Ovatodiolide: Recent Advances in Pharmacological Activities and Mechanisms

Abstract

Ovatodiolide, a macrocyclic diterpenoid isolated from the traditional Chinese medicinal herb Anisomeles indica, exhibits diverse pharmacological activities in recent research. Its antitumor effects involve modulation of key signaling pathways (e.g., NF-κB/MMP-9, JAK2/STAT3, PI3K/AKT/mTOR, and Wnt/β-catenin) and effective targeting of cancer stem cells. For anti-fibrotic activity, it suppresses the TGF-β pathway and directly inhibits glucose-6-phosphate dehydrogenase. Additionally, it demonstrates antiviral, antibacterial, and anti-inflammatory activities. This review comprehensively summarizes current knowledge on ovatodiolide, including its discovery, synthesis, pharmacological actions, and underlying molecular mechanisms against target diseases. A deeper understanding of ovatodiolideʼs multifaceted pharmacological activities and mechanisms of action will accelerate its clinical translation as a therapeutic agent.

Keywords

ovatodiolide - Anisomeles indica - Labiatae - antimicrobial - antitumor - anti-inflammation - anti-fibrosis

Publikationsverlauf

Eingereicht: 19. März 2025

Angenommen nach Revision: 04. September 2025

Accepted Manuscript online:
05. September 2025

Artikel online veröffentlicht:
24. September 2025

• References

• 1 He J. Essential raw herbal medicine. Beijing: Chinese medicine press; 2015: 34
• 2 Ho-Dac-An, Buu-Hoi NP. [Pharmacodynamic properties of ovatodiolide, the active principle of Anisomeles ovata (Labiaceae)]. Therapie 1969; 24: 627-631
• 3 Arisawa M, Nimura M, Ikeda A, Hayashi T, Morita N, Momose Y, Takeda R, Nakanishi S. Biologically active macrocyclic diterpenoids from Chinese drug “Fang Feng Cao”. I. Isolation and structure. Planta Med 1986; 52: 38-41
• 4 Arisawa M, Nimura M, Fujita A, Hayashi T, Morita N, Koshimura S. Biological active macrocyclic diterpenoids from Chinese drug “Fang Feng Cao”; II. Derivatives of ovatodiolids and their cytotoxity. Planta Med 1986; 52: 297-299
• 5 Xiang J, Ding Y, Li J, Zhao X, Sun Y, Wang D, Wang L, Chen Y. Ovatodiolides: scalable protection-free syntheses, configuration determination, and biological evaluation against hepatic cancer stem cells. Angew Chem Int Ed Engl 2019; 58: 10587-10590
• 6 Xiang J, Zhang X, Wang D, Li J, Li Q, Wang Q, Ding Y, Chen T, Sun Y, Bao S, Chen J, Li D, Wang L, Chen Y. Chemical modification of ovatodiolide revealed a promising amino-prodrug with improved pharmacokinetic profile. Chem Commun (Camb) 2020; 56: 11018-11021
• 7 Chen JC, Dai YZ, Tzeng YM, Liao JW. Genotoxicity and 28-day repeated dose oral toxicity study of ovatodiolide in rats. Toxicol Rep 2021; 8: 1783-1791
• 8 Ou J, Meng F, Liu J, Li D, Cao H, Sun B. Ovatodiolide exerts anticancer effects on human cervical cancer cells via mitotic catastrophe, apoptosis and inhibition of NF-kB pathway. J BUON 2020; 25: 87-92
• 9 Chen MY, Hsu CH, Setiawan SA, Tzeng DTW, Ma HP, Ong JR, Chu YC, Hsieh MS, Wu ATH, Tzeng YM, Yeh CT. Ovatodiolide and antrocin synergistically inhibit the stemness and metastatic potential of hepatocellular carcinoma via impairing ribosome biogenesis and modulating ERK/Akt-mTOR signaling axis. Phytomedicine 2023; 108: 154478
• 10 Huang YJ, Yang CK, Wei PL, Huynh TT, Whang-Peng J, Meng TC, Hsiao M, Tzeng YM, Wu AT, Yen Y. Ovatodiolide suppresses colon tumorigenesis and prevents polarization of M2 tumor-associated macrophages through YAP oncogenic pathways. J Hematol Oncol 2017; 10: 60
