Pancreatic cancer (PC) has a five-year survival rate of fewer than 5%, making it the fourth most common cause of cancer-related death [6]. Although there have been improvements in therapeutic approaches, mortality is still not significantly improved by the aggressive nature of PC and its resistance to existing therapy. Conventional modalities of therapy, including chemotherapy, surgery, and radiotherapy, have mostly limited success, and resistance in cancer cells is common. To counter this issue, combination chemotherapy with anti-tumor drugs has been investigated [7]. Natural plant-derived compounds have gained attention for their ability to enhance chemotherapy sensitivity, suppress tumor progression, and target multiple molecular pathways involved in cancer resistance. Apigenin, a naturally occurring flavonoid, has shown promising anti-tumor effects in various cancers, including PC [8]. It regulates major oncogenic signaling pathways such as Akt, Wnt, and Nrf2 and can inhibit epithelial-to-mesenchymal transition (EMT) and thereby inhibit metastasis and cancer cell proliferation. From studies, apigenin, similar to other phytochemicals, curcumin, has the potential to enhance the effectiveness of chemotherapy and inhibit tumor aggressiveness by inhibiting processes that benefit cancer cells. Due to its multiple-targeting potential and low toxicity, apigenin is the ideal natural compound for use in combination therapy against PC. Further studies need to be done to enhance its bioavailability and therapeutic applications [9, 10]. Apigenin suppressed adenoid cystic carcinoma cell growth by downregulating glucose transporter-1 (GLUT-1) expression, implying a metabolic interference anticancer process. In BCPAP cells, apigenin caused autophagic cell death, implying that apigenin kills thyroid cancer cells by modulating autophagy. Apigenin inhibited the proliferation and invasion of osteosarcoma cells by suppressing the Wnt/β-catenin signaling pathway, a critical pathway in bone cancer progression. Apigenin enhanced the therapeutic efficacy of TRAIL (TNF-related apoptosis-inducing ligand) in non-small cell lung cancer by upregulating death receptors DR4 and DR5 in a p53-dependent manner, suggesting a synergistic approach in lung cancer therapy [11]. In MDA-MB-231 breast cancer cells, apigenin induced G2/M phase arrest and promoted histone H3 acetylation-mediated p21 (WAF1/CIP1) expression, leading to inhibited cell proliferation and tumor growth. Apigenin inhibited the proliferation of renal cell carcinoma cells by causing DNA damage and inducing G2/M phase cell cycle arrest through modulation of the ATM signaling pathway [12]. Apigenin exhibited cytotoxic effects on malignant mesothelioma cells in a dose- and time-dependent manner. Treatment led to increased reactive oxygen species (ROS) generation, DNA damage, upregulation of p53, and activation of apoptotic pathways, suggesting its potential in mesothelioma therapy [13]. These mechanistic effects provide a strong basis for synergistic interactions with chemotherapeutic agents such as doxorubicin and cisplatin, where apigenin enhances drug accumulation, modulates apoptosis pathways, and overcomes resistance mechanisms.

Apigenin isolated from Patrinia villosa exhibited anti-proliferative effects towards HCC cell growth. Apigenin induced G1 arrest of HepG2 cells, a cell line of liver cancer, possibly by activating the p38 MAPK-p21 signaling pathway. The process also involved control of the CyclinD1-CDK4 complex, the main figure involved in cell cycle progression. These findings suggest that apigenin is an extremely effective therapeutic drug against HCC through control of cell cycle progression and cancer cell growth [14]. Apigenin treatment of glioblastoma cells (U87MG and T98G) induced the generation of ROS, activation of the p38 MAPK and JNK pathways, intracellular calcium elevation, and apoptosis. Notably, apigenin did not kill normal astrocytes, reflecting its glioblastoma cell-selective cytotoxicity. The results suggest that apigenin may serve as an effective glioblastoma drug with decreased effect on normal cells. These findings strongly support the role of apigenin as a chemosensitizing agent in cancer therapy. Its ability to modulate apoptosis, oxidative stress, and drug resistance pathways highlights its potential for synergistic use with standard chemotherapeutic agents such as doxorubicin and cisplatin, thereby improving therapeutic outcomes and reducing resistance [15].

