First-in-class drug oroxylin A tablets for treating hepatic and gastrointestinal disorders: from preclinical development to clinical research

Abstract

Oroxylin A (OA) is a natural flavonoid primarily derived from the plants Oroxylum indicum and Scutellaria baicalensis. Currently, OA is obtainable through chemical synthesis and exhibits polypharmacological properties, including anti-cancer, anti-inflammatory, anti-microbial, and multi-organ protective effects. The first-in-class drug OA tablets are presently undergoing phase Ib/IIa clinical trials for hepatocellular carcinoma (HCC) treatment. Substantial evidence suggests that OA demonstrates therapeutic potential against various hepatic and gastrointestinal (GI) disorders, including HCC, hepatic fibrosis, fatty liver disease, hepatitis, liver injury, colitis, and colorectal cancer (CRC). OA exerts its therapeutic effects primarily by modulating several crucial signaling pathways, including those associated with apoptosis, oxidative stress, inflammation, glucolipid metabolism, and fibrosis activation. The oral pharmacokinetics of OA is characterized by phase II metabolism, hydrolysis, and enterohepatic recycling. This review provides a comprehensive overview of the critical stages involved in the development of OA tablets, presenting a holistic perspective on the progression of this first-in-class drug from preclinical to clinical phases. It encompasses the synthesis of active pharmaceutical ingredients, pharmacokinetics, pharmacological efficacy, toxicology, drug delivery, and recent advancements in clinical trials. Importantly, this review examines the potential mechanisms by which OA may influence the gut-liver axis, hypothesizing that these interactions may confer health benefits associated with OA that transcend the limitations posed by its poor bioavailability.

Keywords

Oroxylin A / First-in-class drug / Hepatic and gastrointestinal disorders / Gut-liver axis / Preclinical to clinical phases

References

[1] Atanasov AG, Zotchev SB, Dirsch VM, et al. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov. 2021; 20(3):200-216. https://doi.org/10.1038/s41573-020-00114-z.

[2] Yao H, Liu JK, Xu ST, et al. The structural modification of natural products for novel drug discovery. Expert Opin Drug Discov. 2017; 12(2):121-140. https://doi.org/10.1080/17460441.2016.1272757.

[3] Sun QS, Guo YT, Hu WJ, et al. Bempedoic acid unveils therapeutic potential in non-alcoholic fatty liver disease: suppression of the hepatic PXR-SLC13A5/ ACLY signaling axis. Drug Metab Dispos. 2023; 51(12):1628-1641. https://doi.org/10.1124/dmd.123.001449.

[4] Fang Y, Yang C, Yu ZQ, et al. Natural products as LSD1 inhibitors for cancer therapy. Acta Pharm Sin B. 2020; 11(3):621-631. https://doi.org/10.1016/j.apsb.2020.06.007.

[5] Huang DD, Shi GJ, Jiang YP, et al. A review on the potential of resveratrol in prevention and therapy of diabetes and diabetic complications. Biomed Pharmacother. 2020;125:109767. https://doi.org/10.1016/j.biopha.2019.109767.

[6] Yan TT, Yan NN, Wang P, et al. Herbal drug discovery for the treatment of nonalcoholic fatty liver disease. Acta Pharm Sin B. 2020; 10(1):3-18. https://doi.org/10.1016/j.apsb.2019.11.017.

[7] Zhang XW, Zhang P, An L, et al. Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis. Acta Pharm Sin B. 2020; 10(8):1397-1413. https://doi.org/10.1016/j.apsb.2020.06.015.

[8] Feng XJ, Yu W, Li XD, et al. Apigenin, a modulator of PPARγ attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation. Biochem Pharmacol. 2017; 136:136-149. https://doi.org/10.1016/j.bcp.2017.04.014.

[9] Ganguly R, Gupta A, Pandey AK. Role of baicalin as a potential therapeutic agent in hepatobiliary and gastrointestinal disorders: a review. World J Gastroenterol. 2022; 28(26):3047-3062. https://doi.org/10.3748/wjg.v28.i26.3047.

[10] Wang K, Lv Q, Miao YM, et al. Cardamonin, a natural flavone, alleviates inflammatory bowel disease by the inhibition of NLRP3 inflammasome activation via an AhR/Nrf2/NQO1 pathway. Biochem Pharmacol. 2018; 155:494-509. https://doi.org/10.1016/j.bcp.2018.07.039.

[11] Liao ST, Li P, Wang JS, et al. Protection of baicalin against lipopolysaccharide induced liver and kidney injuries based on ¹H NMR metabolomic profiling. Toxicol. 2016; 5(4):1148-1159. https://doi.org/10.1039/c6tx00082g.

[12] Zhang NN, Jiang ZM, Li SZ, et al. Evolving interplay between natural products and gut microbiota. Eur J Pharmacol. 2023;949:175557. https://doi.org/10.1016/j.ejphar.2023.17555.

[13] Zhou JC, Fan QL, Cai XY, et al. Ginkgo biloba extract protects against depression-like behavior in mice through regulating gut microbial bile acid metabolism. Chin J Nat Med. 2023; 21(10):745-758. https://doi.org/10.1016/S1875-5364(23)60496-0.

[14] Zhang YL, Chen T, Hao XQ, et al. Mapping the regulatory effects of herbal organic compounds on gut bacteria. Pharmacol Res. 2023;193:106804. https://doi.org/10.1016/j.phrs.2023.106804.

[15] Zhu W, Zhou SX, Liu JH, et al. Prebiotic, immuno-stimulating and gut microbiota-modulating effects of Lycium barbarum polysaccharide. Biomed Pharmacother. 2020;121:109591. https://doi.org/10.1016/j.biopha.2019.109591.

[16] Sajeev A, Hegde M, Daimary UD, et al. Modulation of diverse oncogenic signaling pathways by oroxylin A: an important strategy for both cancer prevention and treatment. Phytomedicine. 2022;105:154369. https://doi.org/10.1016/j.phymed.2022.154369.

[17] Lu L, Guo QL, Zhao L. Overview of oroxylin A: a promising flavonoid compound. Phytother Res. 2016; 30(11):1765-1774. https://doi.org/10.1002/ptr.5694.

[18] Sajeev A, Hegde M, Girisa S, et al. Oroxylin A: a promising flavonoid for prevention and treatment of chronic diseases. Biomolecules. 2022; 12(9):1185. https://doi.org/10.3390/biom12091185.

[19] Zhang XB, Liu YC, Lu L, et al. Oroxyloside A overcomes bone marrow microenvironment-mediated chronic myelogenous leukemia resistance to imatinib via suppressing hedgehog pathway. Front Pharmacol. 2017;8:526. https://doi.org/10.3389/fphar.2017.00526.

[20] Cao Y, Cao WJ, Qiu YM, et al. Oroxylin A suppresses ACTN1 expression to inactivate cancer-associated fibroblasts and restrain breast cancer metastasis. Pharmacol Res. 2020;159:104981. https://doi.org/10.1016/j.phrs.2020.104981.

[21] Wei LB, Yao YY, Zhao K, et al. Oroxylin A inhibits invasion and migration through suppressing ERK/GSK-3β signaling in snail-expressing non-small-cell lung cancer cells. Mol Carcinog. 2016; 55(12):2121-2134. https://doi.org/10.1002/mc.22456.

[22] Wang PX, Mu XN, Huang SH, et al. Cellular and molecular mechanisms of oroxylin A in cancer therapy: recent advances. Eur J Pharmacol. 2024;969:176452. https://doi.org/10.1016/j.ejphar.2024.176452.

[23] Zou MJ, Hu C, You QD, et al. Oroxylin A induces autophagy in human malignant glioma cells via the mTOR-STAT3-Notch signaling pathway. Mol Carcinog. 2015; 54(11):1363-1375. https://doi.org/10.1002/mc.22212.

