This article was written in a narrative format and focused on compiling views based on both qualitative perspectives and up-to-date scientific literature available with regards to honey in cancer therapy. We surveyed the literature by scanning PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar covering the period 2000–2025. Key terms used in a Boolean search query include ‘honey’, ‘apitherapy’, ‘cancer’, ‘adjuvant therapy’, ‘chemotherapy-induced toxicity’, ‘methylglyoxal’, ‘polyphenols’, ‘flavonoids’, and ‘bioavailability’.

Prioritized studies include those which have original data (in vitro, in vivo, and human studies), described and characterized honey or its active compounds using established analytical methods (HPLC-MS and/or H-NMR spectroscopy), and have focused on mechanistic pathways related to hallmark traits of cancer including apoptosis, proliferation, inflammation, oxidative stress, and metastasis. Human studies targeting the alleviative effects of honey in counteracting chemotherapy or radiotherapy side effects were also prioritized. Commentaries, personal accounts, and studies with undotted aims were excluded in this synthesis.

For each study, data were abstracted for: Author, year of publication, country, type of study, model of cancer or patients, type of honey or composition, dose and duration, comparator, and key findings. Results were categorized thematically according to the main headings in the article, with preclinical and clinical findings separated for clarity. Tables and illustration figures were constructed to emphasize clinical findings, mechanistic pathways, and safety perspectives. As a narrative review, this article aims not to be exhaustive in covering all existing literature but does not include a risk of bias assessment. The focus instead is placed on bridging mechanistic views with those of translational perspectives.

Honey has several biological activities that contribute to its anticancer properties, namely four integrative mechanisms: pro-apoptosis, cell cycle arrest, regulation of inflammatory signaling pathways, and antioxidant activity. These pathways have become a focal point for translational oncology research, these interconnected mechanisms are summarized in Figure 1. One of honey’s most clearly defined anticancer actions is the ability to block the cell cycle and induce apoptosis. For instance, studies with Manuka and Tualang honeys show that they can arrest breast and colorectal carcinoma cells at G0/G1 or G2/M checkpoints by modulating cyclin-dependent kinases (CDK4/6) and elevating p21/WAF1 (29). This cell cycle arrest represents one of honey’s key antiproliferative mechanisms. Chrysin reduces cyclin D1 accumulation, blocking Rb phosphorylation and halting G1/S transition (55). Interestingly, quercetin from acacia honey enhances extrinsic apoptotic signaling by increasing levels of p53 and Fas/FasL in lung adenocarcinoma (56). Mitochondrial apoptosis is another important pathway modified by honey. Methylglyoxal (MGO), a major component of Manuka honey, upregulates the Bax/Bcl-2 ratio and promotes cytochrome c release and caspase-9 and caspase-3 activation in glioblastoma cells (20). These events at the molecular level ultimately act together to inhibit tumor-cell growth. The cell cycle contains the highly-controlled phases, G1, S, G2 and M, which control cellular replication. Checkpoints —especially the G1/S transition —decide whether cells divide, enter a quiescent state, differentiate, or undergo apoptosis (57). Misregulated activation of CDKs and their cyclin partners, especially cyclin D1, is a feature of oncogenic transformation (57). Ki-67, which is not expressed in quiescent (G0) cells but is present in proliferating phases, is the most used tumor proliferation marker (58).

Experimental evidence from both in vitro and in vivo models supports honey’s role in modulating cell cycle progression. In rodent models, daily treatment with honey–Aloe vera formulation (670 µL/kg) profoundly diminished Ki-67 expression in tumor tissues, suggesting cell cycle arrest (59). Honey-related phytochemicals, especially flavonoids and phenolic acids, have also demonstrated the capacity to arrest a range of cancer cells, such as colon, glioma, and melanoma, at the G0/G1 phase (60). This arrest is mediated by downregulation of enzymes and signaling molecules such as tyrosine cyclooxygenase, ornithine decarboxylase and multiple kinases, thus impeding neoplastic proliferation (60). In addition, honey modulates p53-regulated pathways, reinforcing its antiproliferative activity and supporting its potential in integrative cancer therapy (5).

