rb1 via regulating metabolomics profiling and AMP-activated protein kinase-dependent mitophagy. J Ginseng Res. 2022; 46(2):255-265. https://doi.org/10.1016/j.jgr.2021.06.011.

[16] Mao Q, Bai M, Xu JD, et al. Discrimination of leaves of Panax ginseng and P. quinquefolius by ultra high performance liquid chromatography quadrupole/time-of-flight mass spectrometry based metabolomics approach. J Pharm Biomed Anal. 2014; 97:129-140. https://doi.org/10.1016/j.jpba.2014.04.032.

[17] Fu W, Liang Y, Xie Z, et al. Preparation and evaluation of lecithin/zein hybrid nanoparticles for the oral delivery of Panax notoginseng saponins. Eur J Pharm Sci. 2021;164:105882. https://doi.org/10.1016/j.ejps.2021.105882.

[18] Gao B, Huang L, Liu H, et al.Platelet P2Y₁₂ receptors are involved in the haemostatic effect of notoginsenoside Ft1, a saponin isolated from Panax notoginseng. Br J Pharmacol. 2014; 171(1):214-223. https://doi.org/10.1111/bph.12435.

[19] Yang X, Wang R, Zhang S, et al. Polysaccharides from Panax japonicus C. A. Meyer and their antioxidant activities. Carbohydr Polym. 2014; 101(2014):386-391. https://doi.org/10.1016/j.carbpol.2013.09.038.

[20] Li T, Huang MY, Lu JJ. Cancer statistics and trends in China: the potential of natural product application. Chin J Nat Med. 2024; 22(8):673-675. https://doi.org/10.1016/S1875-5364(24)60649-7.

[21] Chen X, Xu T, Lv X, et al. Ginsenoside Rh 2 alleviates ulcerative colitis by regulating the STAT3/miR-214 signaling pathway. J Ethnopharmacol. 2021;274:113997. https://doi.org/10.1016/j.jep.2021.113997.

[22] Cui Z, Gu L, Liu T, et al. Ginsenoside Rd attenuates myocardial ischemia injury through improving mitochondrial biogenesis via WNT5A/Ca²⁺ pathways. Eur J Pharmacol. 2023;957:176044. https://doi.org/10.1016/j.ejphar.2023.176044.

[23] Hu S, Liu T, Wu Y, et al. Panax notoginseng saponins suppress lipopolysaccharide-induced barrier disruption and monocyte adhesion on bEnd. 3 cells via the opposite modulation of Nrf2 antioxidant and NF-κB inflammatory pathways. Phytother Res. 2019; 33(12):3163-3176.

[24] Chen H, Shen J, Li H, et al. Ginsenoside Rb 1 exerts neuroprotective effects through regulation of Lactobacillus helveticus abundance and GABAA receptor expression. J Ginseng Res. 2020; 44(1):86-95. https://doi.org/10.1016/j.jgr.2018.09.002.

[25] Di P, Yan Y, Wang P, et al. Integrative SMRT sequencing and ginsenoside profiling analysis provide insights into the biosynthesis of ginsenoside in Panax quinquefolium. Chin J Nat Med. 2022; 20(8):614-626. https://doi.org/10.1016/S1875-5364(22)60198-5.

[26] Yi YS. Pharmacological potential of ginseng and ginsenosides in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Ginseng Res. 2024; 48(2):122-128. https://doi.org/10.1016/j.jgr.2023.11.003.

[27] Liu ZQ. Chemical insights into ginseng as a resource for natural antioxidants. Chem Rev. 2012; 112(6):3329-3355. https://doi.org/10.1021/cr100174k.

[28] Zhao M, Chen Q, Xu W, et al. Total ginsenosides extract induce autophagic cell death in NSCLC cells through activation of endoplasmic reticulum stress. J Ethnopharmacol. 2019;243:112093. https://doi.org/10.1016/j.jep.2019.112093.

[29] Li J, Wang RF, Zhou Y, et al. Dammarane-type triterpene oligoglycosides from the leaves and stems of Panax notoginseng and their antiinflammatory activities. J Ginseng Res. 2019; 43(3):377-384. https://doi.org/10.1016/j.jgr.2017.11.008.

[30] Kim JH, Kim JW, Kim CY, et al. Korean Red Ginseng ameliorates allergic asthma through reduction of lung inflammation and oxidation. Antioxidants (Basel). 2022; 11(8):1422. https://doi.org/10.3390/antiox11081422.

[31] Gao D, Kim JH, Vinh LB, et al. Effect of citric acid and heat treatment on the content of less-polar ginsenosides in flower buds of Panax ginseng. Prep Biochem Biotechnol. 2022; 52(2):144-153.

[32] Ding L, Qi H, Wang Y, et al. Recent advances in ginsenosides against respiratory diseases: therapeutic targets and potential mechanisms. Biomed Pharmacother. 2023;158:114096. https://doi.org/10.1016/j.biopha.2022.114096.