• 11 Liu SC, Huang CM, Bamodu OA, Lin CS, Liu BL, Tzeng YM, Tsai JT, Lee WH, Chen TM. Ovatodiolide suppresses nasopharyngeal cancer by targeting stem cell-like population, inducing apoptosis, inhibiting EMT and dysregulating JAK/STAT signaling pathway. Phytomedicine 2019; 56: 269-278
• 12 Wu ATH, Srivastava P, Yadav VK, Tzeng DTW, Iamsaard S, Su EC, Hsiao M, Liu MC. Ovatodiolide, isolated from Anisomeles indica, suppresses bladder carcinogenesis through suppression of mTOR/beta-catenin/CDK6 and exosomal miR-21 derived from M2 tumor-associated macrophages. Toxicol Appl Pharmacol 2020; 401: 115109
• 13 Su YK, Bamodu OA, Tzeng YM, Hsiao M, Yeh CT, Lin CM. Ovatodiolide inhibits the oncogenicity and cancer stem cell-like phenotype of glioblastoma cells, as well as potentiate the anticancer effect of temozolomide. Phytomedicine 2019; 61: 152840
• 14 Lin KL, Tsai PC, Hsieh CY, Chang LS, Lin SR. Antimetastatic effect and mechanism of ovatodiolide in MDA-MB-231 human breast cancer cells. Chem Biol Interact 2011; 194: 148-158
• 15 Bamodu OA, Huang WC, Tzeng DT, Wu A, Wang LS, Yeh CT, Chao TY. Ovatodiolide sensitizes aggressive breast cancer cells to doxorubicin, eliminates their cancer stem cell-like phenotype, and reduces doxorubicin-associated toxicity. Cancer Lett 2015; 364: 125-134
• 16 Liu SC, Huang CM, Chang YL, Bamodu OA, Yeh CT, Wang HW, Lee FP, Lin CS. Ovatodiolide suppresses inflammatory response in BEAS-2B cells by regulating the CREB/AQP5 pathway, and sensitizes nasopharyngeal carcinoma cells to radiation therapy. Eur J Pharmacol 2019; 859: 172548
• 17 Mathan SV, Singh RP. Cancer stem cells connecting to immunotherapy: key insights, challenges, and potential treatment opportunities. Cancers (Basel) 2025; 17: 2100
• 18 Du L, Cheng Q, Zheng H, Liu J, Liu L, Chen Q. Targeting stemness of cancer stem cells to fight colorectal cancers. Semin Cancer Biol 2022; 82: 150-161
• 19 Chen W, Dong J, Haiech J, Kilhoffer MC, Zeniou M. Cancer stem cell quiescence and plasticity as major challenges in cancer therapy. Stem Cells Int 2016; 2016: 1740936
• 20 Lu KT, Wang BY, Chi WY, Chang-Chien J, Yang JJ, Lee HT, Tzeng YM, Chang WW. Ovatodiolide inhibits breast cancer stem/progenitor cells through SMURF2-mediated downregulation of Hsp27. Toxins (Basel) 2016; 8: 127
• 21 Lin CS, Bamodu OA, Kuo KT, Huang CM, Liu SC, Wang CH, Tzeng YM, Chao TY, Yeh CT. Investigation of ovatodiolide, a macrocyclic diterpenoid, as a potential inhibitor of oral cancer stem-like cells properties via the inhibition of the JAK2/STAT3/JARID1B signal circuit. Phytomedicine 2018; 46: 93-103
• 22 Huang YJ, Huang TH, Yadav VK, Sumitra MR, Tzeng DT, Wei PL, Shih JW, Wu AT. Preclinical investigation of ovatodiolide as a potential inhibitor of colon cancer stem cells via downregulating sphere-derived exosomal beta-catenin/STAT3/miR-1246 cargoes. Am J Cancer Res 2020; 10: 2337-2354
• 23 Chen CY, Ye YZ, Huang YH, Tzeng YM, Gurbanov R, Wang WL, Chang WW. Ovatodiolide inhibits endometrial cancer stemness via reactive oxygen species-mediated DNA damage and cell cycle arrest. Chem Biol Interact 2024; 403: 111244
• 24 Liao YF, Rao YK, Tzeng YM. Aqueous extract of Anisomeles indica and its purified compound exerts anti-metastatic activity through inhibition of NF-kappaB/AP-1-dependent MMP-9 activation in human breast cancer MCF-7 cells. Food Chem Toxicol 2012; 50: 2930-2936
