Ovatodiolide: Recent Advances in Pharmacological Activities and Mechanisms

Keywords

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

Abbreviation

ACE2: angiotensin-converting enzyme 2

CSCs: cancer stem cells

ECM: extracellular matrix

EMT: epithelial-mesenchymal transition

G6PD: glucose-6-phosphate dehydrogenase

H. pylori: Helicobacter pylori

HIV: human immunodeficiency virus

IRAK3: interleukin-1 receptor-associated kinase 3

MMP-9: matrix metalloproteinase 9

mTOR: mammalian target of rapamycin

NF-κB: nuclear transcription factor κB

NMP-diepoxyovatodiolide: N-methylpiperazine-diepoxyovatodiolide

PPP: pentose phosphate pathway

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

STAT: signal transducer and activator of transcription

T_1/2 : half-life period

TCM: traditional Chinese medicine

TGF-β : transforming growth factor-β

TMPRSS2: transmembrane protease serine 2

TNFRSF12A: TNF receptor superfamily member 12A
 

Introduction

Ovatodiolide ([Fig. 1]) is a macrocyclic diterpenoid that is extracted from Anisomeles indica (L.) Kuntze (Labiatae). The plant is a traditional Chinese medicine (TCM) and was mainly used for the treatment of allergy, dermatoses, and gastrointestinal disease [1]. Ovatodiolide is the major bioactive component of Anisomeles indica, which was first reported in 1969 [2]. After that, researchers endeavored to isolate, purify, and elucidate the stereo-structure of ovatodiolide while also conducting preliminary investigations into its biological activity [3], [4]. Ovatodiolide is a cembrane-type diterpenoid, which has a distinctive ring system consisting of 5/14/5 rings, featuring a butenolide moiety and a trans α-methylene-γ-lactone ([Fig. 1]). In 2019, Xiang and colleagues [5] reported that they successfully achieved the efficient chemical synthesis of the ovatodiolide skeleton for the first time, thereby confirming the absolute stereo configuration of compounds including ovatodiolide, ent-ovatodiolide, and 4,5-epoxy-ovatodiolide. They developed tandem reactions consist of six steps for ovatodiolide synthesis, including a series of ring-opening metathesis and ring-closing metathesis. This method possessed stereoselectivity and allowed for further structural modifications of ovatodiolide.

Fig. 1 Chemical structure of ovatodiolide.

The half-life period (T_1/2) of ovatodiolide incubated with human liver microsomes was determined to be only 0.24 h [6]. This may be attributed to the presence of multiple allylic sites in the ovatodiolide structure that are readily oxidized under the catalysis of cytochrome P450 enzymes in human liver microsomes, leading to the rapid metabolism. To enhance metabolic stability, two double bonds were epoxidized to shield these allylic sites, forming a prodrug N-methylpiperazine-diepoxyovatodiolide (NMP-diepoxyovatodiolide). This modification significantly extended the T_1/2 to 5.12 h [6]. Furthermore, in vivo studies demonstrated liver accumulation of NMP-diepoxyovatodiolide, suggesting its suitability for further investigation in liver diseases [6].

Regarding the toxicity of ovatodiolide, a study in rats demonstrated no adverse reactions after 28 days of once daily gastric gavage administration at doses of 10, 25, and 50 mg/kg or even after a single acute dose of up to 1000 mg/kg [7]. In vitro studies comparing ovatodiolideʼs effects on multiple cervical cancer cell lines versus normal cervical cells found its growth inhibitory effect on normal cells to be significantly less pronounced than on cancer cells [8]. A similar selective cytotoxicity was observed in liver cancer models, where ovatodiolide exhibited markedly reduced toxicity toward the normal human liver cell line THLE-2 [9]. These findings indicate a high safety profile for ovatodiolide and demonstrate its potential for drug development with a wide therapeutic window.

The objective of this review is to critically evaluate the pharmacological activities of ovatodiolide and elucidate its underlying mechanisms of action, thereby providing robust evidence to support its potential clinical applications. Relevant literature was gathered through online scientific databases such as PubMed and Chinese CNKI databases. The following search terms were used: ovatodiolide, Anisomeles indica, Labiatae, antitumor, anti-fibrosis, antimicrobial, anti-inflammation, and the Boolean operators “AND” and “PLUS”.