[33] Chen W, Wang J, Luo Y, et al. Ginsenoside Rb1 and compound K improve insulin signaling and inhibit ER stress-associated NLRP3 inflammasome activation in adipose tissue. J Ginseng Res. 2016; 40(4):351-358. https://doi.org/10.1016/j.jgr.2015.11.002.

[34] Wang Y, Wu J, Zhu J, et al. Ginsenosides regulation of lysophosphatidylcholine profiles underlies the mechanism of Shengmai Yin in attenuating atherosclerosis. J Ethnopharmacol. 2021; 277(2021):114223. https://doi.org/10.1016/j.jep.2021.114223.

[35] Nie X, Wang B, Hu R, et al. Development and evaluation of controlled and simultaneous release of compound Danshen based on a novel colon-specific osmotic pump capsule. AAPS Pharm Sci Tech. 2020; 21(2):38. https://doi.org/10.1208/s12249-019-1603-9.

[36] Qian M, Yi L, Song LL, et al. Chemical profiles and anticancer effects of saponin fractions of different polarity from the leaves of Panax notoginseng. Chin J Nat Med. 2014; 12(1):30-37. https://doi.org/10.1016/S1875-5364(14)60006-6.

[37] Li W, Wu Y, Wan M, et al. Simultaneous determination of three saponins in human plasma after oral administration of compound danshen dripping pills by LC-MS/MS and its application in a pharmacokinetic study. J Pharm Biomed Anal. 2019; 169:254-259. https://doi.org/10.1016/j.jpba.2019.03.008.

[38] Liu JQ, Zhao M, Zhang Z, et al. Rg1 improves LPS-induced parkinsonian symptoms in mice via inhibition of NF-κB signaling and modulation of M1/M2 polarization. Acta Pharmacol Sin. 2020; 41(4):523-534. https://doi.org/10.1038/s41401-020-0358-x.

[39] Zhao JN, Wang RF, Zhao SJ, et al. Advance in glycosyltransferases, the important bioparts for production of diversified ginsenosides. Chin J Nat Med. 2020; 18(9):643-658. https://doi.org/10.1016/S1875-5364(20)60003-6.

[40] Loomba R, Adams LA. Advances in non-invasive assessment of hepatic fibrosis. Gut. 2020; 69(7):1343-1352. https://doi.org/10.1136/gutjnl-2018-317593.

[41] Ginès P, Krag A, Abraldes JG, et al. Liver cirrhosis. The Lancet. 2021; 398(10308):1359-1376. https://doi.org/10.1016/S0140-6736(21)01374-X.

[42] Hammerich L, Tacke F. Hepatic inflammatory responses in liver fibrosis. Nat Rev Gastroenterol Hepatol. 2023; 20(10):633-646. https://doi.org/10.1038/s41575-023-00807-x.

[43] Yuan S, Dong M, Zhang H, et al.Ginsenoside PPD inhibit the activation of HSCs by directly targeting TGFβR1. Int J Biol Macromol. 2022; 194:556-562. https://doi.org/10.1016/j.ijbiomac.2021.11.098.

[44] Xu K, Hu B, Ding X, et al. Alleviation of D-gal-induced senile liver injury by Rg3, a signature component of red ginseng. Aging (Albany NY). 2023; 15(14):6749-6756.

[45] Hu Y, Lang Z, Li X, et al. Ginsenoside Rg 3 promotes hepatic stellate cell ferroptosis by epigenetically regulating ACSL4 to suppress liver fibrosis progression. Phytomedicine. 2024;124:155289. https://doi.org/10.1016/j.phymed.2023.155289.

[46] Liu X, Mi X, Wang Z, et al. Ginsenoside Rg 3 promotes regression from hepatic fibrosis through reducing inflammation-mediated autophagy signaling pathway. Cell Death Dis. 2020; 11(6):454. https://doi.org/10.1038/s41419-020-2597-7.

[47] Lang Z, Yu S, Hu Y, et al. Ginsenoside Rh 2 promotes hepatic stellate cell ferroptosis and inactivation via regulation of IRF1-inhibited SLC7A11. Phytomedicine. 2023;118:154950. https://doi.org/10.1016/j.phymed.2023.154950.

[48] Cui L, Tan YJ, Xu SQ, et al. Ginsenoside Rd, a natural production for attenuating fibrogenesis and inflammation in hepatic fibrosis by regulating the ERRα-mediated P2X7r pathway. Food Funct. 2023; 14(12):5606-5619. https://doi.org/10.1039/D3FO01315D.

[49] Qin BF, Gao S, Feng QY, et al. Regulation of Nur77-TLR4/MyD88 signaling pathway is required for Ginsenoside Rc ameliorates hepatic fibrosis regression by deactivating hepatic stellate cells. Acta Histochem. 2023; 125(7):152079. https://doi.org/10.1016/j.acthis.2023.152079.