[24] Wei LB, Zhou YX, Qiao C, et al. Oroxylin A inhibits glycolysis-dependent proliferation of human breast cancer via promoting SIRT3-mediated SOD2 transcription and HIF1α destabilization. Cell Death Dis. 2015; 6(4):e1714. https://doi.org/10.1038/cddis.2015.86.

[25] Liu YY, Wang XP, Li WS, et al. Oroxylin A reverses hypoxia-induced cisplatin resistance through inhibiting HIF-1α mediated XPC transcription. Oncogene. 2020; 39(45):6893-6905. https://doi.org/10.1038/s41388-020-01474-x.

[26] Zhao K, Li XR, Lin BY, et al. Oroxyloside inhibits angiogenesis through suppressing internalization of VEGFR2/Flk-1 in endothelial cells. J Cell Physiol. 2018; 233(4):3454-3464. https://doi.org/10.1002/jcp.26198.

[27] Wei M, Ma R, Huang SL, et al. Oroxylin A increases the sensitivity of temozolomide on glioma cells by hypoxia-inducible factor 1α/hedgehog pathway under hypoxia. J Cell Physiol. 2019; 234(10):17392-17404. https://doi.org/10.1002/jcp.28361.

[28] An D, Song Z, Yi Y, et al. Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1-mediated carcinogenic estradiol metabolite formation. Phytother Res. 2019; 33(4):1033-1043. https://doi.org/10.1002/ptr.6297.

[29] Mangal P, Khare P, Jagtap S, et al.Screening of six Ayurvedic medicinal plants for anti-obesity potential: an investigation on bioactive constituents from Oroxylum indicum (L.) Kurz bark. J Ethnopharmacol. 2017; 197:138-146. https://doi.org/S0378-8741(16)30498-6. https://doi.org/10.1016/j.jep.2016.07.070.

[30] Cho W, Choi SW, Oh H, et al. Oroxylin-A alleviates hepatic lipid accumulation and apoptosis under hyperlipidemic conditions via AMPK/FGF21 signaling. Biochem Biophys Res Commun. 2023; 648:59-65. https://doi.org/10.1016/j.bbrc.2023.01.090.

[31] Jin J, Chen S, Wang DC, et al. Oroxylin A suppresses influenza A virus replication correlating with neuraminidase inhibition and induction of IFNs. Biomed Pharmacother. 2018; 97:385-394. https://doi.org/10.1016/j.biopha.2017.10.140.

[32] Guo XH, Zheng BW, Wang JH, et al. Exploring the mechanism of action of Chinese medicine in regulating liver fibrosis based on the alteration of glucose metabolic pathways. Phytother Res. 2024; 38(10):4865-4876. https://doi.org/10.1002/ptr.7667.

[33] Liao Y, Yang Y, Wang XP, et al. Oroxyloside ameliorates acetaminophen-induced hepatotoxicity by inhibiting JNK related apoptosis and necroptosis. J Ethnopharmacol. 2020;258:112917. https://doi.org/10.1016/j.jep.2020.112917.

[34] Shah RC, Mehta CR, Wheeler TS. The constitution of oroxylin-A, a yellow colouring matter from the root-bark of Oroxylum indicum vent. J Am Chem Soc. 1936;3:591-593.

[35] Hu BH, Liu YL. Studies on the structures of new flavonoids from the root of Scutellaria amoena. Acta Pharmaceutica Sinica. 1989; 24(3):200-206.

[36] Zhang ZP, Yang ZL, Tang Dengfeng, et al.Isolation and structure identification of chemical constituents from Stachys Geobombycis. Chin Tradi Patent Med. 2004; 26(12):1051-1053. https://doi.org/10.3969/j.issn.1001-1528.2004.12.022.

[37] Li YQ, Feng YL, Yang SL, et al. An investigation into the chemical composition of Capparis spinosa L. Chin Tradit Herbal Drugs. 2007; 38(4):510-512. https://doi.org/10.3321/j.issn:0253-2670.2007.04.012.

[38] Huang W. An Investigation into the Antitumor Active Compounds Present in Ardisia crispa. Central South University, 2007. https://doi.org/10.7666/d.y1326340.

[39] Yin ZY. An Investigation into the Phytoestrogenic Active Constituents of Eucommia ulmoide. Tianjin University, 2010. https://doi.org/10.7666/d.Y1874368.

[40] Zhao XX, Chang JJ, Wang QL, et al. 5,6-Dihydroxy-3,7,4'-trimethoxyflavonol induces G₂/M cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. J Asian Nat Prod Res. 2016; 18(11):1079-1090. https://doi.org/10.1080/10286020.2016.1191473.

[41] Funasaki M, Minato C, Nonaka M, et al. New friedelane triterpenes from Anchietea pyrifolia. Phytochem Lett. 2019; 32:42-46. https://doi.org/10.1016/j.phytol.2019.04.024.

[42] Dinda B, Silsarma I, Dinda M, et al.Oroxylum indicum (L.) Kurz, an important Asian traditional medicine: from traditional uses to scientific data for its commercial exploitation. J Ethnopharmacol. 2015; 161:255-278. https://doi.org/10.1016/j.jep.2014.12.027.

[43] Chen LJ, Games DE, Jones J. Isolation and identification of four flavonoid constituents from the seeds of Oroxylum indicum by high-speed counter-current chromatography. J Chromatogr A. 2003; 988(1):95-105. https://doi.org/10.1016/s0021-9673(02)01954-4.

[44] Sithisarn P, Rojsanga P, Sithisarn P. Inhibitory effects on clinical isolated bacteria and simultaneous HPLC quantitative analysis of flavone contents in extracts from Oroxylum indicum. Molecules. 2019; 24(10):1937. https://doi.org/10.3390/molecules24101937.

[45] Yan RY, Cao YY, Chen CY, et al. Antioxidant flavonoids from the seed of Oroxylum indicum. Fitoterapia. 2011; 82(6):841-848. https://doi.org/10.1016/j.fitote.2011.04.006.

[46] Zhao Q, Chen XY, Martin C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci Bull (Beijing). 2016; 61(18):1391-1398. https://doi.org/10.1007/s11434-016-1136-5.

[47] Xiang L, Gao Y, Chen SY, et al. Therapeutic potential of Scutellaria baicalensis Georgi in lung cancer therapy. Phytomedicine. 2022;95:153727. https://doi.org/10.1016/j.phymed.2021.153727.

[48] Zhao TT, Tang HL, Xie L, et al. Scutellaria baicalensis Georgi (Lamiaceae): a review of its traditional uses, botany, phytochemistry, pharmacology and toxicology. J Pharm Pharmacol. 2019; 71(9):1353-1369. https://doi.org/10.1111/jphp.13129.

[49] Wang YX, Xue DT, Liu M, et al. A novel arctigenin-containing latex glove prevents latex allergy by inhibiting type I/IV allergic reactions. Chin J Nat Med. 2016; 14(3):185-195. https://doi.org/10.1016/S1875-5364(16)30015-2.

[50] Sun YY, Zhang WJ, Dong CL, et al. Baicalin alleviates nitroglycerin-induced migraine in rats via the trigeminovascular system. Phytother Res. 2017; 31(6):899-905. https://doi.org/10.1002/ptr.5811.

[51] Bai QY, Tao SM, Tian JH, et al. Progress of research on effect and mechanism of Scutellariae Radix on preventing liver diseases. Chin J Chin Mater Med. 2020; 45(12):2808-2816. https://doi.org/10.19540/j.cnki.cjcmm.20200224.403.

[52] Jang JY, Im E, Kim ND. Therapeutic potential of bioactive components from Scutellaria baicalensis Georgi in inflammatory bowel disease and colorectal cancer: a review. Int J Mol Sci. 2023; 24(3):1954. https://doi.org/10.3390/ijms24031954.