Apoptosis, a type of controlled cell death required for tissue balance and removal of irregular cells, is commonly defective in cancers (61). Honey has demonstrated the capacity to restore apoptotic signaling in cancer cells via both intrinsic and extrinsic pathways, contributing to its therapeutic potential (Table 3).

The intrinsic, or mitochondrial, pathway is activated by honey’s polyphenolic components that cause mitochondrial membrane depolarization and activate caspases 3, 7, and 9 (84, 85). Apoptotic signaling is closely tied to p53 modulation and ROS induction, mechanisms already described in Section 4.1 (86, 87). Honey can also induce reactive oxygen species (ROS) production, leading to the activation of p53, a significant tumor suppressor, which phosphorylates Bcl-2 and Bak and Bax in favor of apoptosis (86). In vivo studies using Wistar rats in which honey was ingested with Aloe vera showed that these apoptotic effects complement the cell cycle arrest described in Section 4.1 (59). Manuka honey was the most effective in activating the caspase-9 and -3 pathways, resulting in DNA fragmentation and antiapoptotic signals being downregulated. Chrysin’s apoptotic role builds on its cell cycle modulation described in Section 4.1 (62, 88).

The extrinsic, or death receptor-mediated, pathway is also controlled by honey, particularly through its effect on epithelial–mesenchymal transition (EMT)—a key component in tumor invasion and metastasis (62, 89). EMT is associated with decreased E-cadherin and increased N-cadherin expression, which was reversed by Sangju honey in oral carcinoma cells (85). Honey activates death receptor signaling through TRAIL-R1/R2 and DR5, induced by chrysin (25, 90, 91). These effects have been confirmed in vitro, with some clinical trials still needed to fine tune dosing and therapeutic effects. Crucially, honey’s apoptotic effects are concentration- and time dependent. Exposure to as low as 0.6% (w/v) for 24 h had significant cytotoxicity in multiple cancer cell lines (88).

In concert, honey disturbs cell cycle progression, thus limiting unrestrained growth. Saudi Sidr honey was demonstrated to arrest the G0/G1 phase in colorectal (HCT-116), breast (MCF-7) and lung (A-549) cancer cells, shortening the S, G2, and M phases (92). Similar results were observed in pancreatic cancer cell lines (MIA PaCa-2 and AsPC-1), exhibiting arrest at G0, G2/M phases after 24 hr treatment (92). These antiproliferative effects are intimately linked to p53 modulation—honey upregulates wild-type p53 and suppresses mutated variants frequently present in tumors (93–95). Honey’s apoptotic activity is closely linked to its ability to disturb cell cycle progression, as described in Section 4.1. For example, modulation of p21, p27, cyclins D1/E, and CDKs 2/4 contributes to checkpoint arrest and facilitates apoptotic signaling (29). Together, these results underscore honey’s dual role in apoptosis promotion and anti-proliferative activity, strengthening its promise as a natural complementary agent in cancer treatment.

Chronic inflammation is an established driver of tumorigenesis, promoting malignant transformation, angiogenesis, immune evasion, and extracellular matrix remodeling (96). At the heart of these processes are the NF-κB and MAPK signaling pathways, which control the transcription of pro-inflammatory mediators including COX-2, CRP, LOX-2 and cytokines IL-1, IL-6, IL-8 and TNF-α (97–99).

Honey’s polyphenolic constituents, in particular caffeic acid phenethyl ester (CAPE), gallic acid, and chrysin, exert potent anti-inflammatory effects, targeting these molecular pathways (Table 3). CAPE blocks IKKβ phosphorylation, preventing NF-κB nuclear translocation and cytokine expression (16). Gallic acid, on the other hand, activates the Nrf2/ARE axis, increasing antioxidant enzyme activity, for example, SOD and catalase, and decreasing chemotherapy-induced oxidative stress (100). Clinical data support the radioprotective function of honey; Manuka honey, a monofloral honey produced in New Zealand, has been shown to decrease 8-OHdG, a biomarker of oxidative DNA damage, in patients with breast cancer undergoing radiotherapy (101).

