The human genome's sequencing revealed that over 50 % of its sequence consists of repetitive sequences that were once believed to be merely the results of genetic evolutionary forces but are now understood to have crucial roles in biology, including the regulation of chromatin structure, gene expression, DNA replication, and genomic organization. Repeating sequences can fold into alternative DNA structures other than the right-handed DNA double helix, or B-DNA form (Wang and Vasquez, 2014[184]). Most genomic DNA is structured in B-DNA, the most thermodynamically stable configuration. However, at least 15 non-canonical DNA configurations have been described, and up to 13 % of the human genome may be organized into these alternative structures (Guiblet et al., 2018[63]). G4 quadruplexes (G4s) belong to these non-canonical structures which are formed in a dynamic process depending on the cellular context (Marshall et al., 2020[106]). G4 quadruplexes are DNA and RNA secondary structures formed by self-association of guanine bases forming stacked G-tetrads that are stabilized by Hoogsteen hydrogen bonding and connected by stretches of nucleotides, or loops, that vary in length and composition (Varshney et al., 2020[182]). Recent scientific interest in G4s has increased due to their importance in biological processes such as DNA replication, gene expression, telomere maintenance, and cell death (Bochman et al., 2012[19]; Awadasseid et al., 2021[8]). Epigenetic modifications are reversible alterations of nucleic acids that do not change their chromosomal DNA sequence, and are connected to many disorders, including cancer (Esteller, 2008[50]). Thus, chemical agents that revert aberrant epigenetic alterations are potentially promising therapeutic tools. These compounds have been called epigenetic drugs or “epidrugs” (Montalvo-Casimiro et al., 2020[116]). G4 structures are connected to several epigenetic mechanisms and have been identified as structural targets of small aromatic compounds or ligands (Mukherjee et al., 2019[118]). In fact, many G4 binding ligands with the ability to regulate gene expression have been obtained from natural sources (Sengupta et al., 2019[155]). These G4 stabilizing agents have been shown to drastically reduce oncogene expression levels both in vitro and in vivo (Awadasseid et al., 2021[8]). Therefore, G4 ligands ought to be considered in the future development of therapeutic interventions, especially in cancer treatment. Dietary polyphenols are widely recognized for their numerous beneficial effects on human health (Tsao, 2010[177]). Polyphenols regulate epigenetic pathways and have potent anti-cancer activities by modulating genes involved in cell transformation, tumor growth, angiogenesis, and metastasis (Cháirez-Ramírez et al., 2021[25]). These aromatic compounds chemically interact with and stabilize G4 quadruplexes; therefore, understanding the relationship between dietary polyphenols and G4s can further expand the molecular mechanisms by which polyphenols exert their anti-cancer effects (Bag et al., 2023[9]). In this review, we will discuss novel key regulatory elements of the genome, G4 quadruplexes, their role in cancer biology, gene expression control, and the interaction of different dietary polyphenols with these structures. This will highlight the importance of studying polyphenols as novel stabilizing ligands of G4 quadruplexes from an epigenetic perspective. We emphasize on chemical nature, composition, and regulatory functions of polyphenols and their derivatives to promote G4 quadruplex-targeted anti-cancer drug development.