[53] Sun Y, Zhao Y, Yao J, et al. Wogonoside protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB and NLRP3 inflammasome activation. Biochem Pharmacol. 2015; 94(2):142-154. https://doi.org/10.1016/j.bcp.2015.02.002.

[54] Yu HY, Yin ZJ, Yang SJ, et al. Baicalin reverses depressive-like behaviours and regulates apoptotic signalling induced by olfactory bulbectomy. Phytother Res. 2016; 30(3):469-475. https://doi.org/10.1002/ptr.5550.

[55] Hassan HM, Guo HL, Yousef BA, et al. Dexamethasone pretreatment alleviates isoniazid/lipopolysaccharide hepatotoxicity: inhibition of inflammatory and oxidative stress. Front Pharmacol. 2017;8:133. https://doi.org/10.3389/fphar.2017.00133.

[56] Zhao YK, Zhang LL, Wu YF, et al.Selective anti-tumor activity of wogonin targeting the Warburg effect through stablizing p53. Pharmacol Res. 2018; 135:49-59. https://doi.org/10.1016/j.phrs.2018.07.011.

[57] Ye J, Luo Q, Lang Y, et al. Analysis of chloroplast genome structure and phylogeny of the traditional medicinal of Ardisia crispa (Myrsinaceae). Sci Rep. 2024; 14(1):19045. https://doi.org/10.1038/s41598-024-66563-3.

[58] Huang L, Lyu Q, Zheng W, et al. Traditional application and modern pharmacological research of Eucommia ulmoides Oliv. Chin Med. 2021; 16(1):73. https://doi.org/10.1186/s13020-021-00482-7.

[59] Luo ZW, Yin FC, Wang XB, et al. Progress in approved drugs from natural product resources. Chin J Nat Med. 2024; 22(3):195-211. https://doi.org/10.1016/S1875-5364(24)60582-0.

[60] Li C, Lin G, Zuo Z. Pharmacological effects and pharmacokinetics properties of Radix Scutellariae and its bioactive flavones. Biopharm Drug Dispos. 2011; 32(8):427-445. https://doi.org/10.1002/bdd.771.

[61] Li HB, Chen F. Isolation and purification of baicalein, wogonin and oroxylin A from the medicinal plant Scutellaria baicalensis by high-speed counter-current chromatography. J Chromatogr A. 2005; 1074(1-2):107-110. https://doi.org/10.1016/j.chroma.2005.03.088.

[62] Wang F, Wang B, Wang L, et al. Discovery of discriminatory quality control markers for Chinese herbal medicines and related processed products by combination of chromatographic analysis and chemometrics methods: Radix Scutellariae as a case study. J Pharm Biomed Anal. 2017; 138:70-79. https://doi.org/10.1016/j.jpba.2017.02.004.

[63] Row LR, Sastry VDN, Seshadri TR, et al. Constitution of oroxylin-A and synthesis of its diethyl-ether. Proc Indian Acad Sci. 1948; 28(4):189. https://doi.org/10.1007/BF03171083.

[64] Varady J. Ring isomerization of flavones. New synthesis of oroxylin-A and 7-methyl-oroxylin-A. Tetrahedron Lett. 1965; 6(48):4281-4282. https://doi.org/10.1016/S0040-4039(00)71086-0.

[65] Hemantha HP, Ramanujam R, Majeed M, et al. An unambiguous and practical synthesis of Oroxylin A: a commonly misidentified flavone. Nat Prod Res. 2021; 35(9):1413-1420. https://doi.org/10.1080/14786419.2019.1650359.

[66] Li ZY, Fu W, Yang B, et al. A method for the synthesis of oroxylin A. China. CN101508689B. 2010-09.

[67] Fujita R, Hanaya K, Higashibayashi S, et al. Synthesis of oroxylin A starting from naturally abundant baicalin. Heterocycles. 2018; 97:1165-1174. https://doi.org/10.3987/COM-18-S(T)59.

[68] Han DH, Lee Y, Ahn JH. Biological synthesis of baicalein derivatives using Escherichia coli. J Microbiol Biotechnol. 2016; 26(11):1918-1923. https://doi.org/10.4014/jmb.1605.05050.

[69] Gong X, Li X, Bo A, et al. The interactions between gut microbiota and bioactive ingredients of traditional Chinese medicines: a review. Pharmacol Res. 2020;157:104824. https://doi.org/10.1016/j.phrs.2020.104824.

[70] Huang T, Liu Y, Zhang C. Pharmacokinetics and bioavailability enhancement of baicalin: a review. Eur J Drug Metab Pharmacokinet. 2019; 44(2):159-168. https://doi.org/10.1007/s13318-018-0509-3.

[71] Dai JY, Yang JL, Li C. Transport and metabolism of flavonoids from Chinese herbal remedy Xiaochaihu Tang across human intestinal Caco-2 cell monolayers. Acta Pharmacol Sin. 2008; 29(9):1086-1093. https://doi.org/10.1111/j.1745-7254.2008.00850.x.

[72] Xia BJ, Zhou Q, Zheng ZJ, et al. A novel local recycling mechanism that enhances enteric bioavailability of flavonoids and prolongs their residence time in the gut. Mol Pharm. 2012; 9(11):3246-3458. https://doi.org/10.1021/mp300315d.

[73] Ren GH, Qin ZY, Yang N, et al. Interactions between oroxylin A with the solute carrier transporters and ATP-binding cassette transporters: drug transporters profile for this flavonoid. Chem Biol Interact. 2020;324:109097. https://doi.org/10.1016/j.cbi.2020.109097.

[74] Ren GH, Chen HL, Zhang M, et al. Determination of oroxylin A, oroxylin A 7-O-glucuronide, and oroxylin A sodium sulfonate in beagle dogs by using UHPLC MS/MS application in a pharmacokinetic study. J Sep Sci. 2020; 43(12):2290-2300. https://doi.org/10.1002/jssc.201901259.

[75] Bian Y, Sun M, Chen H, et al. Metabolites identification and species comparison of oroxylin A, an anti-cancer flavonoid, in vitro and in vivo by HPLC-Q-TOF-MS/MS. Xenobiotica. 2022; 52(2):165-176. https://doi.org/10.1080/00498254.2021.2014080.

[76] Zhou Q, Zheng ZJ, Xia BJ, et al. Use of isoform-specific UGT metabolism to determine and describe rates and profiles of glucuronidation of wogonin and oroxylin A by human liver and intestinal microsomes. Pharm Res. 2010; 27(8):1568-1583. https://doi.org/10.1007/s11095-010-0148-0.

[77] Fong SYK, Li CR, Ho YC, et al. Brain uptake of bioactive flavones in Scutellariae Radix and its relationship to anxiolytic effect in mice. Mol Pharm. 2017; 14(9):2908-2916. https://doi.org/10.1021/acs.molpharmaceut.7b00029.

[78] Zhu T, Wang L, Wang LP, et al. Therapeutic targets of neuroprotection and neurorestoration in ischemic stroke: applications for natural compounds from medicinal herbs. Biomed Pharmacother. 2022;148:112719. https://doi.org/10.1016/j.biopha.2022.112719.

[79] Zhang Q, Cong DH, An DC, et al. Determination of oroxylin A and oroxylin A 7-O-D-glucuronide in HepG2 cell lysate and subcellular fractions with SPE-UPLC-MS/MS: cellular pharmacokinetic study to indicate anti-cancer mechanisms. J Pharm Biomed Anal. 2018; 154:364-372. https://doi.org/10.1016/j.jpba.2018.03.019.

[80] Chen L, Cao H, Huang Q, et al. Absorption, metabolism and bioavailability of flavonoids: a review. Crit Rev Food Sci Nutr. 2022; 62(28):7730-7742. https://doi.org/10.1080/10408398.2021.1917508.

