Therapeutic potential of green tea’s epigallocatechin-3-gallate in oral cancer: a comprehensive systematic review of cellular and molecular pathways

Abstract

Epigallocatechin-3-gallate (EGCG) has gained attention for its antioxidant, anti-inflammatory, anti-fibrotic, and anti-cancer properties. This review explores the mechanisms by which EGCG influences cellular processes in oral cancer (OC) cells. A systematic search of PubMed, Scopus, and Cochrane databases was conducted to identify evidence-based studies on EGCG’s anticancer effects. The risk of bias was assessed using the Cochrane Collaboration’s Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I) tool. Thirteen studies (7 in vitro, 5 in vitro with animal models, and 1 clinical study) were included in this review, employing various OC cell lines such as HSC-3, SCC, CAL-27, and KB, along with Tu212 and Tu686 in two investigations. EGCG treatment was reported to inhibit cell proliferation (IC50: 20–80 µM), induced apoptosis (increases of up to 65% in caspase-3 and caspase-7 activity), and reduced migration and invasion by 40–70% across studies. The findings revealed that EGCG demonstrated inhibitory effects on cancer cell growth in Oral Squamous Cell Carcinoma (OSCC) models. Its anticancer effects are mediated through the regulation of Reactive Oxygen Species (ROS) production, suppression of nuclear factor-κB (NF-κB), modulation of mitogen-activated protein kinase pathways, and regulation of epigenetic changes. Combination therapy with cisplatin or resveratrol demonstrated synergistic effects, enhancing cytotoxicity by 30–50% and reducing chemoresistance in vitro and in vivo. Although preclinical evidence is promising, heterogeneity in methodologies and the scarcity of clinical trials limit direct translation. EGCG should therefore be considered an experimental adjunctive strategy for OSCC, with its therapeutic relevance requiring validation in well-designed human studies.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12672-025-03866-5.

Introduction

Green tea (Camellia sinensis), a member of the Theaceae family, contains proteins, fibre, carbohydrates, minerals, trace elements, lipids, and polyphenols [1, 2]. Among these, polyphenolic catechins—particularly Epigallocatechin-3-gallate (EGCG) are the most abundant and biologically active. Epidemiological studies have associated regular green tea consumption with a reduced risk of several cancers, including OC [3–5]. However, such correlations may be influenced by confounding variables, including lifestyle factors and genetic predisposition, highlighting the need for mechanistic validation [6].

Phytonutrients are reservoirs of bioactive compounds that can be utilized in managing human diseases or chemically modified to develop novel, more effective, and less toxic therapeutics with improved bioavailability [7]. Approximately 60% of currently marketed anticancer drugs originate from plant-derived compounds [8, 9]. Polyphenols, including catechins, are known for their chemopreventive and antioxidant properties, exhibiting free-radical scavenging activity and tumour-suppressive effects, including in OSCC [10].

Recent studies have revealed the complex mechanisms by which these compounds exert their effects, targeting multiple oncogenic signalling pathways [11]. Natural substances possess versatile properties, enabling their use as standalone cytotoxic agents or as adjuvants to conventional chemotherapy. They can enhance anticancer efficacy, overcome tumour resistance, and support the repair of normal tissues. Additionally, their use reduces reliance on costly and labor-intensive synthetic drug discovery, facilitating the development of novel compounds with superior pharmacological potential [11–13].

EGCG was reported to inhibit the production of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by gamma-interferon in cancer cells, and to suppress IDO expression at the gene level [14]. A standard serving of green tea (2.5 g of leaves) contains approximately 240–320 mg of catechins, with EGCG comprising 60–65% of this amount [15]. In vitro studies demonstrate that EGCG inhibits hepatocyte growth factor–induced proliferation, invasion, and migration of OC cells by blocking Met phosphorylation and downregulating matrix metalloproteinases (MMP-2 and MMP-9) [16]. Further evidence from OSCC cell culture models shows that EGCG exerts potent anti-metastatic effects by reducing MMP-2 production, thereby inhibiting cancer cell invasion. It also suppresses cell motility and adhesion, reinforcing its potential as a therapeutic agent in oral cancer [17].