Experimental studies support honey’s suppression of NF-κB and MAPK signaling in vitro. Gelam honey markedly inhibited these pathways in HIT-T15 pancreatic islet cells at concentrations as low as 20 µg/mL (102). Chrysin also regulates MAPK signaling and potentiates TRAIL-induced apoptosis in melanoma cell lines (B16-F1 and A375) (99, 103)102,106]. In vivo, oral administration of Malasyian gelam honey (1–2 g/kg) reduced leukocyte infiltration and edema in carrageenan-induced rats, thus attenuating acute inflammatory responses (104). Honey’s NSCLC cytotoxic effects have also been associated with its inflammatory cytokine modulation profile (105).

Tualang honey, collected by Apis dorsata bees from Malaysian rainforests, is especially abundant in phenolic acids and flavonoids. Its dark color also indicates increased polyphenol content, which surpasses that of Manuka honey and intensifies its anti-inflammatory and anticancer effects (106, 107).

Honey’s anti-inflammatory activity is notably effective at the tissue level. It enhances mucosal healing in the mouth (63, 108, 109) and modulates the gut microbiome in the colon by boosting short-chain fatty acids, inhibiting harmful bacteria, and promoting beneficial lactobacilli—effects associated with gallic acid and IL-10 (110, 111). On the skin, honey protects keratinocytes from UVB damage by suppressing COX-2 and NF-κB, indicating a potential role in preventing skin cancer (112). Additionally, honey inhibits the activity of matrix metalloproteinases MMP-2 and MMP-9, which are key drivers of chronic inflammation and cancer metastasis (113), further solidifying its broad therapeutic profile.

The feedback loop between chronic inflammation and oxidative stress is a key cancer driver. Honey’s antioxidant activity is largely owed to its abundant polyphenol and flavonoid content through three synergistic mechanisms: (i) neutralization of reactive oxygen species (ROS), (ii) upregulation of several antioxidant enzymes—including SOD, GR, GPx, and CAT, and (iii) transcriptional regulation of genes involved in redox balance (114, 115). Phenolic compounds in honey, which act as electron or hydrogen donors, directly scavenge ROS. Their ortho-dihydroxyl structures—such as gallic, caffeic, and chlorogenic acids—facilitate metal ion chelation and lipid peroxidation inhibition (116–118). Caffeic acid also maintains genome integrity by protecting DNA from oxidative damage, while flavonoids increase electron delocalization through conjugated π-systems and oxo-groups, which optimize radical scavenging ability (119).

Among the many flavonoids in honey, pinocembrin and chrysin stand out for their potent in vivo antioxidant activity. Research shows that pinocembrin can bolster the body’s own defenses by increasing superoxide dismutase (SOD) and reducing the accumulation of malondialdehyde (MDA), a marker of oxidative damage, in both liver and neural tissue (120, 121). Similarly, chrysin’s antioxidant effects complement its antiproliferative and apoptotic roles noted in Sections 4.1 and 4.2 (122) (Table 3).

The relationship between reactive oxygen species (ROS) and cancer is complex. While baseline ROS levels can support cancer cell survival, excessive ROS can damage cellular components and paradoxically fuel tumor development (123, 124). This creates a therapeutic opportunity, as the same oxidative stress can be leveraged to trigger cell death in malignant cells (125). Honey’s diverse antioxidant components—including radical scavengers and redox-active phytochemicals—are believed to exploit this delicate balance, providing a mechanistic basis for its observed ability to suppress tumor progression (126, 127).