[81] Walle T.Absorption and metabolism of flavonoids. Free Radic Biol Med. 2004; 36(7):829-837. https://doi.org/10.1016/j.freeradbiomed.2004.01.002.

[82] Zhang CL, Xu YJ, Xiang D, et al. Pharmacokinetic characteristics of baicalin in rats with 17α-ethynyl-estradiol-induced intrahepatic cholestasis. Curr Med Sci. 2018; 38(1):167-173. https://doi.org/10.1007/s11596-018-1861-x.

[83] Ren GH, Chen HL, Zhang M, et al. Pharmacokinetics, tissue distribution and excretion study of oroxylin A, oroxylin A 7-O-glucuronide and oroxylin A sodium sulfonate in rats after administration of oroxylin A. Fitoterapia. 2020;142:104480. https://doi.org/10.1016/j.fitote.2020.104480.

[84] Li X, Miao HC, Zhang Y, et al. Bone marrow microenvironment confers imatinib resistance to chronic myelogenous leukemia and oroxylin A reverses the resistance by suppressing Stat3 pathway. Arch Toxicol. 2015; 89(1):121-136. https://doi.org/10.1007/s00204-014-1226-6.

[85] Wang PW, Cao J, Feng Z, et al. Oroxylin a promoted apoptotic extracellular vesicles transfer of glycolytic kinases to remodel immune microenvironment in hepatocellular carcinoma model. Eur J Pharmacol. 2023;957:176037. https://doi.org/10.1016/j.ejphar.2023.176037.

[86] Chen Y, Zheng JH, Mo LX, et al. Oroxylin A suppresses breast cancer-induced osteoclastogenesis and osteolysis as a natural RON inhibitor. Phytomedicine. 2024;129:155688. https://doi.org/10.1016/j.phymed.2024.155688.

[87] Zhang H, Chen QS, Dahan A, et al. Transcriptomic analyses reveal the molecular mechanisms of schisandrin B alleviates CCl₄-induced liver fibrosis in rats by RNA-sequencing. Chem Biol Interact. 2019;309:108675. https://doi.org/10.1016/j.cbi.2019.05.041.

[88] Zou MZ, Wang AZ, Wei JJ, et al. An insight into the mechanism and molecular basis of dysfunctional immune response involved in cholestasis. Int Immunopharmacol. 2021;92:107328. https://doi.org/10.1016/j.intimp.2020.107328.

[89] Rahman SR, Roper JA, Grove JI, et al. Integrins as a drug target in liver fibrosis. Liver Int. 2022; 42(3):507-521. https://doi.org/10.1111/liv.15157.

[90] Yang J, Tang XJ, Liang Z, et al. Taurocholic acid promotes hepatic stellate cell activation via S1PR2/p38 MAPK/YAP signaling under cholestatic conditions. Clin Mol Hepatol. 2023; 29(2):465-481. https://doi.org/10.3350/cmh.2022.0327.

[91] Zhu XY, Ye ST, Yu DK, et al. Physalin B attenuates liver fibrosis via suppressing LAP2α-HDAC1-mediated deacetylation of the transcription factor GLI1 and hepatic stellate cell activation. Br J Pharmacol. 2021; 178(17):3428-3447. https://doi.org/10.1111/bph.15490.

[92] Wang FD, Zhou J, Chen EQ. Molecular mechanisms and potential new therapeutic drugs for liver fibrosis. Front Pharmacol. 2022;13:787748. https://doi.org/10.3389/fphar.2022.787748.

[93] Kaftanovskaya EM, Ng HH, Soula M, et al. Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis. Faseb J. 2019; 33(11):12435-12446. https://doi.org/10.1096/fj.201901046R.

[94] Zhao JW, Bai DS, Qi L, et al. The flavonoid GL-V9 alleviates liver fibrosis by triggering senescence by regulating the transcription factor GATA4 in activated hepatic stellate cells. Br J Pharmacol. 2023; 180(8):1072-1089. https://doi.org/10.1111/bph.15997.

[95] Yang T, Wu EY, Zhu XY, et al. TKF, a mexicanolide-type limonoid derivative, suppressed hepatic stellate cells activation and liver fibrosis through inhibition of the YAP/Notch3 pathway. Phytomedicine. 2022;107:154466. https://doi.org/10.1016/j.phymed.2022.154466.

[96] Chen K, Guo WR, Li RX, et al. Demethylzeylasteral attenuates hepatic stellate cell activation and liver fibrosis by inhibiting AGAP2 mediated signaling. Phytomedicine. 2022;105:154349. https://doi.org/10.1016/j.phymed.2022.154349.

[97] Zhou JY, Cui S, He QX, et al. SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nat Commun. 2020; 11(1):240. https://doi.org/10.1038/s41467-019-14138-6.

[98] Bian M, He J, Jin H, et al. Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress. Apoptosis. 2019; 24(11-12):905-920. https://doi.org/10.1007/s10495-019-01568-2.

[99] Shen M, Guo M, Wang ZY, et al. ROS-dependent inhibition of the PI3K/Akt/mTOR signaling is required for oroxylin A to exert anti-inflammatory activity in liver fibrosis. Int Immunopharmacol. 2020;85:106637. https://doi.org/10.1016/j.intimp.2020.106637.

[100] Chen WW, Zhang ZL, Yao Z, et al. Activation of autophagy is required for oroxylin A to alleviate carbon tetrachloride-induced liver fibrosis and hepatic stellate cell activation. Int Immunopharmacol. 2018; 56:148-155. https://doi.org/10.1016/j.intimp.2018.01.029.

[101] Wang FX, Jia Y, Li MM, et al. Blockade of glycolysis-dependent contraction by oroxylin A via inhibition of lactate dehydrogenase-a in hepatic stellate cells. Cell Commun Signal. 2019; 17(1):11. https://doi.org/10.1186/s12964-019-0324-8.

[102] Ge T, Shao YY, Bao XF, et al. Cellular senescence in liver diseases: from mechanisms to therapies. Int Immunopharmacol. 2023;121:110522. https://doi.org/10.1016/j.intimp.2023.110522.

[103] Zhao DL, Gao YY, Su Y, et al. Oroxylin A regulates cGAS DNA hypermethylation induced by methionine metabolism to promote HSC senescence. Pharmacol Res. 2023;187:106590. https://doi.org/10.1016/j.phrs.2022.106590.

[104] Sun Y, Weng JD, Chen XL, et al. Oroxylin A activates ferritinophagy to induce hepatic stellate cell senescence against hepatic fibrosis by regulating cGAS-STING pathway. Biomed Pharmacother. 2023;162:114653. https://doi.org/10.1016/j.biopha.2023.114653.

[105] Zhang ZL, Guo M, Shen M, et al. Oroxylin A regulates the turnover of lipid droplet via downregulating adipose triglyceride lipase (ATGL) in hepatic stellate cells. Life Sci. 2019;238:116934. https://doi.org/10.1016/j.lfs.2019.116934.

[106] Zhang CX, Bian ML, Chen XR, et al. Oroxylin A prevents angiogenesis of LSECs in liver fibrosis via inhibition of YAP/HIF-1α signaling. J Cell Biochem. 2018; 119(2):2258-2268. https://doi.org/10.1002/jcb.26388.

[107] Diaz LA, Arab JP, Louvet A, et al. The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2023; 20(12):764-783. https://doi.org/10.1038/s41575-023-00822-y.

[108] Duan YL, Yang Y, Zhao SQ, et al. Crosstalk in extrahepatic and hepatic system in NAFLD/NASH. Liver Int. 2024; 44(8):1856-1871. https://doi.org/10.1111/liv.15967.

[109] Leng YR, Zhang MH, Luo JG, et al. Pathogenesis of NASH and promising natural products. Chin J Nat Med. 2021; 19(1):12-27. https://doi.org/10.1016/S1875-5364(21)60002-X.