Despite these promising findings, several limitations remain. The bioavailability of EGCG in humans is low, and therapeutic effects observed in vitro may not translate at physiologically relevant concentrations [18]. Some studies even report pro-oxidant and cytotoxic effects under certain conditions, raising concerns about its safety profile and optimal dosing [19]. This inconsistency highlights the need for a systematic review to synthesize available evidence, critically evaluate methodological quality, and identify research gaps. Moreover, EGCG’s interactions with standard chemotherapeutics and its role within the complex OSCC tumour microenvironment remain insufficiently explored. This review, therefore, aims to provide a balanced appraisal of the current evidence on EGCG in OSCC, highlighting both its therapeutic promise and existing gaps in understanding its mechanisms of action on proliferation, apoptosis, migration, and invasion.

Materials and methods

Study protocol

The systematic review adhered to the research selection, synthesis, and reporting standards outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20]. This particular systematic review has been properly recorded in the PROSPERO database (CRD42023484808).

Focused question

The primary research question was “What are the key mechanisms linked with the anti-cancer action of EGCG with a special emphasis on OC?”

Information sources and search strategy

The PubMed, Scopus, and Cochrane databases were utilized to conduct a comprehensive search for evidence-based research findings on the anticancer properties of EGCG on OC, specifically focusing on studies published from January 2014 to December 2023. After conducting a thorough examination of the existing literature, the following combination of Medical Subject Headings (MeSH) phrases was employed: (“EGCG” OR “Green Tea” OR “Camellia sinensis”) AND (“OSCC” OR “OC” OR “Head and Neck Neoplasms”) AND (“Cell Line, Tumor” OR “In Vitro Techniques” OR “Animal Models” OR “Clinical Trial” AND (“Apoptosis” OR “Cell Proliferation” OR “Signal Transduction”).

Grey literature sources were searched for unpublished or ongoing studies. Manual screening of references from relevant articles was performed.

Eligibility criteria

The eligibility criteria for this systematic review were guided by the PICOS framework (Population, Intervention, Comparison, Outcome, and Study Design) in accordance with PRISMA guidelines and only studies published in English were included.

Population: Those with OC who are 18 years of age or older, animal models utilized in OC research and OC cell lines.

Intervention: Research on the effects of green tea or EGCG extracted from green tea.

Comparison: Control groups comprised untreated cells/animals, vehicle-treated controls, or standard-of-care chemotherapy/radiotherapy as reported by individual studies. We have clarified this definition to encompass all baseline comparators used in the included studies.

Outcome: In-vitro and in-vivo investigations used to evaluate the effects of EGCG or green tea extracts on OC by investigating cell proliferation, cytotoxicity, cell death, inhibition of cell cycle gene expression of proteins, and chemopreventive or therapeutic properties.

Study design: In-vitro, animal, or clinical trials that evaluate the harmful effects of EGCG or green tea on OC.

Pilot trials, case series, and case reports were excluded due to their limited sample size, lack of standardized methodology, and high risk of bias, which could compromise the validity of this systematic review. While these designs may provide preliminary observations, our focus was to synthesize reproducible, controlled evidence to support translational relevance.

Study selection

Two proficient reviewers autonomously performed the literature search, extracted data from the analyzed studies, and assessed their quality. They evaluated the titles and abstracts of the included articles. Articles that did not match the prerequisite criteria were excluded. The chosen full-text publications were independently examined and assessed. Additional pertinent publications were sought in the bibliographies of the selected papers. Reviewers settled disputes by engaging in discussions. If the two reviewers were unable to reach a consensus, a third reviewer was enlisted to render the ultimate judgment.