Research isolated apigenin from Portulaca oleracea L. and tested its antibacterial activity against some pathogenic bacteria. The findings showed strong inhibition zones for Salmonella typhimurium and Proteus mirabilis, indicating strong antibacterial activity. This research did not specifically test apigenin’s activity towards Mycobacterium tuberculosis or other mycobacterial species.[16]. The antimycobacterial properties of flavonoids indicated that some flavonoids, like taxifolin, had strong inhibitory action against Mycobacterium tuberculosis. On the other hand, apigenin was found to possess merely moderate to weak mycobacterial activity, indicating that although it does bear some antimycobacterial activity, it is perhaps not as powerful as other flavonoids in this aspect [17]. Also, studies on Schinus terebinthifolius considered the effects of its methanol extract, a particular fraction (A3), and pure apigenin on Mycobacterium bovis BCG growth. The investigation concluded that although the extract and fraction A3 showed some inhibitory activity, pure apigenin showed reduced effect, thus suggesting that other components present in the extract could be accountable for observed antimycobacterial activity. Although apigenin alone exhibits limited antimycobacterial activity, its moderate efficacy suggests potential for synergistic application. Future studies should explore its use in combination with first-line anti-tubercular drugs to enhance efficacy and overcome resistance mechanisms [18].

An examination was made on the impact of apigenin on isolated rat hearts with ischemia/reperfusion (I/R) injury. The findings showed that treatment with apigenin enhanced the cardiac functional recovery, reduced the infarct size in the myocardium, lowered activities of creatine kinase isoenzyme and lactate dehydrogenase in coronary flow, and lowered apoptotic cardiomyocytes. These were linked with the inhibition of the p38 MAPK signaling pathway [19]. Research assessed the effects of apigenin on renovascular hypertension-evoked cardiac hypertrophy in rats. Administering apigenin led to lowered blood pressure, heart weight, cardiomyocyte cross-sectional area, serum angiotensin II, and myocardial free fatty acids. The study indicated that the effects were mediated via down-regulating hypoxia-inducible factor (HIF)-1α and regulating myocardial glucolipid metabolism [20]. Another study investigated apigenin’s cardioprotective activities on diabetic rats with isoproterenol-induced myocardial infarction. Apigenin therapy enhanced hemodynamic parameters, lowered oxidative stress, and lessened apoptosis in myocardial tissue. These responses were attributed to the activation of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathway [21]. Apigenin’s effect on mitigating endotoxin-induced myocardial injury in mice was studied. The results showed that apigenin inhibited the expression of pro-inflammatory cytokines, decreased markers of oxidative stress, and blocked NF-κB nuclear translocation. Apigenin also regulated autophagy-related proteins, implying an overarching protective mechanism for cardiac injury induced by endotoxins [22]. A systematic review highlighted apigenin’s protective roles against cardiometabolic diseases. The review emphasized apigenin's ability to reduce oxidative stress, inflammation, and apoptosis, and to improve glucose and lipid metabolism [23]. The researchers proposed that although preclinical results are promising, clinical trials are necessary to establish the human dosage and bioavailability of apigenin. Recent studies discussed the benefits of apigenin in the prevention of cardiac hypertrophy and heart failure. The research explained that apigenin inhibits cardiac hypertrophy through NADPH oxidase-dependent ROS suppression and HIF-1α down-regulation, enhancing myocardial metabolism and function. These cardioprotective effects suggest that apigenin may serve as an adjunctive agent in cardiovascular therapy. Its antioxidant and anti-inflammatory properties could synergistically enhance the efficacy of standard cardioprotective drugs while reducing oxidative stress-mediated damage [24].