[50] Li N, Zhu C, Fu R, et al. Ginsenoside Rg 5 inhibits lipid accumulation and hepatocyte apoptosis via the Notch1 signaling pathway in NASH mice. Phytomedicine. 2024;124:155287. https://doi.org/10.1016/j.phymed.2023.155287.

[51] Lin L, Li X, Li Y, et al. Ginsenoside Rb 1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis. J Pharm Anal. 2024; 14(5):100902. https://doi.org/10.1016/j.jpha.2023.11.009.

[52] Li T, Su G, Zhao Y. Anti-hepatic fibrosis effects of AD-2 affecting the Raf-MEK signaling pathway and inflammatory factors in thioacetamide-induced liver injury. J Food Sci. 2021; 86(6):2753-2765. https://doi.org/10.1111/1750-3841.15731.

[53] Su GY, Li ZY, Wang R, et al. Signaling pathways involved in p38-ERK and inflammatory factors mediated the anti-fibrosis effect of AD-2 on thioacetamide-induced liver injury in mice. Food Funct. 2019; 10(7):3992-4000. https://doi.org/10.1039/C8FO02405G.

[54] Chen Y, Lin L, Yang C, et al. Ginsenoside AD-2 ameliorating lipopolysaccharide-induced activation in HSC-T6 cells and carbon tetrachloride-induced hepatic fibrosis in mice via regulation of VD-VDR axis. J Agric Food Chem. 2023; 71(7):3459-3471. https://doi.org/10.1021/acs.jafc.2c06804.

[55] Ma L, Wang X, Li W, et al. Conjugation of ginsenoside with dietary amino acids: a promising strategy to suppress cell proliferation and induce apoptosis in activated hepatic stellate cells. J Agric Food Chem. 2019; 67(36):10245-10255. https://doi.org/10.1021/acs.jafc.9b03305.

[56] Li Y, Zhang D, Li L, et al. Ginsenoside Rg1 ameliorates aging-induced liver fibrosis by inhibiting the NOX4/NLRP3 inflammasome in SAMP 8 mice. Mol Med Rep. 2021; 24(5):801. https://doi.org/10.3892/mmr.2021.12441.

[57] Zhou H, Liu Y, Su Y, et al. Ginsenoside Rg1 attenuates lipopolysaccharide-induced chronic liver damage by activating Nrf2 signaling and inhibiting inflammasomes in hepatic cells. J Ethnopharmacol. 2024;324:117794. https://doi.org/10.1016/j.jep.2024.117794.

[58] Zhang R, Li X, Gao Y, et al. Ginsenoside Rg 1 epigenetically modulates Smad7 expression in liver fibrosis via MicroRNA-152. J Ginseng Res. 2023; 47(4):534-542. https://doi.org/10.1016/j.jgr.2022.12.005.

[59] Mo C, Xie S, Zeng T, et al. Ginsenoside-Rg1 acts as an IDO1 inhibitor, protects against liver fibrosis via alleviating IDO1-mediated the inhibition of DCs maturation. Phytomedicine. 2021;84:153524. https://doi.org/10.1016/j.phymed.2021.153524.

[60] Hsu YJ, Wang CY, Lee MC, et al. Hepatoprotection by traditional essence of Ginseng against carbon tetrachloride-induced liver damage. Nutrients. 2020; 12(10):3214. https://doi.org/10.3390/nu12103214.

[61] He Z, Chen S, Pan T, et al. Ginsenoside Rg 2 ameliorating CDAHFD-induced hepatic fibrosis by regulating AKT/mTOR-mediated autophagy. J Agric Food Chem. 2022; 70(6):1911-1922. https://doi.org/10.1021/acs.jafc.1c07578.

[62] Wang F, Park JS, Ma Y, et al. Ginseng saponin enriched in Rh1 and Rg2 ameliorates nonalcoholic fatty liver disease by inhibiting inflammasome activation. Nutrients. 2021; 13(3):856. https://doi.org/10.3390/nu13030856.

[63] Jiang Y, Sui D, Li M, et al. Ginsenoside Re improves inflammation and fibrosis in hepatic tissue by upregulating PPARγ expression and inhibiting oxidative stress in db/db mice. Evid Based Complement Alternat Med. 2021;2021:9003603. https://doi.org/10.1155/2021/9003603.

[64] Zhao M, Wang L, Wang M, et al. Targeting fibrosis, mechanisms and cilinical trials. Signal Transduct Target Ther. 2022; 7(1):206. https://doi.org/10.1038/s41392-022-01070-3.

[65] Weinberger M, Riley PR. Animal models to study cardiac regeneration. Nat Rev Cardiol. 2024; 21(2):89-105. https://doi.org/10.1038/s41569-023-00914-x.

[66] Tallquist MD, Molkentin JD. Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol. 2017; 14(8):484-491. https://doi.org/10.1038/nrcardio.2017.57.