• 25 Hsieh YJ, Tseng SP, Kuo YH, Cheng TL, Chiang CY, Tzeng YM, Tsai WC. Ovatodiolide of Anisomeles indica exerts the anticancer potential on pancreatic cancer cell lines through STAT3 and NF-kappaB regulation. Evid Based Complement Alternat Med 2016; 2016: 8680372
• 26 Chen JH, Wu ATH, Bamodu OA, Yadav VK, Chao TY, Tzeng YM, Mukhopadhyay D, Hsiao M, Lee JC. Ovatodiolide suppresses oral cancer malignancy by down-regulating exosomal mir-21/STAT3/β-catenin cargo and preventing oncogenic transformation of normal gingival fibroblasts. Cancers (Basel) 2019; 12: 56
• 27 Liu M, Bamodu OA, Kuo KT, Lee WH, Lin YK, Wu ATH, Hsiao M, Tzeng YM, Yeh CT, Tsai JT. Downregulation of cancer stemness by novel diterpenoid ovatodiolide inhibits hepatic cancer stem cell-like traits by repressing Wnt/β-catenin signaling. Am J Chin Med 2018; 46: 891-910
• 28 Ho JY, Hsu RJ, Wu CL, Chang WL, Cha TL, Yu DS, Yu CP. Ovatodiolide targets β-catenin signaling in suppressing tumorigenesis and overcoming drug resistance in renal cell carcinoma. Evid Based Complement Alternat Med 2013; 2013: 1-16
• 29 Zhang T, Xiaohan C. Unveiling the Role of JAK2/STAT3 signaling in chemoresistance of gynecological cancers: From mechanisms to therapeutic implications. Crit Rev Oncol Hematol 2025; 211: 104712
• 30 Tu YX, Wang SB, Fu LQ, Li SS, Guo QP, Wu Y, Mou XZ, Tong XM. Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway. Oncotarget 2018; 9: 3267-3277
• 31 Kim YC, Guan KL. mTOR: A pharmacologic target for autophagy regulation. J Clin Invest 2015; 125: 25-32
• 32 Xia Q, Xie J, Zhang J, Zhang L, Zhou Y, Zhu B, Wu Y, Yang Z, Li J. Ovatodiolide induces autophagy-mediated cell death through the p 62-Keap1-Nrf2 signaling pathway in chronic myeloid leukemia cells. Chem Biol Interact 2024; 387: 110819
• 33 Chang HL, Chen HA, Bamodu OA, Lee KF, Tzeng YM, Lee WH, Tsai JT. Ovatodiolide suppresses yes-associated protein 1-modulated cancer stem cell phenotypes in highly malignant hepatocellular carcinoma and sensitizes cancer cells to chemotherapy in vitro. Toxicol In Vitro 2018; 51: 74-82
• 34 Chiou WC, Huang GJ, Chang TY, Hsia TL, Yu HY, Lo JM, Fu PK, Huang C. Ovatodiolide inhibits SARS-CoV-2 replication and ameliorates pulmonary fibrosis through suppression of the TGF-beta/TbetaRs signaling pathway. Biomed Pharmacother 2023; 161: 114481
• 35 Mo M, Zeng Y, Zeng Y, Li S, He X, Chen X, Luo Q, Liu M, Luo C, Dou X, Peng F, Long H. N-methylpiperazine-diepoxyovatodiolide ameliorates peritoneal fibrosis via suppressing TGF-beta/Smad and JAK/STAT signaling pathway. Chem Biol Interact 2023; 382: 110589
• 36 He X, Chen X, Wu W, Tang R, Wu H, Liang Y, Shen L, Zheng X, Zheng Z, Yang P, Long Y, Yang J, Zhao L, Zhang Z, Wang H, Luo C, Peng F, Long H. Ovatodiolide alleviates renal fibrosis through regulating metabolic reprogramming via targeting glucose-6-phosphate dehydrogenase. Phytomedicine 2025; 145: 156983
• 37 Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-beta signal transduction for fibrosis and cancer therapy. Mol Cancer 2022; 21: 104
• 38 Shi X, Yang J, Deng S, Xu H, Wu D, Zeng Q, Wang S, Hu T, Wu F, Zhou H. TGF-beta signaling in the tumor metabolic microenvironment and targeted therapies. J Hematol Oncol 2022; 15: 135
• 39 Friedman SL, Pinzani M. Hepatic fibrosis 2022: Unmet needs and a blueprint for the future. Hepatology 2022; 75: 473-488