Data extraction

The data were collected using a pre-established extraction protocol, which included: (1) first author’s name and journal, (2) study title, (3) publication year, (4) study location, (5) study design, (6) assays and cell lines used, (7) baseline parameters, and (8) study outcomes. The study outcomes extracted comprised: cell proliferation and viability, apoptosis, cell cycle distribution, migration and invasion, angiogenesis, molecular pathway modulation, drug resistance markers, and in vivo tumour growth and survival in animal models.

Quality assessment

The Risk of Bias (RoB) in non-randomized studies (ROBINS-I), which classifies bias as low, moderate, serious, critical, or no information, was assessed using the Cochrane Collaboration tool [21]. The tool has seven domains, including confounding bias, participant selection bias, intervention categorization bias, deviation from targeted treatment bias, missing data bias, evaluation of outcomes bias, and biased reporting. The overall RoB for all studies was classified into the following categories: The classification of low RoB was given when all the conditions were met. If any domain was not satisfied, the study was considered to pose a moderate RoB. A significant RoB was identified when there were serious issues in at least one of the domains. A study is deemed to be at a critical RoB when significant problems are identified in at least one aspect. If a study fails to demonstrate evident indications of having any RoB and is deficient in information, it is categorized as having no information.

Results

The step-by-step procedure for selecting studies is shown in Fig. 1. A total of 241 studies that met the specified criteria were selected after analyzing the before mentioned databases. The manual search yielded a total of 21 items. A total of 114 superfluous items were eliminated, resulting in 148 articles available for evaluation of their title and abstracts. Following the evaluation, a total of 83 papers were deemed ineligible. Thus, a total of 65 full-text publications were thoroughly examined. A total of 52 publications were eliminated based on the following pre-defined criteria: non-oral cancer focus (n = 18), lack of EGCG-specific intervention (n = 12), insufficient data on outcomes (n = 9), inadequate study design (n = 8), non-English and inaccessible full texts (n = 5). Therefore, the current systematic review covered a total of 13 studies [10, 22–34].

Fig. 1.

PRISMA flow chart of the included studies

One clinical study [30], seven cell line studies [10, 23–25, 28, 31, 32] and five studies [22, 26, 27, 29, 33] that utilized both in vitro and animal-based models were included in the review as summarized in Table 1. The research under evaluation employed multiple cell lines with cancer, such as HSC-3 in one study [29], SCC cell lines in four studies [22, 24, 25, 31], CAL-27 in three studies [22, 31, 32] and KB cell lines in one study [33]. Tu212 and Tu686 were utilized in two of the investigations [23, 26]. Five of the studies [10, 24, 27, 29, 32] that were reviewed utilized a single cell line, while the remaining investigations employed two or more cell lines. A total of three investigations were undertaken in the United States [23, 25, 26], three in China [22, 27, 31] and one each in Egypt [10], in Australia [28], in Romania [24], in Korea [33], in Japan [29], in Iran [30] and Taiwan [32]. Specifically, 9 studies assessed inhibition of cell proliferation [10, 22, 24, 25, 28, 29, 31–33], 8 studies reported induction of apoptosis [22, 24, 25, 29, 31–33], and 6 studies demonstrated reduced migration and invasion through downregulation of MsignificaMP-2/MMP-9 and other pathways [17, 22, 25, 31–33].

Table 1.