[67] Dzeshka MS, Lip GYH, Snezhitskiy V, et al. Cardiac fibrosis in patients with atrial fibrillation: mechanisms and clinical implications. J Am Coll Cardiol. 2015; 66(8):943-959. https://doi.org/10.1016/j.jacc.2015.06.1313.

[68] López B, Ravassa S, Moreno MU, et al. Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches. Nat Rev Cardiol. 2021; 18(7):479-498. https://doi.org/10.1038/s41569-020-00504-1.

[69] Xu H, Miao H, Chen G, et al. 20(S)-ginsenoside Rg3 exerts anti-fibrotic effect after myocardial infarction by alleviation of fibroblasts proliferation and collagen deposition through TGFBR1 signaling pathways. J Ginseng Res. 2023; 47(6):743-754. https://doi.org/10.1016/j.jgr.2023.06.007.

[70] Lai Q, Liu FM, Rao WL, et al. Aminoacylase-1 plays a key role in myocardial fibrosis and the therapeutic effects of 20(S)-ginsenoside Rg3 in mouse heart failure. Acta Pharmacol Sin. 2022; 43(8):2003-2015. https://doi.org/10.1038/s41401-021-00830-1.

[71] Li L, Wang Y, Guo R, et al. Ginsenoside Rg3-loaded, reactive oxygen species-responsive polymeric nanoparticles for alleviating myocardial ischemia-reperfusion injury. J Control Release. 2020; 317:259-272. https://doi.org/10.1016/j.jconrel.2019.11.032.

[72] Ren B, Feng J, Yang N, et al. Ginsenoside Rg3 attenuates angiotensin II-induced myocardial hypertrophy through repressing NLRP3 inflammasome and oxidative stress via modulating SIRT1/NF-κB pathway. Int Immunopharmacol. 2021;98:107841. https://doi.org/10.1016/j.intimp.2021.107841.

[73] Ke SY, Liu DH, Wu L, et al. Ginsenoside Rb 1 ameliorates age-related myocardial dysfunction by regulating the NF-κB signaling pathway. Am J Chin Med. 2020; 48(6):1369-1383. https://doi.org/10.1142/S0192415X20500676.

[74] Li C, Zhang X, Li J, et al. Ginsenoside Rb 1 promotes the activation of PPARα pathway via inhibiting FADD to ameliorate heart failure. Eur J Pharmacol. 2023;947:175676. https://doi.org/10.1016/j.ejphar.2023.175676.

[75] Jiang L, Yin X, Chen YH, et al. Proteomic analysis reveals ginsenoside Rb1 attenuates myocardial ischemia/reperfusion injury through inhibiting ROS production from mitochondrial complex I. Theranostics. 2021; 11(4):1703-1720. https://doi.org/10.7150/thno.43895.

[76] Zhai Y, Bai J, Peng Y, et al. Ginsenoside Rb 1 attenuates doxorubicin induced cardiotoxicity by suppressing autophagy and ferroptosis. Biochem Biophys Res Commun. 2024;710:149910. https://doi.org/10.1016/j.bbrc.2024.149910.

[77] Zhang Y, Ji H, Qiao O, et al. Nanoparticle conjugation of ginsenoside Rb3 inhibits myocardial fibrosis by regulating PPARα pathway. Biomed Pharmacother. 2021;139:111630. https://doi.org/10.1016/j.biopha.2021.111630.

[78] Zhao T, Wang X, Liu Q, et al. Ginsenoside Rd promotes cardiac repair after myocardial infarction by modulating monocytes/macrophages subsets conversion. Drug Des Devel Ther. 2022; 16:2767-2782. https://doi.org/10.2147/DDDT.S377624.

[79] Yu T, Xu J, Wang Q, et al. 20(S)-ginsenoside Rh2 inhibits angiotensin-2 mediated cardiac remodeling and inflammation associated with suppression of the JNK/AP-1 pathway. Biomed Pharmacother. 2023;169:115880. https://doi.org/10.1016/j.biopha.2023.115880.

[80] Yu T, Xu X, Wei J, et al. Ginsenoside Rg 5 alleviates Ang II-induced cardiac inflammation and remodeling by inhibiting the JNK/AP-1 pathway. Int Immunopharmacol. 2023;120:110408. https://doi.org/10.1016/j.intimp.2023.110408.

[81] Hou J, Yun Y, Cui C, et al. Ginsenoside Rh 2 mitigates doxorubicin-induced cardiotoxicity by inhibiting apoptotic and inflammatory damage and weakening pathological remodelling in breast cancer-bearing mice. Cell Prolif. 2022; 55(6):e13246. https://doi.org/10.1111/cpr.13246.

[82] Cui Y, Wu J, Wang Y, et al. Protective effects of ginsenoside F2 on isoproterenol-induced myocardial infarction by activating the Nrf2/HO-1 and PI3K/Akt signaling pathways. Phytomedicine. 2024;129:155637. https://doi.org/10.1016/j.phymed.2024.155637.