Honey is even pro-oxidant in certain contexts. Honey’s pro-oxidant effects, linked to ROS generation, complement the apoptotic pathways noted in Section 4.2 (86). This duality is due to phenolic compounds, which may generate ROS in the presence of transition metals like copper (128). These pro-oxidant effects could induce DNA fragmentation and apoptosis in cancer cells (129, 130). Martinotti et al. examined the cytotoxicity of Manuka, buckwheat, and acacia honeys in A431 vulvar epidermal carcinoma cells (131). Manuka honey was the most effective, perturbing intracellular ROS and calcium signaling as well as inducing apoptosis. The suggested mechanism is through aquaporin-3 channel modulation and enhanced H2O2 permeability, allowing ROS buildup and subsequent cell death.

Honey has become a potential natural agent for modulating tumor progression and metastasis. Even though a lot of the evidence is in vitro, an increasing amount of in vivo data backs up its antineoplastic effect in a variety of cancer forms. Metastasis suppression by honey is mainly through MMPs and VEGF signaling inhibition. Tualang honey downregulates MMP-2 and 9 through upregulation of TIMP-1, inhibiting invasive potential in oral squamous cell carcinoma (9). Kaempferol, a flavonoid component of honey, inhibits VEGFR2 phosphorylation, resulting in decreased angiogenesis and microvessel density in melanoma xenografts (132). Gelam honey also reduces EMT by upregulating E-cadherin and downregulating Twist and the transcription factor Snail in colorectal cancer models (22).

Similar anti-metastatic effects have been noted for caffeic and gallic acids, which downregulate MMP and VEGF expression in melanoma and breast cancer cells (5, 126). Honey also influences cell cycle modulators and apoptotic signaling toward its antiproliferative profile. In vitro suppression of Ki-67, already noted in Section 4.1, also extends to OSCC cells, reinforcing honey’s antiproliferative profile (32). Manuka honey (UMF 20+), enriched in methylglyoxal, induced G2/M phase arrest in OSCC cells (32). In breast cancer models, Tamoxifen synergy is discussed in detail under chemotherapy synergy (Section 4.6), but it also reinforces apoptotic signaling (84). Gelam honey, high in quercetin, induced S-phase arrest in colon cancer cell lines (27). Much of these effects are due to bioactive flavonoids like chrysin, which induce G0/G1 arrest and initiate apoptotic cascades.

These effects reflect NF-κB suppression described in Section 4.3, contributing to honey’s chemopreventive role, supporting its chemopreventive role. In randomized controlled trials in pediatric leukemia patients, daily 20 g clover honey was shown to significantly improve neutrophil recovery and reduce infections (133). In head and neck cancer patients receiving radiotherapy, topical honey rinses mitigated mucositis severity and promoted mucosal healing (134). In breast cancer, this synergy is elaborated in Section 4.6 on chemotherapy, highlighting its impact on tumor progression (84).

Honey has revealed capacity as a chemosensitizing agent, enhancing the intracellular retention and therapeutic effectiveness of conventional anticancer treatments. In colorectal cancer patients, co-treatment with Manuka honey (UMF 15+) and 5-fluorouracil (5-FU) increased intratumoral drug concentration by 62%, attributed to inhibition of efflux transporters such as P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) (135). Tualang honey augmented tamoxifen efficacy in breast cancer models, amplifying apoptosis and reducing tumor burden (84).Tualang honey (1.2 g/kg/day) similarly augmented doxorubicin efficacy in triple-negative breast cancer (TNBC). Chemotherapy synergy is partly mediated by NF-κB suppression, as outlined in Section 4.3, as demonstrated in a Phase I/II clinical trial (136). In leukemia models, co-administration of Clover honey with cytarabine mitigated chemotherapy-induced myelosuppression, improving hematologic recovery by 40% (137). Mechanistically, honey enhances chemotherapeutic efficacy through multiple pathways: inhibition of drug efflux pumps (135), ROS-mediated apoptosis induction (136), and suppression of autophagy via AMPK/mTOR axis modulation (121). These mechanisms collectively improve drug bioavailability and cytotoxicity in tumor cells. In addition to efficacy enhancement, honey significantly attenuates chemotherapy-related toxicities, including oral mucositis, nephrotoxicity, and bone marrow suppression. A multicenter randomized trial in head and neck cancer patients revealed that Manuka honey (10% w/v oral rinse) reduced grade 3–4 mucositis incidence by 71% compared to standard care (p = 0.003) (99). These protective effects are attributed to honey’s antioxidant properties (elevate glutathione, SOD), anti-inflammatory actions (decrease IL-6, TNF-α) (138, 139), and its capacity to modulate gut microbiota composition (enhance Lactobacillus spp.) (140). Honey’s therapeutic benefits in chemotherapy settings are mediated by four interdependent mechanisms: antioxidation, inflammation suppression, apoptosis induction, and immune modulation (62, 65, 70, 75). Preclinical protocols involving timed co-administration of honey with cytotoxic agents continue to yield promising outcomes in toxicity mitigation and therapeutic enhancement (83).