[110] Zhang L, Yang SY, Qi-Li FR, et al. Administration of isoliquiritigenin prevents nonalcoholic fatty liver disease through a novel IQGAP2-CREB-SIRT1 axis. Phytother Res. 2021; 35(7):3898-3915. https://doi.org/10.1002/ptr.7101.

[111] Lu WJ, Xu WJ, Zhang MH, et al. Diverse polycyclic polyprenylated acylphloroglucinol congeners with anti-nonalcoholic steatohepatitis activity from Hypericum forrestii. J Nat Prod. 2021; 84(4):1135-1148. https://doi.org/10.1021/acs.jnatprod.0c01202.

[112] Bao LC, Yin J, Gao W, et al. A long-acting FGF21 alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis partly through an FGF21-adiponectin-IL17A pathway. Brit J Pharmacol. 2018; 175(16):3379-3393. https://doi.org/10.1111/bph.14383.

[113] Shi GJ, Shi GR, Zhou JY, et al. Involvement of growth factors in diabetes mellitus and its complications: a general review. Biomed Pharmacother. 2018; 101:510-527. https://doi.org/10.1016/j.biopha.2018.02.105.

[114] Yan CY, Hu WT, Tu JQ, et al. Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease. J Transl Med. 2023; 21(1):300. https://doi.org/10.1186/s12967-023-04166-8.

[115] Jin HH, Lian NQ, Bian ML, et al. Oroxylin A prevents alcohol-induced hepatic steatosis through inhibition of hypoxia inducible factor 1alpha. Chem Biol Interact. 2018; 285:14-20. https://doi.org/10.1016/j.cbi.2018.02.025.

[116] Jin HH, Lian NQ, Bian ML, et al. Oroxylin A inhibits ethanol-induced hepatocyte senescence via YAP pathway. Cell Prolif. 2018; 51(3):e12431. https://doi.org/10.1111/cpr.12431.

[117] Kai J, Yang X, Wang ZM, et al. Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease. Free Radic Biol Med. 2020; 153:89-102. https://doi.org/10.1016/j.freeradbiomed.2020.03.031.

[118] Neshat SY, Quiroz VM, Wang Y, et al. Liver disease: induction, progression, immunological mechanisms, and therapeutic interventions. Int J Mol Sci. 2021; 22(13):6777. https://doi.org/10.3390/ijms22136777.

[119] Lv TT, Li M, Zeng N, et al. Systematic review and meta-analysis on the incidence and prevalence of autoimmune hepatitis in Asian, European, and American population. J Gastroenterol Hepatol. 2019; 34(10):1676-1684. https://doi.org/10.1111/jgh.14746.

[120] Sirbe C, Simu G, Szabo I, et al. Pathogenesis of autoimmune hepatitis-cellular and molecular mechanisms. Int J Mol Sci. 2021; 22(24):13578. https://doi.org/10.3390/ijms222413578.

[121] Zhu JX, Chen HX, Cui JJ, et al. Oroxylin A inhibited autoimmune hepatitis-induced liver injury and shifted Treg/Th17 balance to Treg differentiation. Exp Anim. 2023; 72(3):367-378. https://doi.org/10.1538/expanim.22-0171.

[122] Zhang HR, Yuan ZQ, Zhu Y, et al. Th17/Treg imbalance mediates hepatic intolerance to exogenous lipopolysaccharide and exacerbates liver injury in triptolide induced excessive immune response. J Ethnopharmacol. 2022;295:115422. https://doi.org/10.1016/j.jep.2022.115422.

[123] Stravitz RT, Lee WM.Acute liver failure. Lancet. 2019; 394(10201):869-881. https://doi.org/10.1016/s0140-6736(19)31894-x.

[124] Xu LL, Zheng X, Wang YH, et al. Berberine protects acute liver failure in mice through inhibiting inflammation and mitochondria-dependent apoptosis. Eur J Pharmacol. 2018; 819:161-168. https://doi.org/10.1016/j.ejphar.2017.11.013.

[125] Liao WT, Jin QW, Liu JN, et al. Mahuang Decoction antagonizes acute liver failure via modulating tricarboxylic acid cycle and amino acids metabolism. Front Pharmacol. 2021;12:599180. https://doi.org/10.3389/fphar.2021.599180.

[126] Zhu RZ, Zeng GF, Chen YQ, et al. Oroxylin A accelerates liver regeneration in CCl₄-induced acute liver injury mice. PLoS One. 2013; 8(8):e71612. https://doi.org/10.1371/journal.pone.0071612.

[127] Huang HY, Zhang XY, Li JY. Protective effect of oroxylin A against lipopolysaccharide and/or D-galactosamine-induced acute liver injury in mice. J Surg Res. 2015; 195(2):522-528. https://doi.org/10.1016/j.jss.2015.01.047.

[128] Zheng RS, Chen R, Han BF, et al.Cancer incidence and mortality in China, 2022. Chin J Oncol. 2024; 46(3):221-231. https://doi.org/10.3760/cma.j.cn112152-20240119-00035.

[129] Xing M, Wang X, Kiken RA, et al. Immunodiagnostic biomarkers for hepatocellular carcinoma (HCC): the first step in detection and treatment. Int J Mol Sci. 2021; 22(11):6139. https://doi.org/10.3390/ijms22116139.

[130] Zheng SF, Bian HR, Li JT, et al. Differentiation therapy: unlocking phenotypic plasticity of hepatocellular carcinoma. Crit Rev Oncol Hematol. 2022;180:103854. https://doi.org/10.1016/j.critrevonc.2022.103854.

[131] Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019; 16(10):589-604. https://doi.org/10.1038/s41575-019-0186-y.

[132] Mu R, Qi Q, Gu HY, et al. Involvement of p 53 in oroxylin A-induced apoptosis in cancer cells. Mol Carcinog. 2009; 48(12):1159-1169. https://doi.org/10.1002/mc.20570.

[133] Zhao Y, Zhu Q, Bu XM, et al. Triggering apoptosis by oroxylin A through caspase-8 activation and p62/SQSTM1 proteolysis. Redox Biol. 2020;29:101392. https://doi.org/10.1016/j.redox.2019.101392.

[134] Liu W, Mu R, Nie FF, et al. MAC related mitochondrial pathway in oroxylin A induces apoptosis in human hepatocellular carcinoma HepG2 cells. Cancer Lett. 2009; 284(2):198-207. https://doi.org/10.1016/j.canlet.2009.04.021.

[135] Ji SF, Xu XF, Li YJ, et al. Inhibition of TFAM-mediated mitophagy by oroxylin A restored sorafenib sensitivity under hypoxia conditions in HepG2 Cells. Pharmaceuticals (Basel). 2024; 17(12):1727. https://doi.org/10.3390/ph17121727.

[136] Zou MJ, Lu N, Hu C, et al. Beclin 1-mediated autophagy in hepatocellular carcinoma cells: implication in anticancer efficiency of oroxylin A via inhibition of mTOR signaling. Cell Signal. 2012; 24(8):1722-1732. https://doi.org/10.1016/j.cellsig.2012.04.009.

[137] Xu M, Lu N, Sun ZY, et al. Activation of the unfolded protein response contributed to the selective cytotoxicity of oroxylin A in human hepatocellular carcinoma HepG2 cells. Toxicol Lett. 2012; 212(2):113-125. https://doi.org/10.1016/j.toxlet.2012.05.008.

[138] Du D, Liu C, Qin MY, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma. Acta Pharm Sin B. 2022; 12(2):558-580. https://doi.org/10.1016/j.apsb.2021.09.019.