[83] Li X, Cui X, Zhou S, et al. The novel ginsenoside AD2 prevents angiotensin II-induced connexin 40 and connexin 43 dysregulation by activating AMP kinase signaling in perfused beating rat atria. Chem Biol Interact. 2021;339:109430. https://doi.org/10.1016/j.cbi.2021.109430.

[84] Yao H, He Q, Huang C, et al. Panaxatriol saponin ameliorates myocardial infarction-induced cardiac fibrosis by targeting Keap1/Nrf2 to regulate oxidative stress and inhibit cardiac-fibroblast activation and proliferation. Free Radic Biol Med. 2022; 190:264-275. https://doi.org/10.1016/j.freeradbiomed.2022.08.016.

[85] Zhen J, Bai J, Liu J, et al. Ginsenoside RG1-induced mesenchymal stem cells alleviate diabetic cardiomyopathy through secreting exosomal circNOTCH1 to promote macrophage M2 polarization. Phytother Res. 2024; 38(4):1745-1760. https://doi.org/10.1002/ptr.8018.

[86] Guan S, Xin Y, Ding Y, et al. Ginsenoside Rg 1 protects against cardiac remodeling in heart failure via SIRT1/PINK1/Parkin-mediated mitophagy. Chem Biodivers. 2023; 20(2):e202200730. https://doi.org/10.1002/cbdv.202200730.

[87] Lu ML, Wang J, Sun Y, et al. Ginsenoside Rg 1 attenuates mechanical stress-induced cardiac injury via calcium sensing receptor-related pathway. J Ginseng Res. 2021; 45(6):683-694. https://doi.org/10.1016/j.jgr.2021.03.006.

[88] Wang Q, Fu W, Yu X, et al. Ginsenoside Rg 2 alleviates myocardial fibrosis by regulating TGF-β1/Smad signalling pathway. Pharm Biol. 2021; 59(1):106-113. https://doi.org/10.1080/13880209.2020.1867197.

[89] Li X, Xiang N, Wang Z. Ginsenoside Rg 2 attenuates myocardial fibrosis and improves cardiac function after myocardial infarction via AKT signaling pathway. Biosci Biotechnol Biochem. 2020; 84(11):2199-2206. https://doi.org/10.1080/09168451.2020.1793292.

[90] Yu Y, Sun J, Liu J, et al. Ginsenoside Re preserves cardiac function and ameliorates left ventricular remodeling in a rat model of myocardial infarction. J Cardiovasc Pharmacol. 2020; 75(1):91-97. https://doi.org/10.1097/FJC.0000000000000752.

[91] Sun J, Wang R, Chao T, et al. Ginsenoside Re inhibits myocardial fibrosis by regulating miR-489/myd88/NF-κB pathway. J Ginseng Res. 2023; 47(2):218-227. https://doi.org/10.1016/j.jgr.2021.11.009.

[92] Wang Y, An X, Wang F, et al. Ginsenoside RH 4 inhibits Ang II-induced myocardial remodeling by interfering with NFIL3. Biomed Pharmacother. 2024;172:116253. https://doi.org/10.1016/j.biopha.2024.116253.

[93] Edeling M, Ragi G, Huang S, et al. Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog. Nat Rev Nephrol. 2016; 12(7):426-439. https://doi.org/10.1038/nrneph.2016.54.

[94] Hsu WH, Hua KF, Tuan LH, et al. Compound K inhibits priming and mitochondria-associated activating signals of NLRP3 inflammasome in renal tubulointerstitial lesions. Nephrol Dial Transplant. 2020; 35(1):74-85.

[95] Ni YH, Deng HF, Zhou L, et al. Ginsenoside Rb 1 ameliorated bavachin-induced renal fibrosis via suppressing Bip/eIF2α/CHOP signaling-mediated EMT. Front Pharmacol. 2022;13:872474. https://doi.org/10.3389/fphar.2022.872474.

[96] Liu X, Chen J, Sun N, et al. Ginsenoside Rb 1 ameliorates autophagy via the AMPK/mTOR pathway in renal tubular epithelial cells in vitro and in vivo. Int J Biol Macromol. 2020; 163:996-1009. https://doi.org/10.1016/j.ijbiomac.2020.07.060.

[97] Sui Z, Sui D, Li M, et al. Ginsenoside Rg 3 has effects comparable to those of ginsenoside re on diabetic kidney disease prevention in db/db mice by regulating inflammation, fibrosis and PPARγ. Mol Med Rep. 2023; 27(4):84. https://doi.org/10.3892/mmr.2023.12971.

[98] Shen B, Wang F, Zhou Y, et al. Ginsenoside Rh 2 inhibits renal fibrosis and renal cell apoptosis in rats with diabetic nephropathy by downregulating discoid domain receptor 1. J South Med Univ. 2021; 41(7):1107-1113. https://doi.org/10.12122/j.issn.1673-4254.2021.07.21.