Cancer is a large group of diseases characterized by uncontrolled cell proliferation, driven by transformed cells that undergo evolution through natural selection (Brown et al., 2023[21]). The prevalence of cancer as a fatal disease is evident in its annual global mortality rate of 10 million individuals with a worldwide economic burden surpassing 1 trillion dollars annually. For cancer to initiate, an extended number of cell divisions, an accumulation of oncogenic genetic and epigenetic mutations, and a permissive tissue environment unable to prevent the division and persistence of increasingly abnormal cells are required (Brown et al., 2023[21]). The genetic and epigenetic changes that occur in cancer have been described as Hanahan and Weinberg's "Hallmarks of Cancer" (Hanahan, 2022[66]). These hallmarks include sustaining proliferation, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, activation of invasion and metastasis, deregulation of cellular energetics, evasion of immune destruction and genomic instability (Hanahan, 2022[66]). Cancer is largely driven by the accumulation of genetic abnormalities and genomic instability. G4s, through their potential impact on genomic stability, may play a role in promoting cancer development (Richl et al., 2024[143]). As tumors progress, the intracellular chemical conditions are considerably altered. Indeed, tumors possess different dielectric properties in comparison to normal cells. Such changes can be recognized in aggressive cancer cells, which have been found to overexpress potassium channels. Changes in intracellular K+ ion concentration heavily affect G4 quadruplex stabilities, which in turn can modulate gene expression during tumor progression (Tateishi-Karimata et al., 2018[170]). Due to their prevalence in many cancer-related genes, G4 structures have become attractive targets for cancer therapy (Figueiredo et al., 2023[53]). Notably, there is a global enrichment of G4s in tumors compared to non-cancerous tissues. This increased prevalence of G4 structures may contribute to the activation of transcriptional programs that promote cell proliferation during cancer development. Importantly, cancer cells do not remain epigenetically static, but rather undergo continuous evolution, resulting in dynamic changes in gene expression, as well as modifications in DNA structures like G4s. This epigenetic plasticity in cancer results in the development of drug resistance, which is lethal for patients (Robinson et al., 2025[145]).

Epigenetics, reversible chemical modifications of DNA, RNA and histone proteins, regulate chromatin functions without changing the DNA sequence and allow an organism to develop and adapt to environmental changes (Montalvo-Casimiro et al., 2020[116]). Gene expression changes depending on cellular phenotype or function in response to different stimuli, such as developmental stages, cellular differentiation, or tissue-specific cell lineages. Epigenetics create a regulatory complex layer that links genomic sequences to actionable mutations highlighting the importance of this regulatory system and revealing that epigenetic alterations are some of the main mechanisms underlying many human diseases, such as cancer, which arises from aberrant genetic and epigenetic alterations, which play a key role in malignant transformation, tumor progression, and prognosis. Thus, epigenetics' complex mechanisms and their significance in disease development must be understood for cancer treatment (Montalvo-Casimiro et al., 2020[116]). The epigenetic machinery consists primarily of three interrelated components that operate together in the organization of chromatin and gene expression at the molecular level. These components include DNA methylation, histone post-translational modifications, and regulatory non-coding RNAs (ncRNAs) (Roberti et al., 2019[144]; Zhang et al., 2024[198]). The different patterns of histones and DNA chemical modifications form “the epigenetic code”-a complex interaction of epigenetic components with positive and negative feedback mechanisms that control gene expression (Reina and Cavalieri, 2020[141]). G4s definitively fall into these criteria, as distinctive genomic regions that dynamically adopt interconverting structural conformations that can affect gene expression favorably or negatively, causing transcriptomic alterations due to their genomic localization (Reina and Cavalieri, 2020[141]). G4 quadruplex structures and DNA epigenetic alterations often coexist, establishing a connection between G4s and epigenetic processes which have been observed to be dysregulated in cancer (Montalvo-Casimiro et al., 2020[116]).

