Luteolin as a Cancer Therapeutic: From Preclinical Evidence to Translational Potential

ABSTRACT

Cancer, a condition marked by the atypical development and multiplication of cells that may acquire aggressive properties, ranks among the foremost causes of mortality globally. Because of the problems with existing chemotherapy medications, cancer therapeutic research is being conducted to find substitute treatment approaches that are less harmful to healthy cells. The application of flavonoids has become a prominent area of interest in cancer therapy research. Luteolin, 3′,4′,5,7‐tetrahydroxyflavone, is a common flavonoid that may be found in many plants and medicinal herbs. Luteolin‐rich plants have been used to cure a variety of illnesses, including cancer, inflammatory conditions, and hypertension. Targeting cellular processes such as apoptosis, angiogenesis, migration, and cell cycle progression, luteolin's anticancer properties have been thoroughly studied in a variety of cancer types. It interacts with several proteins and signaling pathways to accomplish this. The development of contemporary luteolin research is outlined in this study, with an emphasis on preclinical data and translational prospects. This article reveals the chemistry, structure–activity relationship, and extraction techniques of luteolin. It explores pharmacological activities, mechanism of action, and advancements in nanoformulation strategies. Furthermore, it explains how luteolin's potential as a cancer treatment is demonstrated from preclinical proof to translational capability.

Anticancer potential of flavonoid luteolin. It is active against several types of cancer, such as breast, liver, lung, pancreatic, gastric, and colon. Its delivery method can be advanced by nanoformulations for targeted drug release.

1. Introduction

One of the most prevalent causes of death globally, cancer is marked by the uncontrolled development and multiplication of cells that may also have invasive characteristics [1]. The disease's impact on the healthcare system is growing yearly. According to the International Agency for Research on Cancer, there will be over 30.2 million new incidences of cancer all over the world by 2040, up from about 19.3 million in 2020 [2]. Even with an abundance of information and research on this illness, there are still safety and efficacy issues with the current treatment options, which have a strong effect on patient acceptability and therapeutic outcomes. The high anticipated occurrence rate along with the significant live loss underscore the necessity to develop innovative, effective, and non‐toxic therapeutic agents for malignancy treatment [3].

Herbal extracts, which are used for the management of both benign and malignant tumors, have long been a great source of natural remedies [4]. The structural and mechanistic properties of plant‐derived bioactive agents have previously been the focus of substantial investigation in preclinical settings against diseases like infection, heart diseases, neurological disorders, and especially cancer. The monitoring event for anticancer activities of herbal chemicals, which was started by the US National Cancer Institute (NCI) in 1960, is a significant component of these investigations [5]. Studies on herbal anticancer medications have made it possible to use the structures that nature offers, such as plants, to synthesize vital substances that are used to develop effective anticancer therapeutics [6].

Over 10 000 flavonoids, plant‐derived bioactive compounds, have been discovered to be present in a variety of plant species, involving dietary plants and herbs like green tea, citrus fruits, cacao, and plenty more [7]. A large number of naturally occurring, low molecular weight molecules that are frequently found in plants as secondary metabolites are called flavonoids. Benzo‐γ‐pyrone, also known as phenylchromone, is a fundamental chemical structure consisting of two benzene rings linked by a pyrane ring [8]. Flavones are a subclass of flavonoids that have an oxidized C4, a double bond between C2 and C3, and no hydroxyl group at C3 [9]. Apigenin, luteolin, diosmetin, chrysin, tangeritin, and others are examples of typical flavones. It is believed that hundreds of flavones have been identified. Numerous fruits, vegetables, herbs, and drinks include these substances, which give these plant‐based meals their color, flavor, and certain benefits for health.

Several studies have examined flavones' possible anticancer effects in vitro, mainly evaluating their cytotoxicity or inhibition of proliferation in cancer cell lines generated from different human organs and tissues [8]. One of the most researched flavones, luteolin, for instance, has shown apoptosis in cancer cell lines derived from prostate, breast, pancreatic, colon, lung, melanoma, liver, stomach, and brain [10]. Additionally, because of its chemical composition, luteolin can act as an antioxidant. Luteolin and its glycosides are antioxidants that can chelate metal ions along with neutralize free radicals produced by oxidative damage [11]. They can also prevent pro‐oxidant enzymes from producing free radicals. Antioxidant enzymes can be induced by luteolin and its glycosides [10]. Although in vitro research offers important insights into the underlying processes of flavones' anticancer benefits, challenges have been highlighted over their applicability in in vivo or clinical applications, where the results may not always be repeated [12].