The Pharmacological Activities of Ovatodiolide

Antitumor effect

Extensive in vitro and in vivo studies have demonstrated that ovatodiolide exhibits broad-spectrum antitumor effects across diverse cancer types, including hepatocellular carcinoma, colon cancer, nasopharyngeal cancer, bladder cancer, glioblastoma, and breast cancer [9], [10], [11], [12], [13], [14], [15]. The compound exerts its anticancer activity by suppressing cellular proliferation, invasion, and migration, while simultaneously inducing apoptosis [9], [10]. Furthermore, ovatodiolide sensitizes cancer cells to a variety of chemotherapeutic agents as well as radiotherapy [9], [16]. In vitro studies demonstrated that ovatodiolide exhibits significant cytotoxicity against most tumor cell lines at concentrations ranging from approximately 2.5 to 20 µM, with treatment durations of 24 – 48 h [9], [10], [11], [12], [13], [14], [15]. This cytotoxic activity exhibited both concentration- and time-dependent effects. The antitumor mechanisms of ovatodiolide are multifaceted, as illustrated in [Fig. 2].

Fig. 2 Signaling pathways modulated by ovatodiolide in cancer therapy. Created in BioRender. Li, J. (2025) https://BioRender.com/d73f065. [rerif]

Notably, ovatodiolide exhibits selective inhibitory effects against cancer stem cells (CSCs). CSCs–a minor subpopulation within tumors–possess unlimited self-renewal capacity and typically remain quiescent until activated by specific stimuli [17]. Critically, CSCs demonstrate resistance to radiotherapy and chemotherapy, drive metastasis via epithelial-mesenchymal transition (EMT) and immune evasion, and constitute a primary factor in tumor initiation, therapeutic resistance, recurrence, and treatment failure [18], [19]. Studies have confirmed that low concentrations of ovatodiolide exert potent cytotoxicity against CSCs in diverse malignancies, including endometrial cancer, hepatocellular carcinoma, glioblastoma, breast cancer, oral cancer, nasopharyngeal carcinoma, and colorectal cancer [11], [20], [21], [22], [23]. This evidence suggests that ovatodiolide may target and eliminate CSCs, thereby addressing a fundamental mechanism of cancer persistence.

Ovatodiolide may suppress cancer cell metastasis [9], [11], [14], [24]. Matrix metalloproteinase 9 (MMP-9), a critical mediator of extracellular matrix (ECM) degradation and tumor cell migration, appears to be suppressed by ovatodiolide [24]. Research suggests this occurs through inhibition of nuclear factor κB (NF-κB) signaling, thereby reducing MMP-9 expression and subsequent ECM degradation [24], [25]. Furthermore, studies demonstrate that ovatodiolide effectively inhibits the expression and phosphorylation of β-catenin in multiple cancer types [11], [22], [26], [27]. It promotes β-catenin destabilization and disrupts its interaction with transcription factor 4 [28]. Consequently, this dual action impedes downstream signal transduction, thereby inhibiting cancer cell viability and suppressing migration and invasion. However, in vivo evidence supporting the inhibitory effect of ovatodiolide on tumor metastasis is currently lacking.

The signal transducer and activator of transcription (STAT) protein family is a vital group of signal transduction factors, and their aberrant activation is closely associated with tumor development. Among the STAT family pathways, the JAK2/STAT3 signaling pathway is particularly well-studied [29]. STAT3 serves as a pharmacological target for diverse small molecule anticancer agents, including ovatodiolide. Ovatodiolide can effectively inhibit the phosphorylation of STAT3, ERK1/2, p38, and AKT and down-regulate the presence of exosomes containing oncomiR-1246 and oncomiR-21, thereby dampening the downstream signaling pathways and contributing to its anticancer effects [12], [21], [22], [25]. In CSCs of chronic myeloid leukemia, ovatodiolide can suppress the expression of STAT5, concomitant with inhibition of the PI3K/AKT/mammalian target of the rapamycin (mTOR) signaling pathway [30].

mTOR is a serine/threonine kinase that actively participates in crucial biological processes, including gene transcription, protein translation, and ribosome synthesis, and exerts significant influence on cellular growth, apoptosis, autophagy, and metabolism [31]. In human liver cancer cell lines (Huh7 and Mahlavu), ovatodiolide suppresses colony formation and proliferation through inhibition of both the ERK1/2 and Akt/mTOR signaling pathways [9]. Furthermore, by targeting mTOR–a well-established autophagy suppressor–ovatodiolide activates autophagy and triggers autophagy-mediated cell death [32].