[99] Qi Z, Li W, Tan J, et al. Effect of ginsenoside Rh2 on renal apoptosis in cisplatin-induced nephrotoxicity in vivo. Phytomedicine. 2019;61:152862. https://doi.org/10.1016/j.phymed.2019.152862.

[100] Han Y, Su Y, Han M, et al. Ginsenoside Rg 1 attenuates glomerular fibrosis by inhibiting CD36/TRPC6/NFAT2 signaling in type 2 diabetes mellitus mice. J Ethnopharmacol. 2023;302(Pt A):115923. https://doi.org/10.1016/j.jep.2022.115923.

[101] Zhang D, Ji P, Sun R, et al. Ginsenoside Rg1 attenuates LPS-induced chronic renal injury by inhibiting NOX4-NLRP3 signaling in mice. Biomed Pharmacother. 2022;150:112936. https://doi.org/10.1016/j.biopha.2022.112936.

[102] Shen X, Dong X, Han Y, et al. Ginsenoside Rg 1 ameliorates glomerular fibrosis during kidney aging by inhibiting NOX4 and NLRP3 inflammasome activation in SAMP8 mice. Int Immunopharmacol. 2020;82:106339. https://doi.org/10.1016/j.intimp.2020.106339.

[103] Ji P, Shi Q, Liu Y, et al. Ginsenoside Rg 1 treatment alleviates renal fibrosis by inhibiting the NOX4-MAPK pathway in T2DM mice. Ren Fail. 2023; 45(1):2197075. https://doi.org/10.1080/0886022X.2023.2197075.

[104] He JY, Hong Q, Chen BX, et al. Ginsenoside Rb 1 alleviates diabetic kidney podocyte injury by inhibiting aldose reductase activity. Acta Pharmacol Sin. 2022; 43(2):342-353. https://doi.org/10.1038/s41401-021-00788-0.

[105] Zhang B, Zhang X, Zhang C, et al. Notoginsenoside R1 protects db/db mice against diabetic nephropathy via upregulation of Nrf2-mediated HO-1 expression. Molecules. 2019; 24(2):247. https://doi.org/10.3390/molecules24020247.

[106] Zhang R, Guan S, Meng Z, et al. Ginsenoside Rb 1 alleviates 3-MCPD-induced renal cell pyroptosis by activating mitophagy. Food Chem Toxicol. 2024;186:114522. https://doi.org/10.1016/j.fct.2024.114522.

[107] Shi Y, Gao Y, Wang T, et al. Ginsenoside Rg 1 alleviates podocyte EMT passage by regulating AKT/GSK3β/β-Catenin pathway by restoring autophagic activity. Evid Based Complement Alternat Med. 2020;2020:1903627. https://doi.org/10.1155/2020/1903627.

[108] Liu Y, Mou L, Yi Z, et al. Integrative informatics analysis identifies that ginsenoside Re improves renal fibrosis through regulation of autophagy. J Nat Med. 2024; 78(3):722-731. https://doi.org/10.1007/s11418-024-01800-7.

[109] Johannson KA, Chaudhuri N, Adegunsoye A, et al. Treatment of fibrotic interstitial lung disease: current approaches and future directions. Lancet. 2021; 398(10309):1450-1460. https://doi.org/10.1016/S0140-6736(21)01826-2.

[110] Xing L, Chang X, Shen L, et al. Progress in drug delivery system for fibrosis therapy. Asian J Pharm Sci. 2021; 16(1):47-61. https://doi.org/10.1016/j.ajps.2020.06.005.

[111] Richeldi L, Collard HR, Jones MG.Idiopathic pulmonary fibrosis. Lancet. 2017; 389(10082):1941-1952. https://doi.org/10.1016/S0140-6736(17)30866-8.

[112] Liu M, Zhang T, Zang C, et al. Preparation, optimization, and in vivo evaluation of an inhaled solution of total saponins of Panax notoginseng and its protective effect against idiopathic pulmonary fibrosis. Drug Deliv. 2020; 27(1):1718-1728. https://doi.org/10.1080/10717544.2020.1856222.

[113] El-Bassouny DR, Omar NM, Khalaf HA, et al. Role of nuclear factor-kappa B in bleomycin induced pulmonary fibrosis and the probable alleviating role of ginsenoside: histological, immunohistochemical, and biochemical study. Anat Cell Biol. 2021; 54(4):448-464. https://doi.org/10.5115/acb.21.068.

[114] Li T, Chen Y, Li Y, et al. Antifibrotic effect of AD-1 on lipopolysaccharide-mediated fibroblast injury in L929 cells and bleomycin-induced pulmonary fibrosis in mice. Food Funct. 2022; 13(14):7650-7665. https://doi.org/10.1039/D1FO04212B.