An experiment examined apigenin’s action on UVA-induced skin aging. The results confirmed that apigenin recovered the viability of human dermal fibroblasts that had been treated with UVA, lowered cellular senescence, and diminished the expression of matrix metalloproteinase-1 (MMP-1), which breaks down collagen. Clinical use of cream with an apigenin component proved to enhance the density of dermis, improve the elasticity of skin, and lessen fine wrinkles, promising apigenin as an anti-aging cosmetic product [25]. Study on the anti-aging protective effects of apigenin in a D-galactose-induced mouse model of aging. Supplementation with apigenin greatly enhanced behavioral deficits, decreased histopathological injury, and lowered cellular senescence and oxidative stress markers. The study concluded that the anti-aging effects of apigenin could be exerted by induction of the Nrf2 pathway, leading to increased expression of antioxidant enzymes [26]. Studies investigated the protective role of apigenin in a D-galactose-induced model of aging in mice. Supplementation with apigenin markedly ameliorated behavioral impairments, lessened histopathological damage, and minimized markers of cellular senescence and oxidative stress. The authors concluded that apigenin’s anti-aging impact could be mediated by the activation of the Nrf2 pathway, which promotes antioxidant enzyme expression. The anti-aging effects of apigenin, particularly through Nrf2 pathway activation, indicate its potential for synergistic use with other antioxidants or dermatological agents. Such combinations may enhance skin protection and delay aging-related cellular damage more effectively than monotherapy [27].

Apigenin’s effects on cognitive performance in APP/PS1 transgenic mice, an Alzheimer’s disease (AD) model, were studied. The findings showed that apigenin enhanced learning and memory impairment, inhibited amyloid-beta (Aβ) accumulation by suppressing BACE1 and β-CTF expression, improved oxidative stress, and restored the ERK/CREB/BDNF neurotrophic pathway in the cerebral cortex. These observations indicate apigenin’s potential to improve cognitive impairment associated with AD [28]. A study proved that apigenin preserved neurovascular coupling in mice from amyloid-β25-35 toxicity, a peptide linked to AD pathology [29]. A transgenic Drosophila model of AD was used in a study that discovered apigenin treatment caused a dose-dependent reduction in oxidative stress, delayed climb loss, inhibition of acetylcholinesterase activity, and blocking of amyloid-β42 aggregation [30]. Another investigation reported that apigenin restored memory function in mice subjected to chronic unpredictable mild stress. The flavonoid improved cognitive performance reduced oxidative stress markers, normalized serum corticosterone levels, and upregulated BDNF, pERK, and pCREB expressions in the prefrontal cortex and hippocampus [31]. Researchers examined apigenin’s neuroprotective effects in neonatal rats subjected to hypoxic-ischemic brain injury. The study found that apigenin significantly reduced infarct volume, decreased cerebral edema, suppressed inflammatory responses, inhibited apoptosis, and promoted tissue structure recovery. Mechanistically, these benefits were attributed to the activation of the PI3K/Akt/Nrf2 signaling pathway, highlighting apigenin’s therapeutic potential for neonatal brain injuries [32]. The preclinical investigations analyzed apigenin’s effects on cognitive and neurobehavioral dysfunctions. The review summed up that apigenin augments learning and memory, enhances locomotor activity, has anxiolytic and antidepressant properties, and corrects sensorimotor and motor coordination impairments in animal models. Suggested mechanisms involve the modulation of neurotransmitter systems, interference with pro-inflammatory cytokine production, reduction of oxidative neuronal damage, and activation of neurotrophic signaling pathways [33]. Rats with temporal lobe epilepsy based on the kainic acid model were employed in a 2019 study to evaluate the impact of apigenin. Apigenin was given orally at 50 mg/kg for six days. The delayed onset and reduced severity of seizures reflected significant anticonvulsant activity. Apigenin also promoted survival in hippocampus hilus neurons and enhanced memory impairments induced by epilepsy. Apigenin decreased cytochrome c release, as indicated by immunohistochemical evaluation, which would indicate that it prevents the mitochondrial apoptotic pathway, one of which may be its neuroprotective effects [34]. Research on vitexin, designated as apigenin-8-C-glucoside, a flavonoid with a structural similarity to apigenin. Vitexin was delivered intraperitoneally at doses of 1.25 to 5 mg/kg in murine models. The research concluded that vitexin exerted dose-dependent protection against seizures induced by GABAergic antagonists like picrotoxin and pentylenetetrazol (PTZ), with the maximum dose conferring protection against tonic-clonic seizures. Nonetheless, vitexin was ineffective against seizures induced by glutamate receptor agonists such as NMDA and kainic acid. Vitexin was also found to have anxiolytic-like activity with no sedation or locomotor impairment, indicating its possible role as a modulator of GABAergic neurotransmission [35]. Another study in 2020 explored apigenin’s impact on oxidative stress and ferroptosis in epileptic brains. The study revealed that apigenin was able to reduce myeloperoxidase-induced oxidative stress and block ferroptosis, a type of regulated cell death in epilepsy. Table 1 presents the key pharmacological activities of apigenin along with their associated molecular pathways, potential drug partners, and proposed synergistic roles. The observations point towards the involvement of the antioxidant activity of apigenin in its anticonvulsant action. Collectively, these findings highlight apigenin’s potential as a neuroprotective adjuvant. Its modulation of oxidative stress and neuroinflammatory pathways supports its synergistic application with existing neurotherapeutics to enhance cognitive function and neuronal survival [36].