Substantial evidence has demonstrated that ovatodiolide significantly enhances the anticancer efficacy of multiple chemotherapeutic agents, including cisplatin, 5-fluorouracil, temozolomide, sorafenib, sunitinib, and imatinib [11], [12], [13], [22], [30], [33]. Moreover, ovatodiolide decreases exosomal levels of miR-21 – 5 p, STAT3, and mTOR in oral squamous cell carcinoma, thereby resensitizing CSCs to cisplatin and suppressing tumorigenicity [26]. These synergistic interactions highlight ovatodiolideʼs potential to reduce therapeutic toxicity and overcome drug resistance in oncology regimens.

Collectively, these findings position ovatodiolide as a promising candidate for development into either an antitumor agent or a therapeutic adjuvant. Its multifaceted activity–simultaneously targeting CSCs, suppressing critical signaling pathways governing cell proliferation, survival, and metastasis, and potentiating conventional anticancer therapies–highlights its unique mechanistic value in oncotherapy. Advancing translational research on ovatodiolide could yield novel strategies to address the unmet clinical needs in cancer treatment.

Anti-fibrotic activity

Ovatodiolide and its semi-synthetic derivative NMP-diepoxyovatodiolide have demonstrated significant inhibitory effects on renal, pulmonary, and peritoneal fibrosis ([Fig. 3]) [34], [35], [36]. Multiple studies indicate that the transforming growth factor-β (TGF-β) signaling pathway plays a pivotal role not only in tumor development but also in fibrogenesis [37]. Overexpression of TGF-β induces EMT, ECM deposition, and the generation of cancer-associated fibroblasts, thereby contributing to both fibrotic diseases and cancer [37], [38], [39]. In silico analysis demonstrated that ovatodiolide may be an inhibitor of TGF-βRI and TGF-βRII kinase [34]. Treatment with ovatodiolide reduced TGF-β expression levels and attenuated TGF-β-induced migration of human lung fibroblasts and their transformation into myofibroblasts [34]. Moreover, prodrug NMP-diepoxyovatodiolide prevents peritoneal fibrosis by inhibiting the TGF-β1/Smad and JAK/STAT signaling pathway [35]. A recent study further identified the direct target of ovatodiolide in anti-renal fibrosis [36]. Specifically, ovatodiolide binds to the Lys403 site of glucose-6-phosphate dehydrogenase (G6PD), inhibiting its enzymatic activity. This suppresses pentose phosphate pathway (PPP) overactivation and mitigates renal fibrosis [36]. This study represents the first identification of a direct molecular target for ovatodiolide and raises the question of whether this mechanism extends to other fibrotic diseases, such as liver fibrosis. However, further studies are needed to confirm ovatodiolideʼs efficacy against fibrosis and to fully elucidate its underlying molecular mechanisms.

Fig. 3 Mechanisms of ovatodiolide in fibrosis suppression. Ovatodiolide suppresses fibrosis through inhibition of TGF-β/Smad signaling and/or by directly binding to G6PD’s Lys403 site. This binding inhibits G6PD dimer formation and reduces its enzymatic activity, leading to PPP suppression and cellular metabolic reprogramming, ultimately attenuating fibrosis. Created in BioRender. Li, J. (2025) https://BioRender.com/ywtfjzy. [rerif]