Honey has shown radioprotective effects based on its ability to enhance DNA repair mechanisms and reduce oxidative damage in irradiated tissues. In breast cancer patients undergoing radiotherapy, Sidr honey (1 g/kg/day) increased BRCA1 and RAD51 expression correlated with 55% less double-strand breaks (DSBs) in the tissues (p < 0.01) (141). Enhanced DNA repair approaches are performed through the activation of base excision repair (BER) via PARP-1 stimulation (142) and by promoting non-homologous end joining (NHEJ) pathways (143). Honey also scavenges free radicals from radiation, thus causing cellular damage. In prostate cancer patients receiving radiotherapy, Gelam honey (500 mg/kg) - and a dramatic 48% decrease (p = 0.002) in the 8-hydroxy-2′-deoxyguanosine (8-OHdG) biomarker and higher catalase activity indicated a boost in oxidative defense in these patients receiving radiotherapy (144).

Honey production and beekeeping practices intersect directly with sustainable food systems and the United Nations Sustainable Development Goals (SDGs), particularly SDG 3 (Good Health and Well-Being) and SDG 12 (Responsible Consumption and Production).

From an ecological perspective, beekeeping has a relatively low environmental footprint compared to other forms of animal husbandry. Bees provide essential pollination services that sustain biodiversity and agricultural productivity, reducing reliance on synthetic inputs and supporting ecosystem resilience (145, 146). For example, diversified beekeeping integrated with crop farming has been shown to strengthen cooperative societies and improve agricultural outcomes in South Africa (147).

Socioeconomic dimensions are equally important. Honey is a locally produced, culturally embedded food that can be harvested and marketed by smallholder farmers, including women and rural communities. This supports SDG 12 by promoting local consumption, reducing transport emissions, and strengthening rural economies (148, 149). International organizations such as the FAO have emphasized the role of beekeeping in poverty alleviation and food security, highlighting its contribution to sustainable livelihoods (150).

Health and nutrition outcomes tie directly to SDG 3. Honey’s role as a natural sweetener and functional food aligns with healthier consumption patterns, offering alternatives to refined sugars. Clinical and preclinical evidence suggests honey can mitigate treatment-related toxicities and support immune function, contributing to SDG 3 targets on reducing non-communicable diseases and improving nutrition (151, 152).

Concrete examples illustrate these connections include, sustainable Manuka honey of New Zealand production integrates ecological conservation with high-value exports, balancing SDG 12 goals of responsible production with SDG 3 outcomes in health (153, 154). In Malaysia, Tualang honey harvesting from rainforest trees demonstrates how traditional practices coexist with biodiversity conservation, linking local livelihoods to global health benefits (151, 155). Sidr honey production in Yemen sustains rural economies and provides accessible therapeutic products, despite geopolitical and economic challenges (152). Globally, comparisons of conventional and organic honey production highlight differences in ecological footprint and quality, reinforcing the importance of responsible consumption and production (156).

Taken together, honey and beekeeping practices exemplify how sustainable food systems can simultaneously advance ecological stewardship, socioeconomic resilience, and public health, thereby contributing meaningfully to SDGs 3 and 12.