Summary characteristics of the reviewed studies

Author	Study design	Sample type	Sample size (total, I, C)	Intervention (I: type & dose)	Comparison (C: type & dose)	Outcomes (Evaluation method + I vs. C results)	Conclusion/limitations
Wei et al., 2022, China [22]	In-vitro + in-vivo	CAL-27, SCC9; K-Ras mice	Total: NR I: EGCG-treated C: untreated/vehicle	EGCG 0–250 µM	Untreated cells, vehicle	Proliferation (CCK-8): ↓ in I vs. C Apoptosis (Western blot, qRT-PCR): ↑ caspase activity Cell cycle: G1 arrest Therapeutic: Notch inhibition	EGCG suppressed tumor growth; Limitation: small sample size
Amin et al., 2021, USA [26]	In-vitro + in-vivo	Tu212, Tu686, xenograft mice	Total: NR I: EGCG + resveratrol C: untreated/vehicle	EGCG 30–80 µM + resveratrol 15–20 µL	Untreated/single agents	Cytotoxicity (Annexin V): ↑ apoptosis Proliferation: ↓ in I vs. C Cell cycle: mTOR pathway inhibition	Synergistic anticancer effect; Limitation: preclinical only
Abubakr et al., 2020, Egypt [10]	In-vitro	Hep2	Total: NR I: EGCG + metformin C: untreated/vehicle	EGCG 10 µL + Metformin (0–100 µg/ml)	Untreated cells	ROS (qRT-PCR, ELISA): ↓ Apoptosis (Caspase-3): ↑ Proliferation (MTT): ↓	Synergistic effect with metformin; Limitation: in vitro only
Chen et al., 2020, China [27]	In-vitro + in-vivo	KBV200; nude mice	Total: NR I: EGCG + vincristine C: untreated/vehicle	EGCG 80–320 mg/L + Vincristine 10–40 mg/kg	Vehicle, Vincristine alone	VEGF downregulation, reduced angiogenesis Apoptosis ↑, tumor growth ↓	EGCG enhances chemosensitivity; Limitation: animal data
Belobrov et al., 2019, Australia [28]	In-vitro	H400, H357	Total: NR I: EGCG-treated C: untreated	EGCG 10 µg/ml	Untreated cells	Proliferation (Western blot): ↓ Migration ↓ EGFR downregulation	Temporary inhibition of OC growth; Limitation: in vitro only
Yoshimura et al., 2019, Japan [29]	In-vitro + in-vivo	HSC-3; xenograft mice	Total: NR I: EGCG-treated C: untreated	EGCG 0–100 µM	Untreated cells	Proliferation ↓ Apoptosis (Caspase-3/-7): ↑ Cell cycle arrest	EGCG inhibited proliferation in vitro/in vivo; Limitation: single cell line
Rafieian et al., 2019, Iran [30]	Case-control clinical study	147 HNSCC cases, 263 controls	Total: 410 I: green tea consumers C: non-consumers	Habitual green tea consumption	No consumption	Risk reduction of HNSCC incidence	Green tea may lower cancer risk; Limitation: observational design
Li et al., 2018, China [31]	In-vitro	CAL-27, SCC15	Total: NR I: EGCG + Simvastatin C: untreated/vehicle	EGCG 80–200 µM + Simvastatin 0–20 µM	Untreated/single agents	Proliferation ↓ Migration ↓ Invasion ↓ Apoptosis ↑ (Hippo-tafazzin signaling)	Co-treatment enhanced apoptosis; Limitation: cell culture only
Yuan et al., 2017, Taiwan [32]	In-vitro	CAL-27	Total: NR I: EGCG + Cisplatin C: untreated/vehicle	EGCG (dose NR) + Cisplatin 10–100 µM	Untreated/Cisplatin alone	Apoptosis ↑ Autophagy ↑ AKT/STAT3 pathway modulation	EGCG overcame drug resistance; Limitation: in vitro only
Shin et al., 2016, Korea [33]	In-vitro + in-vivo	KB, FaDu; syngeneic mouse model	Total: NR I: EGCG + cycloheximide C: untreated	EGCG 30 µM + Cycloheximide 10 µM	Untreated cells	β-catenin signaling inhibition Proliferation ↓ Apoptosis ↑	EGCG suppressed β-catenin; Limitation: combined drug effect
Haque et al., 2015, USA [23]	In-vitro	Tu686, Tu212	Total: NR I: EGCG + Erlotinib C: untreated	EGCG 30 µM + Erlotinib 1 µM	Untreated/single agents	Apoptosis ↑ Bim-mediated regulation Proliferation ↓	Combination enhanced apoptosis; Limitation: cell-based only
Irimie et al., 2015, Romania [24]	In-vitro	SSC-4	Total: NR I: EGCG-treated C: untreated	EGCG 0–200 µM	Untreated cells	Apoptosis ↑ Autophagy ↑ Cell proliferation ↓	EGCG induced cell death via apoptosis/autophagy; Limitation: one cell line
Tao et al., 2014, USA [25]	In-vitro	SCC-25, SCC-9, HGF-1	Total: NR I: EGCG-treated C: untreated	EGCG 100 µM	Untreated cells	ROS modulation Proliferation ↓ Gene expression changes (Sirtuin 3)	EGCG showed distinct pro/antioxidant activity; Limitation: mechanistic only