[115] Yun E, Kwon BS, Kim J, et al. Ginsenoside Rg 3 attenuates pulmonary fibrosis by inhibiting endothelial to mesenchymal transition. Anim Cells Syst (Seoul). 2023; 27(1):159-170. https://doi.org/10.1080/19768354.2023.2244549.

[116] Fu Z, Xu YS, Cai CQ. Ginsenoside Rg 3 inhibits pulmonary fibrosis by preventing HIF-1α nuclear localization. BMC Pulm Med. 2021; 21(1):70. https://doi.org/10.1186/s12890-021-01426-5.

[117] Liu J, Fan G, Tao N, et al. Ginsenoside Rb 1 alleviates bleomycin-induced pulmonary inflammation and fibrosis by suppressing central nucleotide-binding oligomerization-, leucine-rich repeat-, and pyrin domains-containing protein three inflammasome activation and the NF-κB pathway. Drug Des Devel Ther. 2022; 16:1793-1809. https://doi.org/10.2147/DDDT.S361748.

[118] Ren G, Lv W, Ding Y, et al. Ginseng saponin metabolite 20(S)-protopanaxadiol relieves pulmonary fibrosis by multiple-targets signaling pathways. J Ginseng Res. 2023; 47(4):543-551. https://doi.org/10.1016/j.jgr.2023.01.002.

[119] Ma T, Mao X, Meng X, et al. Ginsenoside Rg1 inhibits STAT3 expression by miR-15b-5p to attenuate lung injury in mice with type 2 diabetes mellitus-associated pulmonary tuberculosis. Evid Based Complement Alternat Med. 2022;2022:9017021. https://doi.org/10.1155/2022/9017021.

[120] Huang C, Xue X, Gong N, et al. Ginsenoside Rg 1 suppresses paraquat-induced epithelial cell senescence by enhancing autophagy in an ATG12-dependent manner. Environ Toxicol. 2022; 37(9):2302-2313. https://doi.org/10.1002/tox.23597.

[121] Song L, Wang L, Li X, et al. Ginsenoside Rg 1 alleviates lipopolysaccharide-induced fibrosis of endometrial epithelial cells in dairy cows by inhibiting reactive oxygen species-activated NLRP3. Animals (Basel). 2023; 13(23):3723. https://doi.org/10.3390/ani13233723.

[122] Chen J, Zhu G, Xiao W, et al. Ginsenoside Rg 1 ameliorates pancreatic injuries via the AMPK/mTOR pathway in vivo and in vitro. Diabetes Metab Syndr Obes. 2023; 16:779-794. https://doi.org/10.2147/DMSO.S401642.

[123] Cho DY, Skinner D, Zhang S, et al. Korean Red Ginseng aqueous extract improves markers of mucociliary clearance by stimulating chloride secretion. J Ginseng Res. 2021; 45(1):66-74. https://doi.org/10.1016/j.jgr.2019.09.001.

[124] Xu J, Zhou L, Chen H, et al. Aerosol inhalation of total ginsenosides repairs acute lung injury and inhibits pulmonary fibrosis through SMAD2 signaling-mediated mechanism. Phytomedicine. 2024;133:155871. https://doi.org/10.1016/j.phymed.2024.155871.

[125] Choi SH, Yang KJ, Lee DS. Effects of complementary combination therapy of Korean Red Ginseng and antiviral agents in chronic hepatitis B. J Altern Complement Med. 2016; 22(12):964-969. https://doi.org/10.1089/acm.2015.0206.

[126] Yang DF. Effects of Ginseng and Turtle Shell Decoction Pill on liver function and liver fibrosis indexes in patients with chronic hepatitis B complicated with mild liver fibrosis. Chin J Clin Ration Drug Use. 2024; 17(16):93-95 + 102.

[127] Hong C, Liang J, Xia J, et al. One stone four birds: a novel liposomal delivery system multi-functionalized with ginsenoside Rh2 for tumor targeting therapy. Nanomicro Lett. 2020; 12(1):129. https://doi.org/10.1007/s40820-020-00472-8.

[128] Lu T, Wu T, Zhong H, et al. Computer-driven formulation development of Ginsenoside Rh2 ternary solid dispersion. Drug Deliv Transl Res. 2025; 15(2):700-716. https://doi.org/10.1007/s13346-024-01628-4.

[129] Mao Y, Yuan W, Gai J, et al. Enhanced brain distribution of Ginsenoside F1 via intranasal administration in combination with absorption enhancers. Int J Pharm. 2024;654:123930. https://doi.org/10.1016/j.ijpharm.2024.123930.

[130] Qu D, Wang L, Liu M, et al. Oral nanomedicine based on multicomponent microemulsions for drug-resistant breast cancer treatment. Biomacromolecules. 2017; 18(4):1268-1280. https://doi.org/10.1021/acs.biomac.7b00011.