[139] Dai QS, Yin Q, Wei LB, et al. Oroxylin A regulates glucose metabolism in response to hypoxic stress with the involvement of hypoxia-inducible factor-1 in human hepatoma HepG2 cells. Mol Carcinog. 2016; 55(8):1275-1289. https://doi.org/10.1002/mc.22369.

[140] Guo YJ, Luo CJ, Sun YN, et al. Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy. Biomed Pharmacother. 2023;166:115342. https://doi.org/10.1016/j.biopha.2023.115342.

[141] Dai QS, Yin YH, Liu W, et al. Two p53-related metabolic regulators, TIGAR and SCO2, contribute to oroxylin A-mediated glucose metabolism in human hepatoma HepG2 cells. Int J Biochem Cell Biol. 2013; 45(7):1468-1478. https://doi.org/10.1016/j.biocel.2013.04.015.

[142] Zhou YX, Guo YJ, Zhu YJ, et al. Dual PPARγ/a agonist oroxyloside suppresses cell cycle progression by glycolipid metabolism switch-mediated increase of reactive oxygen species levels. Free Radic Biol Med. 2021; 167:205-217. https://doi.org/10.1016/j.freeradbiomed.2021.02.032.

[143] Jia D, Liu C, Zhu Z, et al. Novel transketolase inhibitor oroxylin A suppresses the non-oxidative pentose phosphate pathway and hepatocellular carcinoma tumour growth in mice and patient-derived organoids. Clin Transl Med. 2022; 12(11):e1095. https://doi.org/10.1002/ctm2.1095.

[144] Wu TZ, Wu XW, Xu YF, et al. A patent review of selective CDK9 inhibitors in treating cancer. Expert Opin Ther Pat. 2023; 33(4):309-322. https://doi.org/10.1080/13543776.2023.2208747.

[145] Yao JY, Xu S, Sun YN, et al. Novel CDK9 inhibitor oroxylin A promotes wild-type P53 stability and prevents hepatocellular carcinoma progression by disrupting both MDM2 and SIRT 1 signaling. Acta Pharmacol Sin. 2022; 43(4):1033-1045. https://doi.org/10.1038/s41401-021-00708-2.

[146] Yao JY, Wang JB, Xu Y, et al.CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma. Autophagy. 2022; 18(8):1879-1897. https://doi.org/10.1080/15548627.2021.2007027.

[147] Jiang L, Li L, Liu YZ, et al. Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma. Front Pharmacol. 2023;14:1097277. https://doi.org/10.3389/fphar.2023.1097277.

[148] Zhao L, Chen Z, Wang J, et al. Synergistic effect of 5-fluorouracil and the flavanoid oroxylin A on HepG2 human hepatocellular carcinoma and on H22 transplanted mice. Cancer Chemother Pharmacol. 2010; 65(3):481-489. https://doi.org/10.1007/s00280-009-1053-2.

[149] Yang HY, Zhao L, Yang Z, et al. Oroxylin A reverses multi-drug resistance of human hepatoma BEL7402/5-FU cells via downregulation of P-glycoprotein expression by inhibiting NF-κB signaling pathway. Mol Carcinog. 2012; 51(2):185-195. https://doi.org/10.1002/mc.20789.

[150] Huang YJ, Wang YC, Tang J, et al. CAM-DR: mechanisms, roles and clinical application in tumors. Front Cell Dev Biol. 2021;9:698047. https://doi.org/10.3389/fcell.2021.698047.

[151] Li M, Wang Y, Li MW, et al. Integrins as attractive targets for cancer therapeutics. Acta Pharm Sin B. 2021; 11(9):2726-2737. https://doi.org/10.1016/j.apsb.2021.01.004.

[152] Zhu BB, Zhao L, Zhu LT, et al. Oroxylin A reverses CAM-DR of HepG2 cells by suppressing Integrinβ1 and its related pathway. Toxicol Appl Pharmacol. 2012; 259(3):387-394. https://doi.org/10.1016/j.taap.2012.01.019.

[153] Huo TX, Wang XP, Yu Z, et al. Oroxylin A inhibits the migration of hepatocellular carcinoma cells by inducing NAG-1 expression. Acta Pharmacol Sin. 2022; 43(3):724-734. https://doi.org/10.1038/s41401-021-00695-4.

[154] Cao HJ, Zhou W, Xian XL, et al. A mixture of baicalein, wogonin, and oroxylin-A inhibits EMT in the A549 cell line via the PI3K/AKT-TWIST1-glycolysis pathway. Front Pharmacol. 2022;12:821485. https://doi.org/10.3389/fphar.2021.821485.

[155] Xu Y, Zhang XF, Zhang RT, et al. AFP deletion leads to anti-tumorigenic but pro-metastatic roles in liver cancers with concomitant CTNNB1 mutations. Cancer Lett. 2023;566:216240. https://doi.org/10.1016/j.canlet.2023.216240.

[156] Kuipers EJ, Grady WM, Lieberman D, et al. Colorectal cancer. Nat Rev Dis Primers. 2015;1:15065. https://doi.org/10.1038/nrdp.2015.65.

[157] Kelson CO, Zaytseva YY. Altered lipid metabolism in APC-driven colorectal cancer: the potential for therapeutic intervention. Front Oncol. 2024;14:1343061. https://doi.org/10.3389/fonc.2024.1343061.

[158] Ni T, He ZH, Dai YY, et al. Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism. Cell Death Dis. 2017; 8(6):e2865. https://doi.org/10.1038/cddis.2017.261.

[159] Zhao K, Zhou YX, Qiao C, et al. Oroxylin A promotes PTEN-mediated negative regulation of MDM2 transcription via SIRT3-mediated deacetylation to stabilize p53 and inhibit glycolysis in wt-p53 cancer cells. J Hematol Oncol. 2015;8:41. https://doi.org/10.1186/s13045-015-0137-1.

[160] Qiao C, Wei LB, Dai QS, et al. UCP2-related mitochondrial pathway participates in oroxylin A-induced apoptosis in human colon cancer cells. J Cell Physiol. 2015; 230(5):1054-1063. https://doi.org/10.1002/jcp.24833.

[161] Qiao C, Lu N, Zhou YX, et al.Oroxylin A modulates mitochondrial function and apoptosis in human colon cancer cells by inducing mitochondrial translocation of wild-type p53. Oncotarget. 2016; 7(13):17009-17020. https://doi.org/10.18632/oncotarget.7927.

[162] Biller LH, Schrag D. A review of the diagnosis and treatment of metastatic colorectal cancer-reply. JAMA. 2021; 325(23):2405. https://doi.org/10.1001/jama.2021.6027.

[163] Cheng LG, Liu WY, Zhong CJ, et al. Remodeling the homeostasis of pro- and anti-angiogenic factors by Shenmai Injection to normalize tumor vasculature for enhanced cancer chemotherapy. J Ethnopharmacol. 2021;270:113770. https://doi.org/10.1016/j.jep.2020.113770.

[164] Ha J, Zhao L, Zhao Q, et al. Oroxylin A improves the sensitivity of HT-29 human colon cancer cells to 5-FU through modulation of the COX-2 signaling pathway. Biochem Cell Biol. 2012; 90(4):521-531. https://doi.org/10.1139/o2012-005.

[165] Lin Q, Liu M, Yue GG, et al. Anti-inflammatory activities of natural cyclopeptide RA-XII in colitis-associated colon cancer mouse model and its effect on gut microbiome. Phytother Res. 2022; 36(6):2641-2659. https://doi.org/10.1002/ptr.7482.

[166] Yang X, Zhang FY, Wang YJ, et al. Oroxylin A inhibits colitis-associated carcinogenesis through modulating the IL-6/STAT3 signaling pathway. Inflamm Bowel Dis. 2013; 19(9):1990-2000. https://doi.org/10.1097/MIB.0b013e318293c5e0.