EGCG dose and exposure

Most in vitro studies reported effective anticancer activity at 20–80 µM EGCG, with IC₅₀ values ranging from 20 to 60 µM across CAL-27, HSC-3, SCC9, and SCC15 lines under experimental conditions [22, 24, 25, 29, 31, 32].

Apoptosis: Significant increases in caspase-3/-7 activity (up to 65%) occurred at ≥ 40 µM, particularly with 48–72 h of exposure [29, 32].

In vivo: Doses of 50–100 mg/kg EGCG reduced tumor volume and improved survival in xenograft models [26, 27].

Mechanistic pathways

Cell Cycle and Apoptosis: EGCG induced G1 phase arrest [29], enhanced pro-apoptotic proteins Bax and cleaved caspase-3/-9, and inhibited multidrug resistance gene expression [32].

ROS Modulation: Selectively increased mitochondrial ROS in OSCC cells while protecting normal fibroblasts [25].

NF-κB/Epidermal growth factor receptor (EGFR) Mitogen activated protein kinase (MAPK) Suppression: Downregulated NF-κB, reduced anti-apoptotic genes (Bcl-2, Bcl-xL), and inhibited EGFR phosphorylation [23, 28].

Notch pathway inhibition: Suppressed Notch1 signaling, enhancing OSCC cell sensitivity to apoptosis in vitro and reducing tumor burden in vivo [22].

β-catenin regulation: Inhibited β-catenin expression and promoted its degradation, with effects influenced by p53 status [33].

Autophagy and drug resistance: Activated autophagy (Atg5, Beclin-1, LC3B-II) and overcame cisplatin resistance in chimeric antigen receptor (CAR) cells [32].

Combination therapy

EGCG + resveratrol: was reported to synergistically inhibit phosphorylated Akt (pAKT)/mammalian target of rapamycin (mTOR) and downstream signaling (pS6, p4EBP1), enhancing apoptosis [26].

EGCG + metformin: Activated AMP-activated protein kinase (AMPK) and suppressed mTOR, resulting in additive anticancer effects [10].

EGCG + erlotinib: Promoted Bim-mediated apoptosis in head and neck cancer cells [23].

Overall, EGCG was reported to exhibit dose-dependent anticancer effects, with concentrations ≥ 40 µM producing significant inhibition of proliferation, induction of apoptosis, and modulation of multiple pathways (ROS, NF-κB, Notch, β-catenin, and autophagy) [10, 22–34].

Quality assessment of the studies reviewed

After using the ROBINS-I technique to assess the RoB, it was found that the majority of the research reviewed had a moderate level of bias, except for one study [33] that had a low RoB. Several of these studies demonstrated a moderate RoB in the measurement of outcomes, as depicted in Fig. 2. Figure 3 illustrates the RoB across the investigations.

Fig. 2.

ROBINS-I tool for assessing the risk of bias within each of the reviewed studies

Fig. 3.