[131] Yang IH, Chen YS, Li JJ, et al. The development of laminin-alginate microspheres encapsulated with Ginsenoside Rg1 and ADSCs for breast reconstruction after lumpectomy. Bioact Mater. 2021; 6(6):1699-1710. https://doi.org/10.1016/j.bioactmat.2020.11.029.

[132] Wang H, Zheng Y, Sun Q, et al. Ginsenosides emerging as both bifunctional drugs and nanocarriers for enhanced antitumor therapies. J Nanobiotechnol. 2021; 19(1):322. https://doi.org/10.1186/s12951-021-01062-5.

[133] Bozzuto G, Molinari A.Liposomes as nanomedical devices. Int J Nanomed. 2015; 10:975-999. https://doi.org/10.2147/IJN.S6886. doi: 10.2147/IJN.S68861.eCollection201.

[134] Li GX, Liu ZQ. The protective effects of ginsenosides on human erythrocytes against hemin-induced hemolysis. Food Chem Toxicol. 2008; 46(3):886-892. https://doi.org/10.1016/j.fct.2007.10.020.

[135] Zhou WX, Yang N, Zhao YQ. Advances in studies on improvement of water solubility of ginsenoside. Drug Evaluation Res. 2016; 39(2):322-327.

[136] Hong C, Wang D, Liang J, et al. Novel ginsenoside-based multifunctional liposomal delivery system for combination therapy of gastric cancer. Theranostics. 2019; 9(15):4437-4449. https://doi.org/10.7150/thno.34953.

[137] Fukuda K, Utsumi H, Shoji J, et al. Saponins can cause the agglutination of phospholipid vesicles. Biochim Biophys Acta. 1985; 820(2):199-206. https://doi.org/10.1016/0005-2736(85)90113-0.

[138] Qi LW, Wang CZ, Yuan CS. Isolation and analysis of ginseng: advances and challenges. Nat Prod Rep. 2011; 28(3):467-495. https://doi.org/10.1039/c0np00057d.

[139] Nag SA, Qin JJ, Wang W, et al. Ginsenosides as anticancer agents: in vitro and in vivo activities, structure-activity relationships, and molecular mechanisms of action. Front Pharmacol. 2012;3:25. https://doi.org/10.3389/fphar.2012.00025.

[140] Qi HY, Li L, Ma H. Cellular stress response mechanisms as therapeutic targets of ginsenosides. Med Res Rev. 2018; 38(2):625-654. https://doi.org/10.1002/med.21450.

[141] Yang H, Yoo G, Kim HS, et al. Implication of the stereoisomers of ginsenoside derivatives in the antiproliferative effect of HSC-T6 cells. J Agric Food Chem. 2012; 60(47):11759-11764. https://doi.org/10.1021/jf303714c.

[142] Farrar CT, DePeralta DK, Day H, et al. 3D molecular MR imaging of liver fibrosis and response to rapamycin therapy in a bile duct ligation rat model. J Hepatol. 2015; 63(3):689-696. https://doi.org/10.1016/j.jhep.2015.04.029.

[143] Désogère P, Tapias LF, Hariri LP, et al. Type I collagen-targeted PET probe for pulmonary fibrosis detection and staging in preclinical models. Sci Transl Med. 2017; 9(384):eaaf4696. https://doi.org/10.1126/scitranslmed.aaf4696.

[144] Zhang H, Yao J, Xiao G, et al. Discovery of drug targets based on traditional Chinese medicine microspheres (TCM-MPs) fishing strategy combined with bio-layer interferometry (BLI) technology. Anal Chim Acta. 2024;1305:342542. https://doi.org/10.1016/j.aca.2024.342542.

[145] Chen X, Wang Y, Ma N, et al. Target identification of natural medicine with chemical proteomics approach: probe synthesis, target fishing and protein identification. Signal Transduct Target Ther. 2020; 5(1):72. https://doi.org/10.1038/s41392-020-0186-y.

[146] Shao J, Ma X, Qu L, et al. Ginsenoside Rh 4 remodels the periphery microenvironment by targeting the brain-gut axis to alleviate depression-like behaviors. Food Chem. 2023;404(Pt B):134639.

[147] Bai X, Fu R, Duan Z, et al. Ginsenoside Rk 3 alleviates gut microbiota dysbiosis and colonic inflammation in antibiotic-treated mice. Food Res Int. 2021;146:110465. https://doi.org/10.1016/j.foodres.2021.110465.

[148] Guo M, Zhu C, Fu R, et al. Ginsenoside Rk 3 regulates nonalcoholic steatohepatitis by modulation of intestinal flora and the PI3K/AKT signaling pathway in C57BL/6 mice. J Agric Food Chem. 2023; 71(24):9370-9380. https://doi.org/10.1021/acs.jafc.3c00789.

[149] Gong GC, Song SR, Su J. Pulmonary fibrosis alters gut microbiota and associated metabolites in mice: an integrated 16S and metabolomics analysis. Life Sci. 2021;264:118616. https://doi.org/10.1016/j.lfs.2020.118616.