G4 quadruplexes exist in living cells and play a critical role in controlling gene expression and other processes making these structures novel targets for drug design (Tian et al., 2018[175]). The development of ligands that are capable of binding and stabilizing G4 structures may not only facilitate the characterization of these structures in vivo but also contribute to the development of new therapeutic and diagnostic strategies (Summers et al., 2021[165]). Many G4 ligands interact in a relatively indiscriminate manner, recognizing G4s of diverse topologies, thereby demonstrating their potential as multi-targeting agents (Figueiredo et al., 2024[54]). These molecules influence cancer cell growth by interacting with G4s and their effects include interference with telomere function, stabilization of G4 in the promoters of oncogenes, post-translational gene regulation by targeting mRNA 5′-untranslated regions, impeding helicase unwinding, induction of genomic instability, and the modulation of the epigenetic machinery to control gene expression. G4 polymorphism provides the opportunity to search and develop compounds that can identify a single G4 topology (Figueiredo et al., 2024[54]). Telomerase is a reverse transcriptase that adds repeated segments to the 3'-end of telomeric DNA and is abundantly expressed in most cancers (Hanahan, 2022[66]). In fact, the initial motivation behind the creation of these innovative therapeutic approaches was the notion that these molecules would bind to telomeric ends and form persistent, liganded G4 structures preventing telomeric ends from being accessed by telomerase for extension (Sun et al., 1997[166]). Nevertheless, studies revealed rapid antitumoral effects that were not consistent with telomerase suppression, which typically requires a prolonged period and multiple cell divisions before inducing cell death (Iachettini et al., 2024[74]). Thus, the antitumoral potential of G4 ligands was further expanded to include G4s found in gene promoters. Ever since, numerous G4-targeted ligands have been identified that can regulate the activity of genes containing a sequence capable of generating a G4 structure in their promoters (Kim, 2019[86]). Stabilized G4s located in promoter regions could impede the movement of RNA polymerases, thus preventing gene transcription, or serve as sites for the recruitment of transcription factors, thereby facilitating gene transcription (Kim, 2019[86]). Currently, there have been limited research investigations that have examined alterations in gene expression on a comprehensive scale across the entire genome (Marchetti et al., 2009[105]). This could be achieved by utilizing techniques that allow the comprehensive identification of ligand binding sites in the natural chromatin environment (Spiegel et al., 2020[162]). Currently, the G-Quadruplex Ligands Database (http://www.g4ldb.com) has over 3200 compounds that specifically target G4 structures (Wang et al., 2022[188]). Targeting G-quadruplex DNA poses a significant scientific challenge due to its great polymorphism and relatively low abundance compared to canonical duplex DNA. G4 quadruplex-stabilization involves π-π stacking and electrostatic interactions, which leads to the binding of a ligand to the G-quartet found on the outer surface of the quadruplex (Hud and Plavec, 2006[72]). In contrast, both the groove and the backbone phosphates can interact with G4 ligands without the need for a flat aromatic structure. Hence, molecules that exhibit decreased planarity and establish interactions with the grooves and/or backbone phosphates may be advantageous for selectively targeting G4s.

The primary challenge in designing compounds that specifically interact with G4 DNA is to create big, planar aromatic structures that can effectively stack with a G quartet platform, while still maintaining sufficient solubility in water. They must display both hydrophobic and hydrophilic properties (Monchaud and Teulade-Fichou, 2008[112]). One way to achieve this duality is by including protonable sidearms, such as amine groups, surrounding the aromatic core that make the molecule water-soluble, with the charges located far from the hydrophobic center (Sun et al., 1997[166]). G4 ligands have a higher aromatic ring count, positive charges, and number of hydrogen bond donors than what would be considered optimal for favorable pharmacokinetic qualities (Spiegel et al., 2020[162]). In fact, no G4 ligand has progressed past Phase II trials due to low pharmacological qualities (Santos et al., 2021[152]). Thus far, the only ligand