By inhibiting nuclear factor kappa B (NF‐κB) and mitogen‐activated protein kinase (MAPK) signaling pathways, luteolin demonstrates strong antioxidant properties, significant anti‐inflammatory effects, and the ability to affect oxidative stress, microglial activation, and synaptic function [13]. These physiological actions identify luteolin as a viable nutraceutical candidate for moderating neuroinflammation and cognitive decline, two major aspects associated with neurodegenerative diseases (NDDs). Multiple processes, such as autophagy or apoptosis, are engaged by which luteolin demonstrates its anticancer effects, which induce the death of malignant cells [10]. Luteolin has pleiotropic antineoplastic effects because it can cause cell cycle arrest, reduce angiogenesis, cancer cell proliferation, and metastatic potential, and cause apoptosis in experimental subjects with cancer. During apoptosis, multiple pathways are implicated such as modulation of mitochondrial membrane, activation of caspase‐3, ‐7, ‐8, and ‐9, release of cytochrome c, suppression of antiapoptotic proteins such as levels of B cell leukemia/lymphoma 2 (Bcl‐2) and Bcl‐Xl [14], increment of death receptors, downregulation of certain factors including TNF receptor, DR4, DR5, Fas/ FasL, and apoptosis‐inducing ligand (TRAIL). After acquiring signals of apoptosis, binding of Fas‐associated death domain (FADD) starts, which results in the synthesis of initiator caspases‐8 and ‐10 due to ongoing recruitment of the death‐induced signaling complex. Many intrinsic and extrinsic apoptotic pathways are also activated due to mitochondrial membrane disruption, which stimulates caspase activities, increases imbalance in the Bcl‐2‐associated X (BAX)/ Bcl‐xL ratio, and lowers the protein expression of survivin, p21, mdm2, and Mcl‐1 [10]. After luteolin therapy, a decrease in cell growth, reduction in antiapoptotic protein Bcl‐2, increase in BAX levels, and induction of apoptosis in BEL‐7402 and SMMC‐7721 cell lines were detected [15].

Increasingly, preclinical and nascent clinical evidence suggests luteolin is able to penetrate the blood‐brain barrier (BBB), decreasing neuroimmune activation, promoting neuronal viability, and improving cognitive function in models of Alzheimer disease (AD), Parkinson Disease (PD), and other neurodegenerative disorders (NDDs) [16]. This review aims to provide a comprehensive overview of the pharmacological action of luteolin and to highlight the key aspects pertaining to its bioavailability, absorption, and metabolism, while crucial steps figure out its safety profiles, given the enormous promise of this natural antioxidant in well‐being. Furthermore, it explains how luteolin's potential as a cancer treatment is demonstrated from preclinical proof to translational capability.

2. Chemical Properties and Biological Disposition of Luteolin

2.1. Chemical Structure, Structure–Activity Relationships and Biosynthesis of Luteolin

Lignan (3¹,4¹,5,7‐tetrahydroxyflavone) is a naturally produced flavonoid that belongs to a class of phytoestrogens and was first identified from the herb lignan, genus lignan, in the family Lignaceae [17]. Glycoside elements can be glycosylated in two major ways: either by the free hydroxyl (OH) group, known as an O‐glycoside, or by the C─C bond, known as a C‐glycoside, as depicted in Figure 1a,b [18].

FIGURE 1.

(a) Synthetic route of flavonoid—O‐β‐D‐glucoside by O‐glycosylation. (b) Synthetic route of flavonoid—C‐β‐D‐glucoside by C‐glycosylation.