ROBINS-I tool for assessing the risk of bias across the reviewed studies

Discussion

OSCC comprises 90% of all cancers of the oral cavity and 38% of head and neck tumours. It is a type of cancer that arises from the cells lining the mouth and throat and is characterized by the detection of keratin or intercellular bridges [34] The specific mechanisms behind the various pharmacological impacts of EGCG entail several crucial enzymes and the transfer of signals. EGCG has been shown to have beneficial effects on cancer in animal and cell-based research, and various pathways have been postulated to explain these benefits.

An appealing mechanism is the ROS-mediated pathway, in which EGCG functions as potent antioxidant. EGCG can exhibit pro-oxidant properties under specific circumstances [35, 36]. The primary mechanism by which EGCG inhibits the formation of tumours is through its anti-angiogenesis activity. Experimental findings have confirmed that EGCG effectively suppresses the formation of blood vessels of the chick embryo chorioallantoic membrane at a dosage range of 80–320 mg/l [27]. EGCG can additionally hinder the release of vascular endothelial growth factor (VEGF) in cancerous cells, leading to inhibited tumour angiogenesis and restricted tumour expansion [37, 38]. The increased levels of the EGFR and its ligands, transforming growth factor-α are seen in 80% of squamous cell carcinoma of head and neck cases. Approximately 90% of cases are associated with a low risk of both disease recurrence and dissemination, as well as a poor general and cure rate [16–22]. EGFR stimulation triggers the phosphorylation and subsequent activation of phosphatidylinositol 3-kinase/Akt signaling. This, consequently, triggers NF-κB, resulting in the transcription of genes that regulate growth, apoptosis, angiogenesis, and invasion, as well as those accountable for chemo-resistance and radiation susceptibility [23]. The genes that are regulated by NF-κB comprise Bcl-2 and Bcl-xL [24, 25] cyclooxygenase 2 [26] and survival [39].

EGCG can limit the invasion of cancer cells by reversing the hypermethylation state of reversion-inducing cysteine rich protein with Kazal motifs (RECK) and reducing the expression of MMP-2 and MMP-9. EGCG has been scientifically recorded as a natural demethylating molecule. It shows potential as a viable therapeutic method for the management of OC, namely in the development of combined chemopreventive and chemotherapeutic strategies [40]. The role of EGCG in apoptotic or autophagy-induced cell death has gained more recognition in recent times [24, 41, 42]. Autophagy can alleviate nutritional and oxidative stress in tumour cells following a rapid proliferation of malignancy. Prolonged and excessive autophagy can result in cellular demise and a reduction in tumour size. Autophagy, which is intriguingly observed in cancer cells, can have either anti-survival or pro-survival benefits depending on the stimuli and nutrition [43]. Yuan et al. demonstrated that EGCG stimulated autophagy in CAR cells by increasing the gene expression levels of Atg5, Atg7, Atg12, Beclin-1, and LC3B-II. LC3 and p62 play crucial roles in the process of autophagy, where the cytoplasmic form of LC3 is transformed into the autophagosomal membrane form, resulting in a higher concentration of LC3B. Therefore, autophagy, or Type II programmed cell death, is crucial for controlling the onset and spread of cancer, in line with apoptosis, or Type I programmed cell death. This suggests that autophagy could serve as a useful therapeutic target for future anticancer investigations [32, 44].

A phase I clinical trial was conducted to assess the safety and efficacy of using EGCG (initially 440 µM/l, three times a day) mouthwash in combination with radiation therapy for the treatment of head and neck cancer. The administration followed a typical 3 plus 3 dose escalation strategy. Weekly evaluations were conducted to assess mucosal toxicity, mucositis-related discomfort, and patient satisfaction. The main objective of the study was to assess the safety of the green tea component, while the secondary objective was to evaluate its effectiveness in relieving mucositis symptoms. The highest acceptable dosage of the EGCG mouthwash was 2200 µM/l. The treatment of EGCG resulted in a substantial reduction in pain scores associated with mucositis over time. It is possible to add this catechin mouthwash to radiotherapy without causing any additional hazardous effects. The optimal dosage for the phase II study has been established at 1760 µM/l. Furthermore, the administration of EGCG resulted in a reduction of radiation-induced oral mucosal damage among patients [45].

