Cancer chemoprevention involves dietary components and natural agents that inhibit the transformation of normal cells into malignant ones (2). Herbs, spices, and plant-based products have long been used in disease prevention (1). Wattenberg classified chemopreventive agents into two categories: blocking agents and suppressing agents (8). The blocking agents prevent carcinogens from binding to DNA, proteins, or RNA. Suppressing agents inhibit the progression of initiated cells into malignant forms. Examples of suppressing agents include β-carotene, curcumin, genistein, and resveratrol (1). These categories remain relevant, particularly for early carcinogenic events where low-toxicity agents can modulate multiple pathways.

Phytochemicals with chemopreventive properties interfere with the multistep process of carcinogenesis. These compounds act during the initiation and promotion stages and can slow or halt the progression of precancerous cells into malignant tumors (43). Figure 3 depicts how natural agents intervene in carcinogenesis, blocking initiation, promotion, and progression to prevent or reverse tumor development (43). These effects occur at physiologically achievable concentrations, typically lower than those used in therapeutic models, highlighting the distinction between preventive and cytotoxic mechanisms.

Chemoprevention by different types of chemopreventive agents

Curcumin, a turmeric-derived polyphenol, modulates NF-κB, COX-2, and PI3K/AKT pathways, reducing inflammation, oxidative stress, and tumor growth (9, 44). Resveratrol, found in grapes and red wine, activates p53 and SIRT1 to induce apoptosis and suppress tumor progression (10). Epigallocatechin gallate (EGCG), a green tea polyphenol, inhibits the PI3K/AKT/mTOR pathway, reducing cancer cell survival (30). Luteolin, a flavonoid in vegetables and fruits, targets the JAK/STAT pathway, suppressing cancer cell growth and immune evasion (26). These mechanisms reflect classical chemopreventive actions, including enhancement of DNA repair, reduction of inflammation, and restoration of tumor-suppressive signaling, rather than induction of high-dose cytotoxicity.

Genistein, a soy isoflavone, modulates tumor suppressor genes and inhibits angiogenesis (29). Quercetin, abundant in apples and onions, induces apoptosis by activating caspase-3 and inhibiting NF-κB (34). Sulforaphane, from cruciferous vegetables, enhances detoxification enzymes and inhibits histone deacetylases (35). Thymoquinone, from black seed oil, induces DNA damage and apoptosis through telomere shortening and oxidative stress (33). Paclitaxel, from the Pacific yew tree, stabilizes microtubules, causing cell cycle arrest and apoptosis (36). Paclitaxel is primarily a therapeutic agent rather than a chemopreventive compound; its inclusion reflects mechanistic diversity rather than preventive relevance. Recent reviews confirm that these compounds act through complementary mechanisms, including apoptosis induction, anti-inflammatory activity, angiogenesis inhibition, detoxification, and microtubule stabilization (41, 45, 46).

An effective chemopreventive agent should meet several criteria, including low toxicity and efficacy at low doses. Despite their potential, many natural chemopreventive agents face limitations such as poor bioavailability, rapid metabolism, and lack of specificity (14, 15). Nanotechnology offers solutions. Nanomaterials, liposomes, polymeric nanoparticles, and albumin-bound carriers improve delivery, stability, solubility, and tumor-specific targeting (16, 39). The integration of nanotechnology with natural products represents a strategy for cancer prevention that may lead to safer, more effective interventions. Nano-enabled delivery is particularly relevant for chemoprevention because it enhances local tissue exposure at early lesion sites, improves intracellular uptake at low doses, and enables sustained modulation of preventive pathways such as NF-κB, PI3K/AKT/mTOR, and p53.

Disease prevention is especially important for conditions that are incurable or difficult to treat, such as cancer. The high cost, severe side effects, and complexity of conventional therapies highlight the need for preventive strategies. Cancer often affects multiple organs and may cause secondary complications, which further emphasize the value of early intervention (6, 7). Cancer chemoprevention refers to the use of natural or synthetic agents to inhibit, delay, or reverse carcinogenesis (8). The multistep nature of cancer, which may take years to progress from initiation to malignancy, provides a critical window for preventive intervention. Dietary and lifestyle factors strongly influence cancer risk. Epidemiological studies show that diets rich in vegetables, fruits, whole grains, and fiber, combined with regular physical activity, reduce the risk of several cancer types (4).