that has progressed to this stage is the fluoroquinolone derivative, quarfloxin (CX-3543) which specifically binds to G4s found in ribosomal DNA and interferes with the binding of nucleolin (Drygin et al., 2009[44]). CX-5461 is another G4 ligand that is now undergoing advanced phase I clinical studies for patients with BRCA1/2 defective malignancies (Xu et al., 2017[193]). Nevertheless, some G4 ligands have demonstrated their effectiveness in human cancer tumor xenografts (Marchetti et al., 2009[105]). Performing structure-activity relationship studies on G4 ligands, focusing on physicochemical qualities such as planarity, polarity, lipophilicity, and rotatable bonds, would allow for achieving balance between G4 binding, solubility, and permeability (Spiegel et al., 2020[162]). The main challenge is to balance selectivity and affinity, even if multiple or genome wide G4 targeting strategies might work (Santos et al., 2021[152]). The small molecule BRACO-19 has been found to downregulate the expression of hTERT, leading to the inhibition of telomerase activity and resulting in the shortening of telomere length (Burger et al., 2005[23]). Additionally, the cationic porphyrin TMPyP4 has been shown to downregulate the expression of c-Myc, an oncogene that is over-expressed in many tumor cells (Thumpati et al., 2025[173]). Studies into the structure of G4 complexes with natural macrocyclic molecules, such as telomestatin and its derivatives, which completely cover the outer G4 quartet in the telomeric G4, revealed significant p-stacking and electrostatic interactions (Wang et al., 2024[186]). Indeed, large macrocyclic molecules often exhibit strong attraction to most G4 DNA configurations, making it difficult to selectively bind to a single G4. Contrary to macrocyclic molecules, small crescent-shaped G4 ligands can stack over the outer G-tetrad by recruiting neighboring residues and forming significant π-π and electrostatic interactions (Wang et al., 2024[186]). The primary obstacle in the pursuit of developing drugs that target G4 structures is achieving G4 selectivity. G4 quadruplexes share a compacted G quartet core surrounded by multiple loops. Consequently, these compounds face challenges in differentiating between various G4 structures, particularly those with similar topologies (Wang et al., 2024[186]). The lack of selectivity of G4 ligands, which are both found in normal and malignant cells, is the main obstacle in the clinical implementation of these compounds as anticancer treatments (Iachettini et al., 2024[74]). Conducting structure-activity relationship studies could greatly enhance the physicochemical properties of ligands and facilitate the process of ligand design and development to achieve specificity and selectivity while maintaining high affinity (Asamitsu et al., 2019[5]).

The polyphenols´ structure comprises multiple hydroxyl groups (-OH) attached to a carbon atom within an aromatic ring, allowing to combine with various functional groups to form esters, ethers, and carbon-carbon bonds, leading to a vast number of different structural arrangements (Liu et al., 2024[101]), including phenolic acids (hydroxybenzoic and hydroxycinnamic acids), stilbenes, lignans, flavonoids (flavanols, isoflavones, anthocyanins, flavanones, flavones, and flavonols), and tannins (condensed and hydrolyzable). More than 50,000 identified polyphenols (Tsao, 2010[177]) and ~8000 compounds have been found and characterized in food and medicinal plants (flavonoids represent ~75 % of total polyphenols in dietary sources). Cancer is influenced by complex physiological and environmental factors, with diet playing a crucial role. Western diets (high in unhealthy fats and refined carbohydrates) are associated with an increased cancer risk. In contrast, diets rich in fruits and vegetables (~1,193 ± 510 mg/day polyphenols intake) have been linked to cancer prevention (Li et al., 2023[96]; Adolph and Tilg, 2024[1]). Polyphenols exert their protective effects through various mechanisms, including epigenetic modulation, which has gained significant attention for its potential in cancer prevention (Silva et al., 2019[159]). Despite the increase in cancer cure rate in recent times (~67 % in adults), the use of synthetic drugs faces significant challenges, including financial burdens and potential side effects in patients, which can affect life quality or even lead to death (van den Boogaard et al., 2022[181]). Numerous studies have suggested that polyphenols are linked to a lower risk of cancer with fewer side effects (Sharma et al., 2022[156]).