The study tested the antibacterial properties of certain flavonoids like apigenin against several bacterial strains. The results showed that apigenin only had weak inhibitory effects on Staphylococcus aureus and no apparent antibacterial effect on other tested bacterial species. This suggests that apigenin may act on bacteria but is not a good antibacterial agent, and more studies are needed to know how it acts and whether it has synergism with other compounds [42]. The study examined the apoptosis-like antibacterial activity of apigenin against Escherichia coli. It was found that apigenin causes bacterial cell death by causing an increase in intracellular calcium levels. Elevated levels of calcium trigger the production of reactive nitrogen and oxygen species that cause oxidative stress. The oxidative stress causes damage to the bacterial cell membrane, leading to cell disruption and death. This action highlights the antimicrobial activity of apigenin through its ability to produce oxidative injury in bacterial cells [43]. Recent research examined the anti-biofilm activity of apigenin-7-O-glucoside (A7G) against Staphylococcus aureus and Escherichia coli. The research demonstrated that A7G significantly inhibits biofilm formation through the inhibition of exopolysaccharide production, a requirement for biofilm stability, disruption of quorum-sensing mechanisms governing bacterial communication, and reducing cell surface hydrophobicity, which is involved in bacterial adherence. These findings suggest that A7G has high potential as a natural anti-biofilm and antibacterial molecule, which could be useful in the elimination of biofilm-producing bacteria that cause chronic infections [44]. The antipathogenic ability of apigenin was recently studied in its ability to combat Helicobacter pylori, a bacterium linked to gastritis and peptic ulcers. Researchers developed a gastroprotective microsponge formulation of apigenin that showed potent in vitro antibacterial activity against a metronidazole-resistant Helicobacter pylori strain. The microsponge formulation worked especially well with antibacterial action that was maintained for up to 72 hours, compared to 36 hours when using pure apigenin. This sustained effect underscores the formulation’s therapeutic potential for long-term action, constituting a promising vehicle for the treatment of Helicobacter pylori infections, especially those refractory to conventional therapies. Despite its moderate standalone antibacterial activity, apigenin demonstrates significant potential for synergistic interactions. Its ability to disrupt bacterial membranes and induce oxidative stress may enhance antibiotic efficacy and help combat antimicrobial resistance [45].