Immune regulation effect

Previous research identified ovatodiolide as the most potent anti-inflammatory compound among 14 tested Anisomeles indica extracts, significantly inhibiting lipopolysaccharide-induced inflammation [40]. Additionally, studies revealed that ovatodiolide downregulated expression of CD80, CD86, and major histocompatibility complex class II on dendritic cells, impeding their maturation and activation [41]. It also inhibited CD4⁺ T cell proliferation and reduced expression of IL-4, IL-5, and TNF-α. In a murine asthma model, ovatodiolide suppressed airway inflammation, mucus production, and attenuated airway hyperresponsiveness by downregulating Th2 cell activation [42]. Crucially, ovatodiolide deactivates NF-κB signaling–the central inflammatory regulator–alleviating histamine-induced stress and ischemia-reperfusion-induced microglial neuroinflammation [16], [43], [44]. This NF-κB inhibition may fundamentally underlie its anti-inflammatory efficacy, positioning ovatodiolide as a promising therapeutic agent for inflammatory diseases, including autoimmune disorders and allergies.

Bioinformatics analyses provide additional support for ovatodiolideʼs role in immune regulation. Molecular docking studies showed that ovatodiolide targeted TNF receptor superfamily member 12A (TNFRSF12A) and exhibited high binding affinity for interleukin-1 receptor-associated kinase 3 (IRAK3) [45], [46], both of which are pivotal regulators of immune responses. However, these computational predictions require experimental validation.

Antiviral and antibacterial activity

Recent studies highlight ovatodiolideʼs potential against human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [34], [47]. Against HIV-1, ovatodiolide inhibited cytopathic effects within a modest concentration range (EC₅₀ = 0.3 µM, IC₅₀ = 3.7 µM) [47]. For SARS-CoV-2, it suppressed viral activity in a concentration-dependent manner (1.56 – 100 µM) with an IC₅₀ of 5.09 ± 0.45 µM [34]. Recent evidence suggests that ovatodiolide targets the expression of angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and neuropilin-1 to prevent SARS-CoV-2 infections [48], [49]. However, the precise mechanisms underlying these antiviral effects remain to be elucidated.

Beyond viral pathogens, ovatodiolide exhibits activity against Helicobacter pylori (H. pylori), a pathogen linked to peptic ulcers, gastric mucosa-associated lymphoid tissue lymphoma, chronic inflammation, and gastric carcinogenesis [50], [51]. As antibiotic resistance compromises H. pylori eradication efficacy, plant-derived compounds such as ovatodiolide represent promising non-antibiotic alternatives for chronic gastritis treatment [52]. It inhibits multidrug-resistant H. pylori strains and alleviates associated inflammation [53], [54], [55], [56]. Mechanistically, it may bind to the hydrophobic pocket of ribosomal protein RpsB, reducing RpsB levels and thereby disrupting global protein synthesis to inhibit H. pylori growth [55]. Additionally, it protects against aspirin-induced gastric ulcers by attenuating IL-1β secretion, reducing TNF-α production, and lowering gastric acid levels [56]. Collectively, these findings indicate that ovatodiolideʼs dual actions–inhibiting H. pylori infection and preventing gastric ulcer formation–support its therapeutic potential against H. pylori-associated gastrointestinal pathologies.

Discussion

Recent years have witnessed significant progress in medicinal chemistry research on ovatodiolide [5], [6]. Successful chemical synthesis has enabled further biological activity studies, facilitating advances in pharmacological research ([Table 1]).

Table 1 Pharmacological activities of ovatodiolide.

Pharmacological activity	Therapeutic effect	Signaling pathway/target involved	Reference
Antitumor effect	Inhibiting cell migration and invasion	NF-κB↓, MMP-9↓, p-AKT↓	[9], [11], [14], [24], [25]
	Suppressing proliferation	mTOR↓, c-myc↓, β-catenin↓, PI3K↓, JAK2↓, STAT3↓, BCR-ABL↓	[12], [13], [22], [27], [30]
	Inhibiting CSCs	p-JAK2↓, p-STAT3↓, β-catenin↓, mTOR↓	[11], [20], [21], [22], [23]
Anti-fibrotic activity	Suppressing EMT, ECM production; Metabolic reprogramming	TβRI/TβRII kinase↓, p-Smad2/3↓, p-JAK2↓, p-STAT3↓, G6PD↓	[27], [34], [35], [36]
Immune regulation effect	Suppressing inflammation	NO↓, TNF-α↓, IL-2↓, IL8↓,IL4↓, IL5↓, IL13↓	[40], [41], [42], [43], [53]
Antiviral and antibacterial activity	Anti-HIV	/	[47]
	Anti-SARS-CoV-2	SARS-CoV-2 3clpro activity↓ ACE2↓ TMPRSS2↓ neuropilin-1↓	[34], [48], [49]
	Anti-H. pylori	RpsB↓	[55]