Luteolin possesses a yellow acicular body that contains water of crystallization. Its molecular formula is C₁₅H₁₀O₆, and it has a basic structure, characterized by C₆‐C₃‐C₆ [19]. According to the molecular arrangement, luteolin is a polyphenol hydroxyl compound [20]. Its lipophilicity as well as hydrophilicity are low because of the intermolecular forces within the hydroxyl groups, but it also has an abundance of pharmacological actions because of the hydroxyl parts on the 5, 7, 3⁰, and 4⁰ carbons in its framework, as well as the presence of two to three double bonds [17, 21]. Research on the structure–activity relationship, as shown in Figure 2 [10, 21, 22], showed that the hydroxyl groups at positions C₅, C₇, C₃₀, and C₄₀ are responsible for Luteolin's potent antioxidant action, whereas the carbonyl oxygen at position C₄ is responsible for its efficacy against microbes [23, 24]. Furthermore, it has been determined that the double bond between C₂ and C₃ provides biocidal properties. Luteolin is predominantly present in plants, primarily as an aglycone lacking a sugar moiety as well as a glycoside, namely LUT‐7‐O‐glucoside (LUT‐7G), with glucose being the principal sugar moiety attached [25]. The chemical constituents of luteolin are the principal difference between its aglycone versus glycoside forms; in the glycoside form, the molecules of sugar are linked by one or more hydroxyl groups [26]. Moreover, the aglycone variant of luteolin exhibited enhanced anti‐inflammatory as well as antidiabetic properties relative to the LUT‐7‐O‐glucoside variant [25]. The phenylalanine route is necessary for the condensation processes that produce luteolin, which include many enzymes [27]. Initially, phenylalanine deaminase, cinnamate 4‐hydroxylase, as well as 4‐coumaroyl coenzyme A ligase sequentially transform L‐phenylalanine into 4‐coumaroyl coenzyme A, a common precursor for flavonoids, through three enzymatic processes [17]. Naringenin chalcone, the fundamental component of all flavonoids, is synthesized when chalcone synthase reduces to a 4‐coumaroyl coenzyme. A molecule comprising three propylene glycol coenzyme A units. Chalcone isomerase (CHI) subsequently catalyses the synthesis of naringenin, a predecessor of luteolin and apigenins, using heterocycle C. Finally, apigenin serves as a substrate for luteolin production in the presence of flavonoid 3 α‐hydroxylase.

FIGURE 2.

SAR study of luteolin as an anticancer scaffold.

2.2. Physicochemical Properties Affecting Bioavailability

Luteolin has been reported as one of the possible bioactive agents that could lead to the pharmacological and proactive benefits of several medicinal plant species according to thorough investigations reported in the literature [28]. Luteolin has several positive health impacts, just like other natural polyphenols. According to numerous preclinical studies, luteolin has a variety of pharmacological effects, like antioxidant and ROS scavenging, anticancer, cardioprotective, and neuroprotective effects [10]. Therefore, it is clear that luteolin can have a variety of positive effects on human health [29].

Luteolin's limited bioavailability has been documented in a number of studies, indicating that this is the main drawback of this bioactive substance [19]. Since flavonoids are polyphenolic substances, their large size restricts their ability to penetrate through the lipoidal membrane. To improve the therapeutic efficacy and potency of these plant‐derived compounds, the bioavailability issue should be resolved because their limited solubility in water is an obstacle that restricts their absorption into the bloodstream to achieve the desired plasma levels for the therapeutic effect [30]. To the best of our knowledge, luteolin is not taken into consideration while compiling comprehensive data on its bioavailability, absorption and metabolism, safety profile, as well as its in vivo pharmacological actions. Additionally, expertise on current research on drug delivery methods created to boost luteolin's bioavailability [31].

2.3. Pharmacokinetics of Luteolin (ADME)

Flavonoids are typically absorbed from the digestive system and converted into glucuronide or sulphate conjugates, whether they are free or glycosylated [32]. Yasuda et al. demonstrated that luteolin can be absorbed effectively after oral ingestion by showing that the free luteolin in the plasma rapidly spiked after 0.5 h post‐administration in rats and attained the peak level at 1 h [33].

Following intestinal absorption, the majority of Luteolin undergoes conjugation—essentially being converted into various compounds—while a little quantity of Luteolin was detected in urine and fecal excretion [34]. The biological benefits of luteolin as well as its glycosylated form are predominantly associated with its metabolite, as demonstrated by Kure et al., who established that the active portion of the luteolin molecule exhibited anti‐inflammatory properties in rat experiments [35]. Furthermore, Wang et al.’s 2017 pharmacokinetics analysis in rats revealed that UDP‐glucuronosyl transferases (UGTs) and catechol‐O‐methyltransferases (COMTs) were primarily responsible for catalyzing the metabolites of luteolin because glucuronidation and methylation are thought to be two crucial pathways in Phase II metabolism and the metabolic fate of luteolin and luteolin‐7‐Oglucoside [36].