In an experimental study, the apigenin effects were investigated in a murine model of asthma with mice that were sensitized and ovalbumin (OVA) challenged to induce a model of allergic asthma response. When apigenin-treated mice, the asthma symptoms significantly improved. Apigenin reduced inflammatory cell invasion into the lungs, which is typically a feature of inflammation in asthma [46]. It also inhibited airway hyperresponsiveness, an over-reaction of the airway to stimuli, and decreased total immunoglobulin E (IgE) levels, a key antibody in allergy. Apart from that, apigenin altered the immune response from the T-helper type 2 (Th2) predominant pattern, typical of allergic inflammation, to the pattern of a T-helper type 1 (Th1) profile. Th1 responses are also accompanied by anti-inflammatory actions and a reduced tendency for allergic reactions. This conversion shows that apigenin may possess anti-inflammatory activities that can benefit in managing allergic asthma by modulating immune reactions [47]. The research investigated the anti-asthmatic effects of apigenin in an OVA-induced asthma model. Apigenin treatment caused decreased airway resistance, decreased numbers of eosinophils, and decreased pro-inflammatory cytokine levels (IL-6, TNF-α, and IL-17A). The research also detected strong inhibition of T-helper 17 (Th17) cells and down-regulation of RORγt protein expression, suggesting that apigenin could be useful in managing asthma progression through modulation of the Th17 cell response and reduction of inflammation [48]. Research compared the actions of natural flavones, such as apigenin, on late-phase and immediate asthmatic responses in guinea pigs sensitized to OVA. Apigenin therapy significantly reduced certain airway resistance in both phases and inhibited leukocyte mobilization, histamine release, and activity of phospholipase A₂ and eosinophil peroxidase in bronchoalveolar lavage fluid. These findings show that apigenin possesses anti-asthmatic activity through inhibition of airway hyperresponsiveness and inflammation [49]. An experimental study investigated apigenin’s potential to alleviate airway inflammation in PM2.5-exposed asthmatic mice. Apigenin significantly decreased airway hyperresponsiveness and suppressed eosinophil and neutrophil infiltration in bronchoalveolar lavage fluid and lung tissue. The study also showed significant reductions in total serum IgE and cytokines IL-4, IL-13, and IL-17 levels. In addition, apigenin suppressed the mRNA level of the NF-κB p65 subunit in lung tissue, which implies its involvement in inflammatory response modulation in asthma induced by PM2.5 exposure. These immunomodulatory and anti-inflammatory effects suggest that apigenin may act synergistically with conventional anti-asthmatic drugs. Such combinations could improve therapeutic outcomes by targeting multiple inflammatory pathways simultaneously [50].

Researchers isolated apigenin from the Portulaca Oleracea plant and evaluated its antibacterial activity against several pathogenic bacteria, including Salmonella typhimurium. The study reported a zone of inhibition of 17.36 ± 0.18 mm for Salmonella typhimurium, indicating significant antibacterial activity. However, the minimum inhibitory concentration (MIC) for all tested bacterial strains, including Salmonella typhimurium, was found to be greater than 4 mg/mL, suggesting that higher concentrations of apigenin are required to inhibit bacterial growth effectively [51]. This study focused on the antibacterial mechanism of apigenin in Escherichia coli. The researchers found that apigenin induced apoptosis-like death in Escherichia coli by increasing intracellular calcium levels and promoting the production of reactive nitrogen and oxygen species. While this study did not directly assess apigenin’s effect on Salmonella typhimurium, the findings suggest a potential mechanism by which apigenin could exert antibacterial effects on similar Gram-negative bacteria [43]. This study examined the inhibitory activity of apigenin against multiple bacterial species. The results for Salmonella typhimurium were mixed, with some studies reporting no significant inhibition, while others observed antibacterial effects. These discrepancies may be attributed to differences in experimental conditions, bacterial strains, and apigenin concentrations used. A comprehensive review highlighted apigenin’s antimicrobial potential, noting that its inhibitory effects are strain-specific. In certain cases, although apigenin did not inhibit the growth of pathogenic bacteria, it reduced toxin production and mitigated pathogen-induced injury. Additionally, synergistic effects have been observed when apigenin is combined with other antibiotics. Although apigenin requires higher concentrations for direct antibacterial effects, its mechanism of inducing oxidative stress in bacteria supports its potential as a synergistic agent. Combination with standard antibiotics may enhance efficacy against resistant strains [52].