A substantial body of research has focused on the potential antitumor activity of ovatodiolide. Numerous studies indicate that ovatodiolide likely exerts its antitumor effects by modulating key signaling pathways, such as the NF-κB/MMP-9, JAK2/STAT3, PI3K/AKT/mTOR, and Wnt/β-catenin signaling pathways [24], [25], [26], [27]. However, the underlying molecular pharmacological mechanisms remain incompletely elucidated. For instance, the specific molecular targets of ovatodiolide have yet to be definitively identified, and reported pathway changes may represent secondary effects of the compoundʼs cytotoxicity. Notably, a key advantage of ovatodiolideʼs antitumor activity is its targeting of CSCs, accounting for the significant research interest in its oncotherapeutic potential.

Research on ovatodiolideʼs anti-fibrotic activity remains limited, yet it demonstrates significant inhibitory effects against fibrosis in critical organs such as the kidneys and lungs. Mechanistic studies preliminarily indicate that, beyond suppressing the key fibrotic TGF-β pathway, ovatodiolide additionally targets G6PD [34], [36], thereby modulating cellular metabolic reprogramming to mitigate damage and suppress fibrosis. Whether these effects extend to liver fibrosis–a severe consequence of chronic liver disease–requires further investigation.

Research on ovatodiolideʼs antiviral activity is also limited, with only preliminary in vitro data suggesting potential efficacy against HIV and SARS-CoV-2 [34], [47]; thus, its therapeutic potential for viral infections remains uncertain. In contrast, ovatodiolide exhibits direct inhibitory activity against H. pylori–potentially underpinning Anisomeles indica’s traditional use in gastrointestinal disorders [53], [55]. Evidence further indicates ovatodiolide possesses anti-inflammatory properties, suggesting therapeutic promise for autoimmune diseases (e.g., autoimmune hepatitis and systemic lupus erythematosus) and allergic conditions. However, thorough investigation is needed regarding its effects on lymphocyte development, differentiation, activation, and macrophage polarization. Notably, potential modulation of the gut microbiome and metabolome could represent an additional immunomodulatory mechanism, warranting focused study.

A major limitation in ovatodiolideʼs pharmacokinetic profile is its extremely short half-life [6]. Prodrug derivatization (e.g., NMP-diepoxyovatodiolide) offers a viable strategy to overcome this issue, enhancing bioavailability and supporting clinical translation [6]. However, the toxicity profiles of these derivatives require rigorous evaluation. Addressing this critical knowledge gap is essential to advance its translational development.

Conclusion

This review summarizes the pharmacological activities of ovatodiolide, focusing on its antitumor, anti-fibrotic, immunomodulatory, and antimicrobial effects, while highlighting existing research limitations. Future research directions should prioritize the following areas: (1) target identification and mechanistic elucidation: identify the direct molecular targets of ovatodiolide and investigate its precise mechanisms of action; (2) advancement of preclinical studies: conduct comprehensive preclinical research, including long-term safety assessments, pharmacokinetic profiling, and development of combination therapeutic strategies, to facilitate clinical translation; (3) derivative development: explore ovatodiolide derivatives with improved structural stability, enhanced bioavailability, simplified synthetic routes, and reduced production costs. Progress in these areas will accelerate the clinical translation of ovatodiolide.

Contributorsʼ Statement

Conception and design of the work: Z. X. Yang and J. Li. Data collection: Y. Y. Zhou and J. G. Zhang. Analysis and interpretation of the data: Y. Y. Zhou, J. G. Zhang, Q. Q. Xia, L. M. Zhang, M. M. Zhang, and L. J. Lu. Drafting the manuscript: Y. Y. Zhou and J. G. Zhang. Critical revision of the manuscript: Z. X. Yang and J. Li.

• 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