Zinc, an essential trace element, is widely distributed throughout oral ecosystems, including dental plaque, saliva, dental structures, and mucosal tissues, where it serves as a critical biological reservoir (16). This micronutrient plays a pivotal role in multiple physiological processes, including cellular proliferation, immune regulation, collagen synthesis, and tissue repair (17). Notably, clinical studies have established a significant association between zinc deficiency and increased susceptibility to oral cancer (18), with tumor patients frequently exhibiting depleted zinc levels, likely due to its consumption during fibrotic processes, inflammatory responses, and free radical-scavenging activities (19). The therapeutic and prophylactic effects of zinc are mediated through several distinct mechanisms: First, as a cofactor for copper-zinc superoxide dismutase (SOD), zinc exhibits anticancer activity, particularly in OSF (20). Second, it modulates collagen metabolism by suppressing lysyl oxidase (LOX)-mediated collagen deposition while simultaneously promoting matrix metalloproteinase (MMP)-dependent degradation, thereby enhancing mucosal flexibility and alleviating clinical symptoms (21–24). Third, by upregulating glutathione levels, zinc synergizes with vitamins A and C to maintain epithelial integrity and reduce mucosal discomfort (25, 26). Furthermore, emerging evidence suggests that zinc reinforces mucosal barrier function through immunomodulatory effects and oxidative stress mitigation (27, 28). Research indicates that zinc supplementation physiologically modulates immune responses by suppressing excessive activation, while its depletion during severe infections leads to widespread upregulation of NF-κB signaling. In vitro experiments reveal that zinc downregulates NF-κB-mediated pathways along with associated pro-inflammatory cytokines, including TNF-α and IL-1β. Concurrently, it enhances transcriptional activity of A20 and PPAR-α, both of which are zinc-dependent regulators exhibiting anti-inflammatory functions (27).

In the pathogenesis of OLP, a condition marked by cytotoxic T-cell activation, MMP dysregulation, cyclooxygenase-2 (COX-2) overexpression, and redox imbalance, zinc demonstrates significant protective effects (29). As MMPs depend on zinc for their activation, zinc exerts precise control over inflammatory responses by inhibiting MMP-1-mediated lymphocyte infiltration and preventing MMP-9-induced basement membrane disruption (22, 23). Additionally, zinc functions as a potent reactive oxygen species (ROS) scavenger, suppressing COX-2/prostaglandin E2 (PGE2) signaling and thereby attenuating oxidative stress-driven inflammation in OLP patients (30). Collectively, zinc exerts its anti-carcinogenic and anti-inflammatory effects through multifaceted mechanisms, including modulation of the SOD/MMP axis, inhibition of COX-2–PGE2 signaling, and maintenance of redox homeostasis and epithelial integrity. These mechanistic pathways are strongly correlated with enhanced mucosal healing and clinical symptom relief in patients with oral cancer and OLP.

Copper ions serve as a critical micronutrient in numerous oxidoreductases including cytochrome oxidase and tyrosinase, essential for cellular homeostasis and biological functions (31, 32). While physiologically important, dysregulated copper metabolism exhibits dual roles in oral pathogenesis. On one hand, copper deficiency impairs SOD1 activity, compromising antioxidant defenses and leading to oxidative stress accumulation (33). On the other hand, elevated copper levels in biological fluids have been consistently associated with premalignant conditions and squamous cell carcinomas, particularly in OSF, a condition with high malignant transformation potential (34, 35). The oncogenic properties of copper involve multiple interconnected mechanisms: (1) activation of LOX-mediated collagen deposition, driving OSF progression (36); (2) induction of ROS-dependent growth genes (c-fos, c-jun); (3) stimulation of angiogenic factors (VEGF, b-FGF); and (4) promotion of proliferative signaling pathways (37–39). Notably, the copper-CER-SOD1 axis forms a critical regulatory network, where ceruloplasmin facilitates copper delivery for SOD1 biosynthesis, while SOD1 upregulation conversely depletes circulating copper pools (20). This delicate balance is further evidenced by studies showing that copper deficiency reduces antioxidant enzyme activities (GSH-Px, SOD1) while increasing oxidative markers (LPO, MDA), effects reversible upon copper supplementation (40, 41). The therapeutic potential of copper modulation is underscored by preclinical studies demonstrating that chelation therapy can simultaneously target multiple oncogenic pathways, including ROS reduction, SOD1 inhibition, and suppression of angiogenic factors (VEGF, MMP-9) (41, 42). However, current evidence remains limited to xenograft models, highlighting the need for clinical investigations in oral cavity cancers (43, 44). Importantly, dose–response studies reveal a narrow therapeutic window, with micromolar copper iron concentrations stimulating keratinocyte proliferation by ROS accumulation (45), emphasizing the necessity to precisely define physiological ranges that maintain redox homeostasis without inducing either deficiency or toxicity.