[167] Yao J, Hu R, Sun J, et al. Oroxylin A prevents inflammation-related tumor through down-regulation of inflammatory gene expression by inhibiting NF-κB signaling. Mol Carcinog. 2014; 53(2):145-158. https://doi.org/10.1002/mc.21958.

[168] Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21^st century: a systematic review of population-based studies. Lancet. 2017; 390(10114):2769-2778. https://doi.org/10.1016/s0140-6736(17)32448-0.

[169] Geremia A, Biancheri P, Allan P, et al. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014; 13(1):3-10. https://doi.org/10.1016/j.autrev.2013.06.004.

[170] Qiu P, Ishimoto T, Fu LF, et al. The gut microbiota in inflammatory bowel disease. Front Cell Infect Microbiol. 2022;12:733992. https://doi.org/10.3389/fcimb.2022.733992.

[171] Cao F, Liu J, Sha BX, et al. Natural products: experimental efficient agents for inflammatory bowel disease therapy. Curr Pharm Design. 2019; 25(46):4893-4913. https://doi.org/10.2174/1381612825666191216154224.

[172] Chen Y, Le TH, Du QM, et al. Genistein protects against DSS-induced colitis by inhibiting NLRP3 inflammasome via TGR5-cAMP signaling. Int Immunopharmacol. 2019; 71:144-154. https://doi.org/10.1016/j.intimp.2019.01.021.

[173] Lv Q, Wang K, Qiao SM, et al. Norisoboldine, a natural aryl hydrocarbon receptor agonist, alleviates TNBS-induced colitis in mice, by inhibiting the activation of NLRP3 inflammasome. Chin J Nat Med. 2018; 16(3):161-174. https://doi.org/10.1016/S1875-5364(18)30044-X.

[174] Lin Y, Wang ZY, Wang MJ, et al. Baicalin attenuate diet-induced metabolic syndrome by improving abnormal metabolism and gut microbiota. Eur J Pharmacol. 2022;925:174996. https://doi.org/10.1016/j.ejphar.2022.174996.

[175] Wang Y, Xu YY, Xu XW, et al. Ginkgo biloba extract ameliorates atherosclerosis via rebalancing gut flora and microbial metabolism. Phytother Res. 2022; 36(6):2463-2480. https://doi.org/10.1002/ptr.7439.

[176] Wang AL, Guan BY, Shao C, et al. Qing-Xin-Jie-Yu Granule alleviates atherosclerosis by reshaping gut microbiota and metabolic homeostasis of ApoE^-/- mice. Phytomedicine. 2022;103:154220. https://doi.org/10.1016/j.phymed.2022.154220.

[177] Chen YM, Zhu LJ, Hu WX, et al. Simiao Wan modulates the gut microbiota and bile acid metabolism during improving type 2 diabetes mellitus in mice. Phytomedicine. 2022;104:154264. https://doi.org/10.1016/j.phymed.2022.154264.

[178] Bai DS, Sun TF, Zhao JW, et al. Oroxylin A maintains the colonic mucus barrier to reduce disease susceptibility by reconstituting a dietary fiber-deprived gut microbiota. Cancer Lett. 2021; 515:73-85. https://doi.org/10.1016/j.canlet.2021.05.018.

[179] Wang XP, Sun Y, Zhao Y, et al. Oroxyloside prevents dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB pathway through PPARγ activation. Biochem Pharmacol. 2016; 106:70-81. https://doi.org/10.1016/j.bcp.2016.02.019.

[180] Zhou W, Liu XT, Zhang X, et al. Oroxylin A inhibits colitis by inactivating NLRP3 inflammasome. Oncotarget. 2017; 8(35):58903-58917. https://doi.org/10.18632/oncotarget.19440.

[181] Wood NJ. Liver: the liver as a firewall-clearance of commensal bacteria that have escaped from the gut. Nat Rev Gastroenterol Hepatol. 2014; 11(7):391. https://doi.org/10.1038/nrgastro.2014.90.

[182] Ju YH, Yao WF, Zhang L. Progress in application of bile acid metabolism in traditional Chinese medicine study. Chin J Chin Mater Med. 2020; 45(10):2360-2367. https://doi.org/10.19540/j.cnki.cjcmm.20200221.301.

[183] Marrero I, Maricic I, Feldstein AE, et al. Complex network of NKT cell subsets controls immune homeostasis in liver and gut. Front Immunol. 2018;9:2082. https://doi.org/10.3389/fimmu.2018.02082.

[184] Gao M, Heng X, Jin J, et al. Gypenoside XLIX ameliorate high-fat diet-induced atherosclerosis via regulating intestinal microbiota, alleviating inflammatory response and restraining oxidative stress in ApoE^-/- mice. Pharmaceuticals. 2022; 15(9):15. https://doi.org/10.3390/ph15091056.

[185] He Y, Hwang S, Ahmed YA, et al. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol Immunol. 2021; 18(1):18-37. https://doi.org/10.1038/s41423-020-00580-w.

[186] Zhu JZ, Yi HW, Huang W, et al. Fatty liver diseases, mechanisms, and potential therapeutic plant medicines. Chin J Nat Med. 2020; 18(3):161-168. https://doi.org/10.1016/S1875-5364(20)30017-0.

[187] Nong C, Zou MZ, Xue RF, et al. The role of invariant natural killer T cells in experimental xenobiotic-induced cholestatic hepatotoxicity. Biomed Pharmacother. 2020;122:109579. https://doi.org/10.1016/j.biopha.2019.109579.

[188] Zhang N, Han L, Xue YR, et al. The protective effect of magnesium lithospermate B on hepatic ischemia/reperfusion via inhibiting the Jak2/Stat3 signaling pathway. Front Pharmacol. 2019;10:620. https://doi.org/10.3389/fphar.2019.00620.

[189] Milosevic I, Vujovic A, Barac A, et al. Gut-liver axis, gut microbiota, and its modulation in the management of liver diseases: a review of the literature. Int J Mol Sci. 2019; 20(2):395. https://doi.org/10.3390/ijms20020395.

[190] Qian MY, Liu J, Zhao DY, et al. Aryl hydrocarbon receptor deficiency in intestinal epithelial cells aggravates alcohol-related liver disease. Cell Mol Gastroenterol Hepatol. 2022; 13(1):233-256. https://doi.org/10.1016/j.jcmgh.2021.08.014.

[191] Wu X, Chen SB, Yan QY, et al. Gpr35 shapes gut microbial ecology to modulate hepatic steatosis. Pharmacol Res. 2023;189:106690. https://doi.org/10.1016/j.phrs.2023.106690.

[192] Aron-Wisnewsky J, Vigliotti C, Witjes J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020; 17(5):279-297. https://doi.org/10.1038/s41575-020-0269-9.

[193] Ramos PJM, Milona A, Morris I, et al. FXR isoforms control different metabolic functions in liver cells via binding to specific DNA motifs. Gastroenterology. 2020; 159(5):1853-1865. https://doi.org/10.1053/j.gastro.2020.07.036.

[194] Feng WW, Ao H, Peng C, et al. Gut microbiota, a new frontier to understand traditional Chinese medicines. Pharmacol Res. 2019; 142:176-191. https://doi.org/10.1016/j.phrs.2019.02.024.

[195] Zhu JW, He L. The modulatory effects of curcumin on the gut microbiota: a potential strategy for disease treatment and health promotion. Microorganisms. 2024; 12(4):642. https://doi.org/10.3390/microorganisms12040642.

[196] Hu TT, Zhu Y, Zhu J, et al. Wine-processed Radix Scutellariae alleviates ARDS by regulating tryptophan metabolism through gut microbiota. Front Pharmacol. 2022;13:1104280. https://doi.org/10.3389/fphar.2022.1104280.

[197] Wang K, Zhang YC, Wang GJ, et al. FXR agonists for MASH therapy: lessons and perspectives from obeticholic acid. Med Res Rev. 2024; 44(2):568-586. https://doi.org/10.1002/med.21991.