Researchers demonstrated that apigenin inhibits the expression of adhesion molecules induced by high glucose and tumor necrosis factor-alpha in human endothelial cells, suggesting a protective role against vascular complications in diabetes [53]. They found that apigenin improves diabetes by modulating biochemical pathways, enhancing GLUT4 translocation, and altering CD38 expression, thereby improving glucose uptake and metabolism [54]. A study by Ren et al. showed that apigenin ameliorates glucose and lipid metabolism disorders and improves vascular dysfunction in type 2 diabetic rats, indicating its multifaceted benefits in managing diabetes [55]. A systematic review highlighted apigenin’s role in alleviating insulin resistance, regulating glycolipid metabolism, and mitigating oxidative stress through various mechanisms, including the inhibition of insulin receptor kinase activity and modulation of microRNAs [23]. Recent research focused on synthesized apigenin analogs revealed significant inhibitory effects on α-glucosidase, an enzyme involved in carbohydrate digestion, suggesting potential therapeutic applications for type 2 diabetes. A study published in the Uttar Pradesh Journal of Zoology examined the effects of apigenin in alloxan-induced diabetic rats. The outcomes reported that apigenin dramatically lowered blood glucose levels, suppressed the activity of α-amylase, and improved the activity of antioxidant enzymes. The outcomes indicate that apigenin alone and combined with metformin could be efficacious in the management of hyperglycemia and oxidative stress in diabetes [56]. Table 2 provides a consolidated overview of the diverse pharmacological activities of apigenin, along with their proposed mechanisms and experimental models. A published study in the European Journal of Pharmacology reviewed the impact of apigenin on cognitive impairment caused by hyperglycemia in zebrafish. The test revealed that apigenin improved learning and spatial memory, reduced blood glucose levels, and mitigated brain oxidative stress. Such protective effects on the brain were attributed to Nrf2/ARE pathway induction, highlighting apigenin’s potential in reducing diabetic-related cognitive impairment.[57]. Research work in Bioorganic Chemistry examined synthesized apigenin analogs as α-glucosidase inhibitors. Among the compounds being tested, one analog was reported to possess significant inhibitory activity, lowering fasting blood glucose and reducing insulin resistance in a mouse model of type 2 diabetes. This points to the potential of apigenin derivatives in the development of new antidiabetic agents [58]. Apigenin has been studied for its influence on pancreatic β-cells and has been reported to increase glucose-stimulated insulin secretion together with protection against ER stress-induced apoptosis. Such protective effects may be attributed to the possible downregulation of proteins crucial for stress, namely, CHOP and TXNIP, by apigenin. Modulation of these molecular pathways helps apigenin to preserve β-cell function and cell survival, which could suggest a therapeutic role for this flavonoid in preventing or managing diabetes-related β-cell dysfunction. These findings indicate that apigenin holds strong potential as an adjunct in diabetes management. Its ability to regulate glucose metabolism and oxidative stress supports synergistic use with antidiabetic drugs such as metformin to improve glycemic control and reduce complications [59].

The combination of apigenin with conventional chemotherapeutic agents has emerged as a promising strategy to enhance anticancer efficacy while overcoming drug resistance. Apigenin has been shown to potentiate the therapeutic effects of drugs such as doxorubicin, cisplatin, and TRAIL through multi-targeted mechanisms involving apoptosis induction, oxidative stress modulation, and regulation of key signaling pathways [63]. The co-administration of apigenin with doxorubicin has demonstrated significant enhancement in anticancer activity across various cancer cell lines. This combination leads to increased intracellular accumulation of doxorubicin, primarily through the inhibition of efflux transporters such as P-glycoprotein, thereby reducing multidrug resistance. Mechanistically, apigenin promotes p53 activation, enhances ROS generation, and facilitates mitochondrial-mediated apoptosis. The combined treatment results in amplified DNA damage, caspase activation, and a marked increase in apoptotic cell death compared to monotherapy [64].

Similarly, the synergistic interaction between apigenin and cisplatin has been widely reported to improve therapeutic outcomes. Apigenin sensitizes cancer cells to cisplatin by modulating key survival pathways such as PI3K/Akt and NF-κB, which are often implicated in chemoresistance. Additionally, apigenin enhances oxidative stress within tumor cells, leading to mitochondrial dysfunction and apoptosis [65]. This combination has been shown to reduce cisplatin-induced toxicity while maintaining or enhancing anticancer efficacy, thereby improving the therapeutic index. Apigenin also exhibits strong synergy with TRAIL, particularly in TRAIL-resistant cancer cells [66]. The combination enhances apoptosis by upregulating death receptors DR4 and DR5 in a p53-dependent manner, thereby restoring TRAIL sensitivity. Furthermore, apigenin inhibits anti-apoptotic proteins such as Bcl-2 and survivin, while activating cascades. Collectively, these interactions result in increased apoptotic signaling and reduced tumor cell survival, highlighting apigenin’s potential as a sensitizing agent in targeted cancer therapies [67].