• 40 Rao YK, Fang SH, Hsieh SC, Yeh TH, Tzeng YM. The constituents of Anisomeles indica and their anti-inflammatory activities. J Ethnopharmacol 2009; 121: 292-296
• 41 Rao YK, Chen YC, Fang SH, Lai CH, Geethangili M, Lee CC, Tzeng YM. Ovatodiolide inhibits the maturation of allergen-induced bone marrow-derived dendritic cells and induction of Th2 cell differentiation. Int Immunopharmacol 2013; 17: 617-624
• 42 Wang CN, Lee YL, Lin YP, Chung WH, Tzeng YM, Lee CC. Ovatodiolide suppresses allergic airway inflammation and hyperresponsiveness in a murine model of asthma. Eur J Pharmacol 2017; 812: 9-17
• 43 Hu C, Zhang S, Chen Q, Wang R. Ovatodiolide protects ischemia-reperfusion-induced neuronal injury via microglial neuroinflammation via mediating SIRT1/NF-kappaB pathway. Brain Res Bull 2022; 180: 97-107
• 44 Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2017; 2: e17023
• 45 Wu ATH, Lawal B, Tzeng YM, Shih CC, Shih CM. Identification of a novel theranostic signature of metabolic and immune-inflammatory dysregulation in myocardial infarction, and the potential therapeutic properties of ovatodiolide, a diterpenoid derivative. Int J Mol Sci 2022; 23: 1281
• 46 Chen JH, Wu ATH, Lawal B, Tzeng DTW, Lee JC, Ho CL, Chao TY. Identification of cancer hub gene signatures associated with immune-suppressive tumor microenvironment and ovatodiolide as a potential cancer immunotherapeutic agent. Cancers (Basel) 2021; 13: 3847
• 47 Shahidul Alam M, Quader MA, Rashid MA. HIV-inhibitory diterpenoid from Anisomeles indica . Fitoterapia 2000; 71: 574-576
• 48 Chen YR, Jiang WP, Deng JS, Chou YN, Wu YB, Liang HJ, Lin JG, Huang GJ. Anisomeles indica extracts and their constituents suppress the protein expression of ACE2 and TMPRSS2 in vivo and in vitro. Int J Mol Sci 2023; 24: 15062
• 49 Hsieh MS, Chen MY, Chang YS, Huang CS, Hsu TN, Huang MS, Yeh CT, Tzeng YM. Targeting the neuropilin-1 receptor with ovatodiolide and progress in using periodontal ligament organoids for COVID-19 research and therapy. Life Sci 2024; 351: 122764
• 50 Lim MCC, Jantaree P, Naumann M. The conundrum of Helicobacter pylori-associated apoptosis in gastric cancer. Trends In Cancer 2023; 9: 679-690
• 51 Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: Epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol 2023; 20: 338-349
• 52 Lee SY, Shin YW, Hahm KB. Phytoceuticals: mighty but ignored weapons against Helicobacter pylori infection. J Dig Dis 2008; 9: 129-139
• 53 Rao YK, Lien HM, Lin YH, Hsu YM, Yeh CT, Chen CC, Lai CH, Tzeng YM. Antibacterial activities of Anisomeles indica constituents and their inhibition effect on Helicobacter pylori-induced inflammation in human gastric epithelial cells. Food Chem 2012; 132: 780-787
• 54 Lien HM, Wang CY, Chang HY, Huang CL, Peng MT, Sing YT, Chen CC, Lai CH. Bioevaluation of Anisomeles indica extracts and their inhibitory effects on Helicobacter pylori-mediated inflammation. J Ethnopharmacol 2013; 145: 397-401
• 55 Lien HM, Wu HY, Hung CL, Chen CJ, Wu CL, Chen KW, Huang CL, Chang SJ, Chen CC, Lin HJ, Lai CH. Antibacterial activity of ovatodiolide isolated from Anisomeles indica against Helicobacter pylori. Sci Rep 2019; 9: 4205
• 56 Lien HM, Wang YY, Huang MZ, Wu HY, Huang CL, Chen CC, Hung SW, Chen CC, Chiu CH, Lai CH. Gastroprotective effect of Anisomeles indica on aspirin-induced gastric ulcer in mice. Antioxidants (Basel) 2022; 11: 2327