Natural compounds such as curcumin, EGCG, luteolin, genistein, resveratrol, paclitaxel, quercetin, sulforaphane, and thymoquinone have been extensively studied for their chemopreventive potential. These agents exhibit anti-inflammatory, antioxidant, and pro-apoptotic properties, and they modulate key signaling pathways involved in cancer development (9, 10, 12, 26). Some have advanced to clinical trials, demonstrating translational relevance (50,51,52). Despite this promise, many natural chemopreventive agents face limitations of poor solubility, low bioavailability, and non-specific distribution (14). These limitations hinder clinical effectiveness. Nanotechnology-based delivery systems address these issues. Liposomes, polymeric nanoparticles, and albumin-bound systems improve pharmacokinetic and pharmacodynamic profiles (16, 39). The integration of nanotechnology with natural products represents a strategy for cancer prevention that may reduce cancer incidence and improve public health outcomes (42, 48, 49). Nano-enabled systems are relevant for chemoprevention because they enhance local tissue exposure at early lesion sites, improve intracellular uptake at low doses, and sustain pathway modulation over longer periods than free compounds.

The discovery of oncogenes such as MYC, RAS, BRAF, and KIT, along with tumor suppressors TP53, BRCA1, and PTEN, has transformed understanding of cancer biology (3). Dysregulation of intracellular signaling pathways is a hallmark of cancer, driving uncontrolled proliferation, resistance to apoptosis, angiogenesis, and metastasis (23). Figure 4 illustrates the inhibitory effects of natural compounds, including curcumin, EGCG, luteolin, genistein, resveratrol, paclitaxel, quercetin, sulforaphane, and thymoquinone, on major cancer-related signaling pathways such as PI3K/AKT/mTOR, Ras/MAPK, Wnt/β-catenin, JAK/STAT, NF-κB, Hedgehog, Hippo, and cancer stem cell-associated signaling (9, 10, 30, 41, 45). Figure 4 also shows the nanoparticle-mediated delivery steps involving mechanistic pathways with nano-enabled chemoprevention.

Inhibitory effects of selected compounds on major cancer-related signaling pathways

The PI3K/AKT/mTOR pathway, frequently altered in breast, prostate, and thyroid cancers, regulates cell growth, proliferation, and survival. Mutations in PI3K, AKT, or PTEN often drive its activation (28). Natural compounds such as curcumin and resveratrol inhibit this pathway, offering chemopreventive benefits (28). Genistein also inhibits this pathway, suggesting a preventive role (29). The Ras/MAPK pathway, critical for cell proliferation and differentiation, is commonly mutated in melanoma, colorectal, and thyroid cancers (24). Genistein inhibits this pathway, supporting its potential in prevention (29). Natural products can suppress two of the most frequently dysregulated growth pathways in cancer.

The Wnt/β-catenin pathway, essential for cell proliferation and stem cell maintenance, is often dysregulated in colon, liver, and breast cancers. Sulforaphane and quercetin inhibit this pathway (34, 35). The JAK/STAT pathway, which is involved in cell growth, survival, and immune response, is frequently dysregulated in leukemia, breast cancer, and head and neck cancers (26). Curcumin and genistein inhibit this pathway. These compounds converge on Wnt and JAK/STAT signaling, reducing proliferation and immune evasion (9, 29).

The NF-κB pathway regulates inflammation, immune response, and cell survival, and its activation promotes tumor proliferation, angiogenesis, and resistance to apoptosis. The Hedgehog pathway, critical for embryonic development and stem cell maintenance, is dysregulated in breast, gastric, and pancreatic cancers (53). Sulforaphane inhibits this pathway, showing promise in cancer prevention (35). The Hippo pathway, which regulates organ size, proliferation, and apoptosis, is frequently altered in breast, colorectal, and liver cancers (31). Curcumin and resveratrol modulate this pathway (9, 10). Natural products act on NF-κB, Hedgehog, and Hippo signaling to reduce tumor growth and survival (42, 49). These effects represent chemopreventive mechanisms that operate at low, non-cytotoxic concentrations, distinguishing them from therapeutic agents that rely on high-dose cytotoxicity.