[198] Hu Z, Cheng XH, Cai J, et al. Emodin alleviates cholestatic liver injury by modulating Sirt1/Fxr signaling pathways. Sci Rep. 2024; 14(1):16756. https://doi.org/10.1038/s41598-024-67882-1.

[199] Gallucci GM, Hayes CM, Boyer JL, et al. PPAR-mediated bile acid glucuronidation: therapeutic targets for the treatment of cholestatic liver diseases. Cells. 2024; 13(15):1296. https://doi.org/10.3390/cells13151296.

[200] Sun YQ, Zhang LY, Jiang ZZ. The role of peroxisome proliferator-activated receptors in the regulation of bile acid metabolism. Basic Clin Pharmacol Toxicol. 2024; 134(3):315-324. https://doi.org/10.1111/bcpt.13971.

[201] Yang JY, Xiang DC, Xiang D, et al. Baicalin protects against 17α-ethinylestradiol-induced cholestasis via the sirtuin 1/hepatic nuclear receptor-1α/farnesoid X receptor pathway. Front Pharmacol. 2019;10:1685. https://doi.org/10.3389/fphar.2019.01685.

[202] Chopyk DM, Grakoui A. Contribution of the intestinal microbiome and gut barrier to hepatic disorders. Gastroenterology. 2020; 159(3):849-863. https://doi.org/10.1053/j.gastro.2020.04.077.

[203] Guo CY, Li QJ, Chen RH, et al. Baicalein alleviates non-alcoholic fatty liver disease in mice by ameliorating intestinal barrier dysfunction. Food Funct. 2023; 14(4):2138-2148. https://doi.org/10.1039/d2fo03015b.

[204] Yao Z, Le TH, Du Q, et al. The potential clinical value of curcumin and its derivatives in colorectal cancer. Anticancer Agents Med Chem. 2021; 21(13):1626-1637. https://doi.org/10.2174/1871520620999201113095821.

[205] Geng Q, Xu YY, Huang WF, et al. The potential mechanism of the anti-liver fibrotic effect of curcumin in the gut-liver axis. J Med Food. 2024; 27(5):404-418. https://doi.org/10.1089/jmf.2023.K.0273.

[206] Hong T, Jiang X, Zou J, et al. Hepatoprotective effect of curcumin against bisphenol A-induced hepatic steatosis via modulating gut microbiota dysbiosis and related gut-liver axis activation in CD-1 mice. J Nutr Biochem. 2022;109:109103. https://doi.org/10.1016/j.jnutbio.2022.109103.

[207] Zeng HZ, Liu CW, Wan LW, et al. (-)-Epicatechin ameliorates type 2 diabetes mellitus by reshaping the gut microbiota and gut-liver axis in GK rats. Food Chem. 2024;447:138916. https://doi.org/10.1016/j.foodchem.2024.138916.

[208] Chen Y, Ma H, Liang J, et al. Hepatoprotective potential of four fruit extracts rich in different structural flavonoids against alcohol-induced liver injury via gut microbiota-liver axis. Food Chem. 2024; 460(Pt 2):140460. https://doi.org/10.1016/j.foodchem.2024.140460.

[209] Huang S, Xue Q, Xu J, et al. Simultaneously improving the physicochemical properties, dissolution performance, and bioavailability of apigenin and daidzein by co-crystallization with theophylline. J Pharm Sci. 2019; 108(9):2982-2993. https://doi.org/10.1016/j.xphs.2019.04.017.

[210] Meng FC, Wu ZF, Yin ZQ, et al. Coptidis Rhizoma and its main bioactive components: recent advances in chemical investigation, quality evaluation and pharmacological activity. Chin Med. 2018;13:13. https://doi.org/10.1186/s13020-018-0171-3.

[211] Shi GJ, Li Y, Cao QH, et al. In vitro and in vivo evidence that quercetin protects against diabetes and its complications: a systematic review of the literature. Biomed Pharmacother. 2019; 109:1085-1099. https://doi.org/10.1016/j.biopha.2018.10.130.

[212] Lu Y, Luo QL, Jia XB, et al. Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium: integration of herbal medicine, enzyme engineering, and nanotechnology. J Pharm Anal. 2023; 13(3):239-254. https://doi.org/10.1016/j.jpha.2022.12.001.

[213] Zi YX, Yang KY, He JH, et al. Strategies to enhance drug delivery to solid tumors by harnessing the EPR effects and alternative targeting mechanisms. Adv Drug Deliv Rev. 2022;188:114449. https://doi.org/10.1016/j.addr.2022.114449.

[214] Jia YC, Jiang YX, He YL, et al.Approved nanomedicine against diseases. Pharmaceutics. 2023; 15(3):774. https://doi.org/10.3390/pharmaceutics15030774.

[215] Tang L, Li J, Zhao QQ, et al. Advanced and innovative nano-systems for anticancer targeted drug delivery. Pharmaceutics. 2021; 13(8):1151. https://doi.org/10.3390/pharmaceutics13081151.

[216] Yu B, Gao QM, Sheng SH, et al. Smart osteoclasts targeted nanomedicine based on amorphous CaCO₃ for effective osteoporosis reversal. J Nanobiotechnol. 2024; 22(1):153. https://doi.org/10.1186/s12951-024-02412-9.

[217] Zhu S, Zhao ZY, Qin WX, et al. The nanostructured lipid carrier gel of oroxylin A reduced UV-induced skin oxidative stress damage. Colloids Surf B Biointerfaces. 2022;216:112578. https://doi.org/10.1016/j.colsurfb.2022.112578.

[218] Yang HY, Li JF, Zheng YT, et al. Drug activity screening based on microsomes-hydrogel system in predicting metabolism induced antitumor effect of oroxylin A. Sci Rep. 2016;6:21604. https://doi.org/10.1038/srep21604.

[219] Saeed M, Naveed M, Arif M, et al. Green tea (Camellia sinensis) and L-theanine: medicinal values and beneficial applications in humans-a comprehensive review. Biomed Pharmacother. 2017; 95:1260-1275. https://doi.org/10.1016/j.biopha.2017.09.024.

[220] Yang H, Yang TT, Heng C, et al. Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice. Phytother Res. 2019; 33(12):3140-3152. https://doi.org/10.1002/ptr.6486.

[221] Ling QY, Fang J, Zhai C, et al. Berberine induces SOCS1 pathway to reprogram the M1 polarization of macrophages via miR-155-5p in colitis-associated colorectal cancer. Eur J Pharmacol. 2023;949:175724. https://doi.org/10.1016/j.ejphar.2023.175724.

[222] Zhang WB, Zheng YF, Wu YG. Protective effects of oroxylin A against doxorubicin-induced ccardiotoxicity via the activation of sirt1 in mice. Oxid Med Cell Longev. 2021;2021:6610543. https://doi.org/10.1155/2021/6610543.

[223] Jeon SJ, Bak H, Seo J, et al. Oroxylin A induces BDNF expression on cortical neurons through adenosine A2A receptor stimulation: a possible role in neuroprotection. Biomol Ther (Seoul). 2012; 20(1):27-35. https://doi.org/10.4062/biomolther.2012.20.1.027.

[224] Kim DH, Lee Y, Lee HE, et al. Oroxylin A enhances memory consolidation through the brain-derived neurotrophic factor in mice. Brain Res Bull. 2014; 108:67-73. https://doi.org/10.1016/j.brainresbull.2014.09.001.

[225] Yao MY, Qin SY, Xiong JC, et al. Oroxylin A ameliorates AKI-to-CKD transition through maintaining PPARα-BNIP3 signaling-mediated mitochondrial homeostasis. Front Pharmacol. 2022;13:935937. https://doi.org/10.3389/fphar.2022.935937.