Polyphenols have been related to multiple anticancer benefits such as tumor growth reduction, fewer side effects, and efficacy enhancement of therapies like chemotherapy and radiation. However, to date, their full potential has not been fully explored. Polyphenols are increasingly being recognized as an alternative for concomitant therapies and as chemosensitizers because of their diversity and accessibility, with higher biocompatibility and lower systemic toxicity when used in moderate doses (Duda-Chodak and Tarko, 2023[48]; Jakobušić Brala et al., 2023[76]). A promising objective is to incorporate them into current cancer therapies, as they enhance the sensitivity of cancer cells. G4-quadruplexes (G4s) promote recombination events and mutations essential for cancer progression. Polyphenols can inhibit transcription and telomere elongation in cancerous cells, making them crucial targets for research focused on therapeutic applications. Investigating the binding properties of naturally occurring compounds that interact with G4s, like dietary polyphenols, is highly beneficial for drug discovery, particularly regarding their selectivity for polymorphic G4 configurations (Bag et al., 2023[9]). When compared to most G4 ligands, polyphenols have fewer aromatic cores, and their configuration (phenolic rings connected through a styrene double bond and many -OH groups) promotes hydrogen bonding with G4 loops and grooves instead of stacking, as demonstrated in laboratory studies and simulations (Platella et al., 2020[134]). This interaction with G4 grooves and loops could increase selectivity and lower toxicity in vivo compared to stacker ligands (Platella et al., 2020[134]) (Figure 5(Fig. 5)). Polyphenols are also well-suited for further modification to enhance targeting via chemical analysis and the custom design of G4 ligands (Ye et al., 2024[195]). Polyphenols must penetrate the cellular membrane to reach the nucleus and bind with promoter G4 quadruplexes to modulate gene expression. Complexation assays have demonstrated nuclear fluorescence of four flavonoids-azaleatin, quercetin, fisetin, and morin-in neuroblastoma cells, suggesting effective cellular uptake (De et al., 2022[39]). Curcumin exhibited strong nuclear fluorescence in SF-767 glioma cells (Ghosh and Ryan, 2014[60]) while galangin and kaempferol displayed higher nuclear autofluorescence in mouse hepatocellular carcinoma Hepa-1c1c7 cells (Mukai et al., 2009[117]). Quercetin accumulates in the nucleus and mitochondria of HepG2 cells through an active mechanism independent of nuclear pore transport, thereby affecting transcription (Notas et al., 2012[122]). Curcumin, extracted from the rhizome of Curcuma longa, is a prominent polyphenol with notable G-quadruplex (G4) binding capabilities, as demonstrated in Table 2(Tab. 2) (References in Table 2: AL Zahrani et al., 2020[3]; Anand David et al., 2016[4]; Ashrafizadeh et al., 2020[7]; Bag et al., 2023[9]; Bai et al., 2013[11], 2021[10]; Balaga et al., 2023[12]; Bhattacharjee et al., 2016[16], 2017[17], 2018[15]; Calderon-Montano et al., 2011[24]; Chen et al., 2021[29]; Dabeek and Marra, 2019[36]; De et al., 2022[39]; Delmas et al., 2011[41]; Du et al., 2013[46]; Dwivedi et al., 2021[49]; Franceschin et al., 2014[55]; Franciosoa et al., 2014[56]; Garcia-Canton et al., 2012[58]; Ghosh and Ryan, 2014[60]; Goh et al., 2022[61]; Imran et al., 2021[75]; Jakobušić Brala et al., 2023[76]; Jha et al., 2016[79]; Khojasteh et al., 2014[84]; Kong et al., 2021[89]; Krasieva et al., 2015[91]; Lakhanpal and Rai, 2007[93]; Mikutis et al., 2013[110]; Mondal et al., 2016[114]; Mukai et al., 2009[117]; Neveu et al., 2010[121]; Notas et al., 2012[122]; Obeng et al., 2020[123]; Pandya et al., 2021[127]; Pattanayak et al., 2016[129]; Paul et al., 2019[131]; Platella et al., 2021[134]; Rajput et al., 2021[137]; Ribaudo et al., 2022[142]; Rocca et al., 2024[146]; Roy et al., 2022[147], 2023[148]; Sanchez-Martin et al., 2022[151]; Sarao