A substantial body of laboratory and animal research supports honey’s anticancer potential across a range of tumor types. These studies demonstrate mechanisms such as apoptosis induction, cell cycle arrest, suppression of inflammatory signaling, and inhibition of metastasis. Table 4 summarizes key findings from preclinical models, grouped by honey type, species, tumor model, and mechanism. These findings provide mechanistic insight into honey’s anticancer effects and form the basis for translational research.

Although clinical studies remain limited in scale, emerging data suggest honey may offer therapeutic benefits in oncology, particularly as a supportive agent. Table 5 summarizes clinical trials and observational studies by honey type, cancer indication, dose, duration, and outcomes. These studies highlight honey’s potential to mitigate treatment-related toxicities and enhance therapeutic outcomes, though larger trials are needed.

The therapeutic variability of honey is largely attributed to its botanical origin, geographic source, and chemical composition, and these differences pose significant challenges for clinical standardization and reproducibility. Manuka honey, produced in New Zealand, is distinguished by its high methylglyoxal (MGO) content, which contributes to its antibacterial and cytotoxic properties. The Unique Manuka Factor (UMF™) grading system quantifies MGO and related markers, but its ability to predict anticancer efficacy remains uncertain (153, 164). In contrast, Tualang honey, collected in Malaysian rainforests, is darker in color and richer in flavonoids and phenolic acids compared to Manuka. These compounds confer strong antioxidant and anti-inflammatory activity, which have been linked to enhanced anticancer effects in preclinical models (106, 107). Sidr honey, traditionally harvested in Yemen, has a distinct phytochemical profile with evidence of immunomodulatory and anti-inflammatory effects, but its composition varies widely depending on floral biodiversity and regional conditions, complicating reproducibility in clinical applications (100, 152) (Table 6).

Despite promising findings across these varieties, the absence of unified compositional profiling systems makes it difficult to recommend therapeutic doses or compare outcomes across studies. Variability in bioactive components such as MGO, leptosperin, and quercetin underscores the need for standardized metabolomic characterization to identify therapeutic-grade formulations and enable reproducibility in clinical oncology (29, 168).

Although honey is widely regarded as safe, its therapeutic application requires context-specific evaluation. Contaminants such as heavy metals (arsenic, cadmium, lead), pesticide residues, and hydroxymethylfurfural (HMF) have been detected in some samples, necessitating rigorous quality control and source verification (45). Adverse effects are generally minimal, but certain populations—particularly individuals with type 2 diabetes mellitus (DM2)—may require caution. While some studies suggest honey may serve as a healthier alternative to refined sugars due to its antioxidant and anti-inflammatory properties (169), others report unfavorable metabolic outcomes, including increased LDL cholesterol and reduced adiponectin following daily intake of 50 g natural honey (170). These effects were linked to its high fructose content, with adulteration ruled out. Additional investigations have noted elevations in glycated hemoglobin (HbA1c) at similar doses (171, 172), whereas lower intakes (5–25 g/day) did not significantly affect glycemic parameters (171). Hence, the honey intake should be personalized, particularly among old cancer patients suffering from metabolic comorbidities. Selecting a specific strategy could allow to get the most out of the therapy while at the same time reducing metabolic disturbances. This evaluation of safety does not consider the cases of allergic reactions to plant materials and the risks stemming from the use of impure products, as they categorized under food safety and allergen monitoring practices. Honey usually produces a lower glycemic response than refined sugars. Still, its metabolic effects are dose-dependent, and excessive intake may worsen glycemic control and lipid profiles in patients with diabetes, obesity, or metabolic syndrome. (156). Clinical and preclinical evidence suggests that moderate intakes of Malaysian Tualang honey (5–20 g/day) can be tolerated without adverse metabolic effects, while excessive consumption may exacerbate risks in patients with diabetes or obesity (151, 155). In oncology settings, honey has been used as a supportive adjunct, but patients with metabolic comorbidities represent an at-risk group requiring individualized monitoring (152). These clarifications emphasize that honey should be considered in carefully monitored amounts, with attention to dose ranges and patient risk profiles. In cancer patients with metabolic comorbidities, benefit–risk assessment is critical. While honey provides antioxidant and anti-inflammatory compounds that may support therapy, its glycemic load can exacerbate hyperglycemia, a known risk factor for cancer progression through metabolic reprogramming (Warburg effect). Clinical evidence suggests that small supportive doses (5–20 g/day) are generally tolerated, but in patients with diabetes, obesity, or metabolic syndrome, excessive intake may negate potential antioxidant benefits by worsening glycemic control. Therefore, honey should be considered cautiously in oncology practice, with individualized monitoring of metabolic status to balance therapeutic potential against metabolic risks (151, 152, 156).