The administration of EGCG successfully delayed the onset, reduced the dimensions, alleviated the abnormal growth of tumour formations, extended the lifespan of mice, and suppressed the activation of the Notch signalling system [22]. The Notch pathway is a highly evolved cellular signalling system that is crucial in multiple biological events, including cell survival, proliferation, differentiation, apoptosis, tissue patterning, cell fate determination, and morphogenesis. Notch signalling has established itself as an inducer of cancer growth in many types of malignancies. Over the past few years, there has been a significant development of multiple medications that primarily inhibit the Notch cascade. These drugs include γ-secretase inhibitors, interleukins, and different antibodies. The purpose of these drugs is to re-establish the natural equilibrium of biological processes [13].

EGCG exhibits a dual pro-oxidant/antioxidant profile that is central to its anticancer activity. While it scavenges free radicals and mitigates oxidative stress, it can also act as a pro-oxidant under specific conditions—such as high concentrations or within tumor cells—promoting ROS-mediated apoptosis [35, 36]. This context-dependent behavior, coupled with contradictory preclinical findings, highlights the complexity of its biological effects. Moreover, EGCG’s poor bioavailability, rapid metabolism, and systemic clearance limit its clinical potential [5], underscoring the need for advanced delivery systems [46], dose-response optimization, and long-term safety evaluations to facilitate its effective translation into OSCC therapy.

The present study’s strength lies in its comprehensive synthesis of in vitro, in vivo, and clinical evidence, supported by a systematic methodology that integrates molecular, pharmacological, and clinical perspectives on EGCG in OSCC. However, this review also has limitations. First, the majority of the included evidence is derived from in vitro and animal studies, which may not fully reflect the clinical complexity of OSCC. The effective EGCG concentrations reported in experimental models (20–80 µM) are often higher than physiologically achievable levels in humans due to its low oral bioavailability and rapid metabolism. Second, substantial heterogeneity exists across studies in terms of cell lines, dosing regimens, and outcome measures, which complicates direct comparisons. Third, although synergistic interactions with agents such as cisplatin, resveratrol, and metformin are encouraging, these observations are restricted to preclinical settings and lack clinical confirmation. Finally, the single available clinical trial was small, non-randomized, and primarily focused on safety and symptom relief rather than therapeutic efficacy. Collectively, these limitations highlight the need for standardized protocols and well-designed randomized controlled trials to validate EGCG’s translational potential.

Conclusion

EGCG exhibits promising anticancer effects in OSCC models by regulating oxidative stress, modulating NF-κB and MAPK signaling, influencing apoptotic and autophagy pathways, and suppressing angiogenesis and invasion. Preclinical studies consistently demonstrate dose-dependent inhibition of proliferation, induction of apoptosis, and enhanced efficacy when combined with conventional agents. However, these findings are largely limited to in vitro and animal studies, with only preliminary clinical data available. Critical barriers such as low bioavailability, rapid metabolism, variability in experimental designs, and the absence of robust randomized clinical trials restrict its immediate clinical applicability. Future investigations should prioritize well-designed clinical studies, standardized EGCG formulations, and advanced delivery systems to clarify its therapeutic potential. Until such evidence emerges, EGCG should be regarded as an experimental adjunct rather than a validated treatment option for oral cancer.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

S.R. and V.P.V. conceptualized the study. S.R., V.P.V., and A.P.F. were responsible for drafting the methodology. P.N.A., C.R., and D.K. collected and curated the data and performed the initial formal analysis. S.R., A.P.F., and C.R. prepared the original manuscript draft. P.N.A., C.R., M.B. made substantial intellectual contributions, including re-analysis of data, additional interpretation, and critical revisions, and D.K. contributed to the review and editing of the manuscript.

Funding

The authors did not receive any funding for the research work.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.