According to earlier pharmacokinetics research, luteolin is quickly absorbed when taken orally; amounts of the medication can be seen in the plasma within 30 min, although they are very minimal and quickly eliminated by the kidneys [37]. Because luteolin is poorly soluble in water, its systemic absorption is limited [38].

To date, a number of pharmacological studies have been carried out to improve the solubility and bioavailability of luteolin by concentrating on the primary concept of slowing the blood's breakdown to prolong luteolin's circulation period [39]. For example, Khan et al. improved the bioavailability and effectiveness of luteolin in the treatment of inflammatory liver injury by using the phospholipid complex [40]. They discovered that the percentage in vivo bioavailability of luteolin‐containing phospholipid complex increased to 535.31% compared to luteolin‐lacking phospholipid complex [40]. In a different study, Dang et al. (2014) improved the bioavailability and pharmacokinetic profile of luteolin for both in vitro and in vivo investigations using a nanoparticle drug delivery technology [41]. Their research showed that employing the specific nanoparticle method increased the concentration of luteolin in the plasma [42].

3. Preclinical Pharmacological Activities of Luteolin: In Vivo Evidence

The characteristics effect of luteolin have been widely recognized and examined through numerous in vitro and in vivo research. Despite luteolin's established antioxidant and anti‐inflammatory properties, its potential for use as an anticancer flavonoid has gained prominence over the past decade, with numerous preclinical studies demonstrating its proapoptotic as well as antiproliferative effects. The following Table 1 illustrates the diverse pharmacological actions of luteolin, encompassing its anti‐inflammatory and anticancer properties in several in vivo models.

TABLE 1.

Anticancer effects of luteolin in in vivo cancer models.