The pharmacokinetic behavior and systemic bioavailability of honey’s bioactive constituents remain poorly defined, posing challenges for its integration into evidence-based oncology. Honey contains sugars, polyphenols, enzymes, and trace compounds. However, the absorption, distribution, metabolism, and excretion (ADME) of these molecules remain poorly defined. (172). Honey contains diverse phenolic and flavonoid compounds whose pharmacokinetics and bioavailability are influenced by both chemical structure and gut microbiota interactions. Studies on pollinator-dependent crops highlight that flavonoid diversity directly affects absorption and metabolic pathways (146). Comparative analyses of conventional and organic honey show differences in phenolic content that translate into variable bioavailability profiles (156). In oncology-related contexts, Malaysian Tualang honey has demonstrated that flavonoids such as quercetin and kaempferol undergo rapid absorption but are extensively metabolized, with gut microbiota playing a role in generating bioactive metabolites (151, 155). Similarly, Sidr honey has been reported to contain phenolic acids whose systemic availability depends on microbial transformation, underscoring the importance of microbiota interactions in therapeutic outcomes (152). These examples clarify ADME processes and highlight how microbiota contribute to the bioavailability of honey’s major bioactive compounds. Emerging data suggest that gastrointestinal pH, enzymatic degradation, and interactions with gut microbiota significantly influence the bioavailability of honey-derived phenolics (63, 171). The absence of standardized analytical techniques for quantifying these metabolites in biological matrices further complicates pharmacokinetic modeling and dose optimization (173). Advancements in metabolomics and nanocarrier technologies may enhance targeted delivery and systemic retention of honey’s therapeutic components. In vivo tracer studies are urgently needed to elucidate absorption kinetics and metabolic fate. A further limitation concerns the discrepancy between effective concentrations reported in vitro and the actual bioavailability achievable in vivo. Many cell culture studies employ phenolic and flavonoid concentrations that exceed those attainable in human plasma following oral ingestion of honey. For example, comparative analyses of conventional and organic honey demonstrate variability in phenolic content, but systemic levels after ingestion remain modest (156). Evidence from Malaysian Tualang honey indicates that compounds such as quercetin and kaempferol undergo extensive metabolism, reducing their circulating concentrations despite high in vitro activity (151, 155). Similarly, Sidr honey phenolic acids show therapeutic potential, yet their systemic availability depends on microbial transformation and is lower than in vitro dosing (152). These differences highlight the need for cautious interpretation of in vitro findings and underscore the importance of pharmacokinetic studies to establish clinically relevant dose ranges.

Despite its promising therapeutic profile, integrating honey into mainstream oncology requires a decisive shift from traditional use to evidence-based practice. While preclinical studies have robustly demonstrated honey’s immunomodulatory, anti-inflammatory, and direct anticancer properties, its adoption in clinical protocols remains limited. This gap is primarily due to a scarcity of large-scale randomized controlled trials and persistent regulatory ambiguity (174). Current scientific frameworks increasingly position honey as a supportive agent, particularly for managing treatment side effects like chemotherapy-induced mucositis, accelerating tissue repair, and improving quality-of-life metrics (152). A significant hurdle, however, is its widespread classification as a dietary supplement. This designation typically allows honey to bypass the rigorous safety and efficacy evaluation required for pharmaceutical compounds by agencies like the FDA, thereby complicating its formal approval for clinical use (174).