Cancer stem cells (CSCs), identified in acute myeloid leukemia, breast, colon, and liver cancers, drive tumor growth, recurrence, and therapy resistance (54). The key CSC pathways include Notch, Wnt, and PI3K/AKT. Curcumin and resveratrol target CSCs by modulating these pathways (9, 10). An elevated HDAC7 and HDAC1 maintain CSC traits in breast cancer, while inducible nitric oxide synthase (iNOS) promotes Notch signaling in liver CSCs, accelerating tumor development (55). Carboxypeptidase A4 (CPA4) regulates inflammation and fibrosis in liver cancer and is linked to poor prognosis (21). The lower CD44 mRNA levels in hepatic metastases correlate with better survival in colorectal cancer, while co-expression of CD44 and CD133 marks aggressive disease (26). Natural compounds may suppress CSC-driven tumor progression by targeting epigenetic regulators and stem cell signaling. Nano-enabled formulations further enhance these effects by improving CSC-targeted delivery and sustaining intracellular concentrations in stem-like tumor niches.

The MAPK and PI3K pathways are key drivers in thyroid tumor development (24). The PI3K pathway also regulates growth, proliferation, and angiogenesis in breast cancer, with clinical trials increasingly favoring PI3K inhibitors (30). Oral cancer develops through dysregulation of PI3K/AKT/mTOR, Ras/MAPK, Wnt, NF-κB, and Hippo pathways, with genetic alterations in TP53, PTEN, and others contributing to progression (11). The NF-κB pathway, normally inhibited by I-κB, regulates genes such as Bcl2, VEGF, and IL-6, promoting proliferation and chemoresistance (55). The Wnt pathway is crucial in breast, lung, and oral cancers, with its activation linked to poor prognosis (53). Hypoxia in oral cancer upregulates Notch target genes HEY1 and HES1, promoting proliferation (11). The MAPK pathway, through ERK1/2, JNK, ERK5, and p38 branches, regulates apoptosis, proliferation, and metastasis (24). The Hippo pathway, disrupted in breast, colorectal, and liver cancers, controls tumor growth via MST and LATS kinases (31). The Hedgehog pathway is activated through canonical and non-canonical mechanisms, which drive breast and gastric cancers (56, 57).

EGCG demonstrates multi-target effects across PI3K/AKT, EMT suppression, and inflammatory signaling, supporting its role as a chemopreventive scaffold (49). Sulforaphane modulates Nrf2 at the epigenetic level via DNA methyltransferase regulation in intestinal models, strengthening its detoxification and antioxidant rationale (40, 42). Herbal anticancer products show convergent mechanisms, including apoptosis, autophagy, ferroptosis, and pathway modulation across curcumin, resveratrol, EGCG, and ginsenosides (45). Natural compounds act through multi-level regulatory effects across signaling, epigenetics, and cell-death programs. This multi-target behavior aligns with nano-enabled chemoprevention, where improved delivery enhances coordinated modulation of these interconnected pathways.

Cancer is characterized by genomic instability, driven by persistent DNA damage and impaired repair mechanisms. The DNA damage response (DDR) preserves genomic integrity by detecting and repairing lesions caused by oxidative stress, radiation, or carcinogens (58). Natural compounds modulate DDR pathways by either enhancing DNA repair in normal cells or inducing lethal damage in cancer cells, offering therapeutic potential for chemoprevention (9, 17). Chemopreventive agents typically act by reducing oxidative stress and enhancing repair fidelity at low, non-cytotoxic doses, whereas therapeutic agents induce high levels of DNA damage to trigger apoptosis.

Natural compounds regulate DNA damage and repair through diverse mechanisms across multiple cancer types. These bioactive agents influence apoptosis, oxidative stress, and DNA repair, making them promising candidates for cancer prevention (41, 45). Table I summarizes the major classes of natural compounds, their representative molecules, mechanisms of action, and the cancer types they target. Nano-enabled formulations enhance DNA-modulatory effects by improving stability, intracellular uptake, and sustained exposure at early lesion sites.

Natural compounds influence DNA damage and repair through multiple mechanisms, ranging from apoptosis induction and oxidative stress modulation to telomere shortening and immune activation. Their ability to selectively enhance DNA repair in normal cells while inducing lethal damage in cancer cells positions them as powerful chemopreventive agents (47, 48). Nano-enabled delivery strengthens dual actions by improving pharmacokinetics, enhancing tissue-specific accumulation, and sustaining intracellular availability of DNA-modulatory phytochemicals at preventive doses.

Polyphenols, abundant in fruits, vegetables, and tea, are renowned for their antioxidant and anticancer properties. They can induce DNA damage in cancer cells to promote apoptosis or enhance DNA repair in healthy cells (1). Curcumin, derived from Curcuma longa, selectively targets cancer cells by promoting apoptosis and inhibiting NF-κB, while enhancing DNA repair (9). Resveratrol induces