Type of cancer	Cell line/animal model	Dose concentration	Major pathways modulated	Key anticancer effects	Ref.
Liver cancer	The HAK‐1B human hepatocellular carcinoma (HCC) cell line was implanted into BALB/c nude mice to create a xenograft tumor growth model.	50 or 200 mg/kg.	The overproduction as well as constitutive activation of STAT3 have been linked to a negative outcome in individuals with HCC. In HCC models, the oncogenic mechanisms of STAT3 have been thoroughly investigated. Consequently, STAT3 has emerged as a potential target for the therapy of HCC.	Tumors in the luteolin‐treated groups started to shrink after four to six weeks of treatment, but tumors in the control group kept growing. Following luteolin therapy, tumor tissues showed a decline in the amount of phosphorylated STAT3.	[43]
	Mouse model of liver carcinogenesis induced by DEN (Diethyl nitrosamine)	20 µg/kg luteolin i.p. every alternate day.	Mostly responsible for initiating redox homeostasis, antioxidant enzymes, and inflammatory cytokines alongside.	Luteolin also improved antioxidant effects, reduced ALT/AST, decreased inflammatory cytokines, and mitigated liver carcinogenesis progression.	[44]
	DEN‐induced HCC in rats with luteolin + galangin + doxorubicin	Combination with galangin and DOX (dose not specified)	Majorly take part in the role of Caspase‐3 activation, and along with that decreased α‐fetoprotein‐L3 and GPC‐3 expression.	Combination therapy of DEN‐induced HCC in rats with luteolin + galangin + doxorubicin showed enhanced antitumor activity, increased apoptosis markers, and decreased HCC markers.	[45]
Lung cancer	To ensure that the tumor is immunologically acceptable with the host strain, it makes use of the Lewis lung carcinoma (LLC) model, which was initially developed from a random C57BL/6 lung carcinoma cell line.	Luteolin treatment reduced tumor growth by 40% at a dose of 2 mg/kg and by 60% at 10 mg/kg.	In order to create lung tumors, LLC cells were first inserted into the right flank of male C57BL/6 mice. On day 13, luteolin dramatically decreased the production of proliferating cell nuclear antigen (PCNA), a marker of cell proliferation, while increasing the levels of terminal deoxynucleotidyl transferase biotin‐dUTP nick end labeling (TUNEL), a hallmark of programmed cell death, according to immunohistochemical analysis of tumor regions.	These results imply that luteolin inhibits cell proliferation and promotes apoptosis to provide its anticancer effects in lung cancer.	[46]
	Luteolin + TRAIL (in combination vs. alone) in A549 NSCLC (Non‐small cell lung cancer) xenograft.	Dose is not specified.	Apoptosis sensitization and enhanced TRAIL‐induced apoptosis.	Treatment shows inhibition of tumor growth has been greater with combination; and increased apoptosis vs. control or single agents.	[47]
	H460 NSCLC (Non‐small cell lung cancer) xenograft (nude mice) model.	Dose is not specified	Upregulation of miR‐34a‐5p; increased MDM4; increased p53/p21; and activation of caspase‐3/9.	Significant suppression of tumor growth, reduced proliferation, increased apoptosis.	[48]
Gastric cancer	Human gastric cancer cell line MKN28 was subcutaneously injected into nude mice to cause tumors.	Luteolin was administered for four weeks at 10 mg/kg.	Luteolin‐treated tumor tissues showed reduced concentrations of β‐catenin, Notch1, and Ki‐67, according to immunohistochemistry analysis. This suggests that the Notch1 signaling pathway is a major mechanism behind luteolin's capacity to prevent cancer cell growth in this paradigm. The results showed significantly reduced tumor volume and weight in luteolin‐treated groups compared to controls.	When compared with the controls, the luteolin‐treated groups' tumor weight and volume were significantly lower.	[49]
	MKN45/BGC823 Subcutaneous xenograft (20 mg/kg)	20 mg/kg i.p. luteolin was administered.	Luteolin generally activates the Notch1, PI3K/Akt/mTOR, ERK, and STAT3 signaling pathways.	Reduced tumor volume and weight; decreased Ki‐67 (proliferation marker); increased apoptosis (TUNEL).	[50]
	cMet‐overexpressing gastric cancer PDTX Models	10 mg/kg i.p. luteolin daily	Activate cMet/Akt/ERK signaling pathway.	Significant inhibition of tumor growth in patient‐derived xenografts; decreased cMet, MMP‐9, and Ki‐67.	[51]
Colon cancer	The human colorectal cancer LoVo cell line was injected subcutaneously into the flank of naked mice to cause tumors in a CDX model (cell line‐derived xenograft model).	The tumor inhibition rate was 27%, 51%, and 60% in animals treated with 10, 20, and 40 mg/kg luteolin, respectively.	According to the researchers, luteolin increases the therapeutic action of cisplatin by upregulating the levels of p53 protein.	In this paradigm, luteolin exhibited dose‐ and time‐dependent tumor inhibitory impact.	[52]
	CT26 colon cancer xenografts (BALB/c mice)	20–40 mg/kg of luteolin i.p. was administered in the xenograft mice model.	Generally, it increases p53 gene regulation, increased caspase‐3, decreased Bcl‐2, decreased Cyclin D1 activation.	Mainly, luteolin inhibits tumor growth; promotion of apoptosis through p53 activation.	[53]
	AOM‐DSS‐induced colon carcinogenesis (mouse model)	Luteolin in diet or via gavage (typically 0.05–0.1%)	Decreased Inflammation (IL‐6, TNF‐α), decreased COX‐2 and NF‐κB activation.	Reduced tumor incidence, multiplicity, and size; decreased inflammation and tumorigenesis.	[54]
Breast cancer	T47‐D cells, a cell line for breast cancer, were injected into xenograft models of progestin‐dependent human breast cancer.	Following T47‐D cell inoculation, luteolin was administered ten times at a dose of 20 mg/kg (i.p.) between days 61 and 79.	Luteolin may have anti‐angiogenesis properties because it reduced blood vessel density and vascular endothelial growth factor (VEGF) production in tumor tissues.	In the model, naked mice pretreated with estradiol and medroxyprogesterone acetate had T47‐D cells, a cell line for breast cancer, injected into their flanks. In comparison to the untreated controls, the luteolin‐treated group's tumor volume was considerably decreased after Day 76.	[55]
	MDA‐MB‐231 human TNBC xenografts in nude mice.	0.01–0.05% luteolin in diet.	Decreased EGFR/MAPK/AKT signaling activation; cell cycle arrest; increased p21, Bax regulation.	Significant reduction in tumor burden and proliferation.	[56]
	Orthotopic TNBC (likely 4T1) in BALB/c mice	Multiple doses (low vs. high; e.g., ∼10–40 mg/kg)	Decreased SGK1; increased FOXO3a, BNIP3 regulation; induction of apoptosis & autophagy	Dose‐dependent reductions in tumor volume & weight; increased apoptosis and autophagy markers.	[57]
Pancreatic cancer	The naked mouse model's pancreas was administered directly with the human pancreatic cancer cell line BxPC‐3.	Luteolin was administered intraperitoneally (i.p.) at a high dose of 84 mg/kg 7 times per week for the first week and 5 times per week for 2–6 weeks following tumor transplantation.	Several cancer‐related markers, such as K‐Ras (Kirsten rat sarcoma virus), GSK‐3β (glycogen synthase kinase‐3β), caspase 3, and Bcl‐2/Bax (BCL2 associated X) ratio, did not show any alterations.	After six weeks of treatment, luteolin had no discernible effect on tumor mass as determined by the pancreatic weight to body weight ratio. Furthermore, in pancreatic tumor tissue, luteolin suppressed PCNA expression.	[58]
	PC‐3M‐luc xenografts in SCID mice (luteolin with ellagic & punicic acids)	Combination (Luteolin + ellagic acid + punicic acid)	(Ellagic acid + punicic acid) Inhibited CXCL12/CXCR4 chemotaxis; Decreased angiogenic factors IL‐8 & VEGF	Inhibited primary tumor growth and prevented metastasis; reduced angiogenesis in vivo.	[59]
	LNCaP human prostate cancer xenografts in SCID mice.	Dose is not specified.	Decreased Androgen receptor (AR) expression via Hsp90 disruption; promotes proteasome‐mediated AR degradation	Suppressed tumor growth; decreased PSA levels and cell proliferation; induced apoptosis.	[60]