et al., 2021[153]; Shen et al., 2022[158]; Soriano-Lerma et al., 2024[161]; Stężycka and Frańska, 2023[164]; Sun et al., 2006[167], 2007[168]; Tawani and Kumar, 2015[171]; Tawani et al., 2017[172]; Tian and Liu, 2020[174]; Touil et al., 2011[176]; Tyagi et al., 2020[179]; Wang et al., 2015[185]; Wright et al., 2013[191]; Zenkov et al., 2022[197]; Zhang et al., 2009[199]; Zhao et al., 2023[200]). Studies have demonstrated its ability to stabilize G4 structures in the promoters of KRAS and c-Myc, leading to a reduction in oncogene expression and promoting cytotoxicity in metastatic breast cancer cells. At the same time, synthetic derivatives such as Cur-4 and dimethylcurcumin enhance these effects by increasing binding affinity and targeting mechanisms, promoting the degradation of the androgen receptor in prostate cancer (Jha et al., 2016[79]; Pattanayak et al., 2016[129]; Dwivedi et al., 2021[49]; Pandya et al., 2021[127]; Roy et al., 2022[147]). Quercetin, a flavonoid present in citrus fruits, onions, and several other foods, can decrease c-Myc expression by as much as 50 % in cancer cell lines, while rutin, the glycosylated form of quercetin, enhances the stability of the G4-polyphenol complex, offering an additional benefit (Sun et al., 2006[167]; Lakhanpal and Rai, 2007[93]; Tawani and Kumar, 2015[171]; Anand David et al., 2016[4]; Bhattacharjee et al., 2017[17]; Tawani et al., 2017[172]; Tyagi et al., 2020[179]; Zenkov et al., 2022[197]; Bag et al., 2023[9]). Indeed, rutin, which is derived from Styphnolobium japonicum, exhibits selective binding to c-Myc and telomeric G4s (see Table 2(Tab. 2)) (Sun et al., 2007[168]; Ribaudo et al., 2022[142]; Stężycka and Frańska, 2023[164]). Likewise, kaempferol, which is abundant in green leafy vegetables and herbs, is more effective than its isomer morin, present in mulberries, figs, and other plants, in stabilizing c-Myc and VEGF G4s, achieving reductions in c-Myc expression of up to 77 % in malignant cells, due to their differing molecular structures (Calderon-Montano et al., 2011[24]; Bhattacharjee et al., 2018[15]; Dabeek and Marra, 2019[36]; Paul et al., 2019[131]; Rajput et al., 2021[137]; Zenkov et al., 2022[197]; Balaga et al., 2023[12]). Resveratrol, derived from grapes and red wine, along with its derivatives, polydatin and viniferin, engage with c-Myc and telomeric G4s, demonstrating effects that hinder the proliferation of melanoma cells, with the dimeric form of viniferin exhibiting a greater G4 affinity (see Table 2(Tab. 2)) (Tian and Liu, 2020[174]; Platella et al., 2021[134]). In contrast, naringenin, commonly found in citrus fruits, tends to bind to duplex DNA over G4, whereas fisetin, which is found in strawberries and nuts, prefers G4 binding, highlighting how structural differences affect their interactions (Touil et al., 2011[176]; Bhattacharjee et al., 2016[16]). A wider range of polyphenols-including rosmarinic acid from rosemary, luteolin from celery, genistein and daidzein from legumes, gallic acid from tea and fruits, myricetin from berries, EGCG from green tea, and xanthones from tricyclic structures-also interact with G4s, often reducing oncogene activity or hindering tumor growth, as indicated in Table 2(Tab. 2) (Zhang et al., 2009[199]; Mikutis et al., 2013[110]; Franceschin et al., 2014[55]; Tawani and Kumar, 2015[171]; Mondal et al., 2016[114]; Dwivedi et al., 2021[49]; Sanchez-Martin et al., 2022[151]).

In summary, these polyphenolic compounds exemplify the diverse therapeutic possibilities of polyphenols derived from natural sources. Considering the significant evidence of their G4-mediated actions, polyphenols offer a compelling chance to utilize these readily available plant compounds for cancer therapy. However, challenges remain in enhancing their specificity, stability, and practical application in clinical environments, necessitating additional research to fully realize their potential as effective therapeutic agents.