Apigenin has demonstrated promising synergistic effects when combined with standard antidiabetic agents such as metformin, offering improved glycemic control and metabolic regulation. Metformin is a first-line oral antihyperglycemic agent widely used in the management of type 2 diabetes mellitus and acts primarily by reducing hepatic glucose production and improving insulin sensitivity [68]. The combination of apigenin with metformin has been shown to enhance glucose uptake and utilization through modulation of GLUT4 translocation and activation of AMPK pathways. Apigenin complements metformin’s action by improving insulin sensitivity and reducing insulin resistance at the cellular level. Additionally, apigenin exerts antioxidant effects that mitigate oxidative stress, a key contributor to diabetic complications [69].

Recent studies also suggest that metformin may exhibit indirect or adjuvant antimicrobial effects, possibly mediated through host metabolic modulation, alteration of gut microbiota, and AMPK-dependent pathways. While metformin is not classified as an antibiotic, these findings highlight its potential ancillary role in influencing microbial processes [70]. Mechanistically, apigenin regulates key enzymes involved in carbohydrate metabolism and suppresses inflammatory mediators associated with insulin resistance. The combined treatment has been reported to improve lipid profiles, reduce hyperglycemia, and protect against vascular complications. This synergistic interaction suggests that apigenin can act as an effective adjuvant to conventional antidiabetic therapy, enhancing therapeutic outcomes while potentially lowering drug dosage requirements [71].

The combination of apigenin with conventional antibiotics represents a promising strategy to combat antimicrobial resistance and improve therapeutic efficacy. Although apigenin alone exhibits moderate antibacterial activity, its synergistic interactions with antibiotics significantly enhance antimicrobial effects against a range of pathogenic microorganisms. Apigenin has been shown to disrupt bacterial cell membrane integrity, leading to increased permeability and facilitating enhanced antibiotic uptake [72]. This membrane-disruptive action weakens bacterial defense mechanisms and potentiates the activity of co-administered antibiotics. Additionally, apigenin interferes with bacterial quorum-sensing systems, thereby inhibiting communication pathways essential for virulence and survival. A key mechanism underlying this synergy is the inhibition of biofilm formation, which is a major factor contributing to chronic infections and antibiotic resistance. Apigenin reduces exopolysaccharide production and alters cell-surface properties, thereby preventing bacterial adhesion and biofilm maturation. These effects enhance bacterial susceptibility to antibiotics and improve treatment outcomes. Furthermore, apigenin-induced oxidative stress within bacterial cells contributes to cellular damage and apoptosis-like death, further amplifying antimicrobial efficacy. This combination approach holds significant potential in addressing multidrug-resistant infections and reducing the burden of antibiotic resistance [73].

Emerging evidence suggests that apigenin may enhance the efficacy of neuroprotective agents through synergistic interactions targeting oxidative stress, neuroinflammation, and neuronal survival pathways. Although studies in this area are relatively limited, available data indicate promising therapeutic potential in neurodegenerative disorders. Apigenin, when used in combination with neuroprotective drugs or agents targeting cognitive impairment, has been shown to improve neuronal function and reduce neurotoxicity. The synergistic effects are primarily mediated through the modulation of PI3K/Akt, ERK/CREB/BDNF, and Nrf2 signaling pathways, which play critical roles in neuronal survival, synaptic plasticity, and antioxidant defense [74]. Additionally, apigenin enhances mitochondrial function, reduces the accumulation of neurotoxic proteins such as amyloid-β, and attenuates neuroinflammation by inhibiting pro-inflammatory cytokines. These combined effects contribute to improved cognitive performance and neuroprotection in experimental models. The integration of apigenin with existing neurotherapeutics may offer a multi-targeted approach for the management of neurodegenerative diseases such as AD and epilepsy. However, further studies are required to validate these findings in clinical settings and to establish optimal dosing strategies for combination therapy [75]. Table 3 summarizes key studies demonstrating the synergistic effects of apigenin in combination with conventional small-molecule drugs, highlighting therapeutic outcomes, underlying mechanisms, and experimental models.