Selenium (Se), an essential trace element, functions through selenoproteins including glutathione peroxidase (GSH-Px) and thioredoxin reductase (TxRs), which serve as pivotal antioxidants (46). These proteins exhibit organelle-specific localization and tissue-dependent expression patterns, with activity sensitive to Se availability (47). Epidemiological evidence associates Se deficiency with elevated cancer risk due to impaired selenoprotein function (48). In lichen planus (LP), serum Se levels inversely correlate with lesion severity and chronicity (49). Notably, OLP demonstrates reduced Se levels in malignant progression, suggesting its chemopreventive role (50). Mechanistically, Se insufficiency diminishes GPX-1 activity, compromising H₂O₂ detoxification post-SOD2 reaction, thereby accelerating neoplastic transformation in OLP (51). The selenium-GPX axis restores H₂O₂ detoxification and suppresses pro-inflammatory cytokines via inhibition of NF-κB transcriptional activity (52). These pathways correlate with reduced OLP recurrence, improved epithelial repair, and reduced mucosal pain, demonstrating both molecular and clinical relevance. Beyond antioxidant effects, Se modulates immune responses and oxidative stress (53, 54). At the molecular level, Se suppresses NF-κB binding to cytokine gene promoters to mitigate inflammation, including TNF-α, IL-1, and IL-6 (55, 56). It also normalizes CD3⁺/CD4⁺ and CD4⁺/CD8⁺ ratios and Th1/Th2 balance, reducing OLP recurrence (57, 58). OLP pathogenesis involves ROS amplification, where ROS overproduction by CD4⁺ T cells perpetuates keratinocyte lipid membrane damage and localized inflammation. Se interrupts this cycle by neutralizing H₂O₂ and organic peroxides, preserving mucosal integrity (55).

Vitamin A encompasses fat-soluble compounds, including retinol, retinoic acid, retinal, and carotenoids, that play crucial roles in modulating epithelial keratinization, inflammatory responses, and immune function (59–61). As a key antioxidant within the glutathione peroxidase system, vitamin E (α-tocopherol) effectively mitigates oxidative membrane damage by neutralizing ROS (62). While both vitamins exhibit lipid peroxidation inhibitory effects, emerging evidence suggests potential antagonistic interactions when administered concurrently (63). Clinical studies have established a strong correlation between deficiencies in these antioxidants and an elevated risk of oral cavity carcinogenesis, particularly in OLK and OLP progression (64–66). The pathogenesis involves tobacco-and betel nut-derived carcinogens that generate excessive ROS and malondialdehyde (MDA), leading to cytotoxic and genotoxic effects that promote mucosal malignant transformation (67). Antioxidant supplementation demonstrates therapeutic potential, with carotenoids showing particular efficacy in precancerous lesion regression (68). Notably, vitamin A or β-carotene supplementation reduces OLK lesion size and nuclear abnormalities, even with persistent carcinogen exposure (69). For refractory OLP cases, isotretinoin (9-cis retinoic acid) exhibits clinical efficacy, potentially through retinoic acid receptor activation or AP-1 pathway suppression, though the mechanisms underlying treatment resistance require further investigation (70, 71). α-Tocopherol demonstrates significant regulatory effects on free radicals and lipid peroxides in precancerous conditions (72). A recent network meta-analysis identified lycopene combined with vitamin E as the most effective intervention for OSF (73). However, the clinical application of systemic vitamin A therapy remains limited by its transient efficacy and notable adverse effects, including cheilitis, mucosal pigmentation, and impaired wound healing (74). These limitations underscore the need for developing safer vitamin A derivatives to enable sustained chemoprevention strategies in oral potentially malignant disorders.

Vitamin C (L-ascorbic acid) is a potent water-soluble antioxidant that plays a crucial role in neutralizing organic free radicals and protecting biological membranes from oxidative damage (75). Its antioxidant mechanism involves two key aspects: direct radical scavenging and synergistic interaction with other antioxidants. Notably, vitamin C regenerates α-tocopherol from oxidized vitamin E, thereby restoring the antioxidant capacity of vitamin E (76, 77). In the context of carcinogenesis, where reactive oxygen/nitrogen species (ROS/RNS) induce significant DNA damage, vitamin C demonstrates diagnostic potential when combined with other biomarkers. Studies show that the combination of vitamins C/E significantly improves diagnostic sensitivity for oral precancerous lesions compared to using single biomarkers alone (78). The unique solubility properties of vitamin C enable its antioxidant action in both intracellular and extracellular compartments, effectively mitigating oxidative stress induced by infections (79). Furthermore, vitamin C exhibits a bimodal activity pattern through dose-dependent modulation of redox-sensitive signaling pathways, including NF-κB and MAPK cascades. These molecular interactions can lead to either DNA repair activation or cytotoxic effects, depending on the concentration of vitamin C, highlighting its complex role in cellular redox regulation. Nicolae et al. observed reduced urinary vitamin C in infected lichen planus (LP) patients, correlating with disease severity (79). Animal studies reveal elevated ascorbate in immune cells, bolstering infection resistance (79). Abdolsamadi et al. reported higher salivary MDA and lower antioxidants, such as vitamins A/E, in erosive OLP patients, linking OS to lesion susceptibility (63). Vitamin C also modulates OS-driven metabolic pathways. Depletion elevates ROS, oxidizing DNA (8-hydroxydeoxyguanosine), proteins (carbonyls), and lipids (8-iso-PGF2α), while altering glucose/cholesterol metabolism, enhancing cancer invasiveness (80). Importantly, Vitamin C exhibits concentration-dependent “bimodal” behavior. At physiological concentrations, it functions as an antioxidant, quenching ROS and stabilizing cell membranes (81). However, at pharmacologic or supraphysiological doses, it reduces transition metal ions such as Fe³⁺ to Fe²⁺ or Cu²⁺ to Cu⁺, facilitating Fenton-like reactions that produce hydrogen peroxide (H₂O₂) and hydroxyl radicals in situ (82, 83). This pro-oxidant effect selectively induces oxidative stress in cancer cells, which often have impaired catalase activity and a weakened antioxidant defense system, leading to DNA strand breaks, mitochondrial dysfunction, and apoptosis. This mechanism underpins the cytotoxic activity of high-dose Vitamin C in tumor settings (80).