Natural products and their related drugs compose approximately 35 % of the worldwide pharmaceutical industry, with 85 % of the global population depending on traditional medicine and 60 % of drugs in developed countries being natural or derived from natural sources (Mathur and Hoskins, 2017[107]; Najmi et al., 2022[119]; Nasim et al., 2022[120]). Despite promising bioactivities reported for polyphenols, they require safety and efficacy evaluations to minimize possible toxicity. Detailed preclinical and clinical research, including those listed on ClinicalTrials.gov, examining their safety, bioavailability, and effectiveness in preventing and treating cancer is presented in Table 3(Tab. 3). Curcumin has been shown to be safe and exhibit modest effects in colorectal cancer (Kanai et al., 2011[82]). Nevertheless, a Phase II trial on endometrial carcinoma did not reveal significant anti-inflammatory or immunomodulatory effects, although there was a noted improvement in quality of life (Tuyaerts et al., 2019[178]). The results concerning resveratrol in prostate cancer are mixed: one study suggested it delayed recurrence by extending the prostate-specific antigen (PSA) doubling time by 5.3 months (Paller et al., 2015[124]), while another study found no effect on prostate volume or PSA levels, raising doubts about its efficacy (Kjær et al., 2015[88]). The instability of polyphenols in various physiological conditions and the interindividual variability-arising from variations in metabolism, absorption, and interactions with dietary constituents-make their application and use complex. Only 5-10 % of the polyphenols consumed are absorbed in the small intestine; the remainder is metabolized by gut microbiota in the large intestine into more easily absorbable low-molecular-weight compounds that then undergo phase I and II metabolism (Farhan, 2023[51]; Li et al., 2023[96]). Nanotechnology can potentially enhance polyphenols' therapeutic effects by improving bioavailability and facilitating targeted delivery (Kim et al., 2023[85]). Nonetheless, polyphenols might interfere with drug metabolism by inhibiting cytochrome P450 enzymes and interacting with transporters like P-glycoprotein, which could lead to adverse effects (Duda-Chodak and Tarko, 2023[48]). Unlike epidrugs such as DNMT inhibitors (like 5-azacytidine) and HDAC inhibitors (such as vorinostat), which reliably reverse epigenetic alterations (Umehara, 2022[180]), the multitarget nature of polyphenols enables them to influence various pathways, potentially reducing resistance and toxicity when combined with chemotherapy (Herranz-López et al., 2018[69]). These complex factors are challenging for drug screening yet simultaneously provide prospects for synergistic effects in combination therapies. While there are challenges concerning stability, absorption, and drug interactions, the potential of polyphenols to affect various pathways, particularly in epigenetic regulation, presents a hopeful opportunity for innovation. As clinical trials progress, the transition from conventional remedies to effective treatments appears very encouraging, with polyphenols poised to be integral in the future of cancer treatment.

G-quadruplexes (G4s) are attractive targets in anticancer drug design. The presence of G4 structures in oncogenic promoters and telomeres indicates their potential role in regulating gene expression, making them critical in cancer biology. G4s structures play a crucial role in epigenetic regulatory mechanisms, influencing DNA methylation, histone modifications, and nuclear architecture. Their dysregulation is directly linked to various diseases, particularly cancer, where they drive gene expression changes that facilitate malignant transformation. The study of G4s deepens our understanding of gene regulation complexity and unveils new potential targets for therapeutic intervention, especially in cancer treatment. Natural products such as dietary polyphenols and their derivatives are invaluable resources for finding and developing new drugs. They could lead to safer anticancer medicines with strong selectivity for G-quadruplexes over duplex DNA, potentially leading to lower toxicity in vivo and minimizing side effects associated with traditional treatments. Polyphenols have significant potential as anticancer agents due to their ability to regulate epigenetic pathways and modulate gene expression involved in cancer progression; therefore, they could be developed into effective therapeutic interventions for cancer treatment. Although there is limited research on regulating G4s by polyphenols through an epigenetic mechanism, ample evidence shows that polyphenols regulate the epigenetic machinery. For example, it has been reported that compounds such as Curcumin, resveratrol, EGCG, quercetin, genistein, and kaempferol can regulate distinct epigenetic mechanisms, including DNMTs and HDAC enzymes. This can lead to the reactivation of tumor suppressor genes silenced by hypermethylation. Notably, studies have demonstrated that resveratrol can increase TERRA transcript expression and telomeric heterochromatin markers (H3K27me3 and H4K20me3), decreasing the proliferation of multiple myeloma cells. However, more studies are needed to fully harness polyphenols' therapeutic potential and better understand the molecular mechanisms by which they interact with G4 structures and their overall impact on cancer biology. Meanwhile, promoting a diet rich in polyphenols as a healthy eating habit may be linked to a lower cancer risk, highlighting the importance of dietary choices in cancer prevention strategies.