4. Pharmacokinetics, Bioavailability, and Strategies to Improve Bioavailability

4.1. Limitations of Bioavailability

Luteolin has been shown to have a number of positive health impacts. Beyond this vast understanding of luteolin's medicinal potential, however, concerns about its bioavailability, absorption, and metabolism are crucial in determining its safety profiles and overall health benefits [61]. Despite their potential significance, there are very few investigations on luteolin's bioavailability in human as well as animal models, and this field is still neglected. Upon absorption, the molecule must cross the intestinal wall and surpass hepatic metabolism, which is known as the first‐pass effect. Based on this, it is evident that a greater understanding of luteolin's absorption and metabolism is required to comprehend its bioavailability [62].

4.1.1. Absorption of Luteolin

Since the initial biological barrier to oral administration is the penetration of polyphenols through the gut epithelium, it is essential to comprehend intestinal uptake as well as efflux mechanisms in order to assess the effectiveness of these advantageous substances [63]. Typical luteolin glycosides are primarily produced by glycosylation of aglycone (1) via free hydroxyl (OH) groups (called O‐glycosides) and/or (2) via C─C bonds (called C‐glycosides) [64].

In rats and two human volunteers, Shimoi et al. examined the absorption of luteolin and luteolin 7‐O‐β‐glucoside in the intestine [65]. In this study, intestinal absorption as well as metabolite profiles were assessed using luteolin and O‐methyl luteolin (chrysoeriol) extracted from perilla seed [37]. Rat small intestine was isolated and cultured in a specific solution including 1 mM luteolin or luteolin 7‐O‐β‐glucoside to investigate the gastrointestinal absorption of both compounds from the mucosa to the serosal side [33]. The components that appeared on the serosal side were measured using high‐performance liquid chromatography (HPLC); chromatograms revealed the existence of the luteolin peak along with two metabolite peaks that were observed at various times. The administration of β‐glucuronidase and sulfatase resulted in a reduction of intermediate peaks and an increase in the luteolin peak, indicating that both of the metabolites were glucuronide and/or sulfate derivatives of luteolin [66]. These findings imply that luteolin is absorbed following the hydrolysis of luteolin 7‐O‐β‐glucoside to luteolin and that luteolin glucuronide metabolites were produced during absorption [37].

4.1.2. Metabolism of Luteolin

Flavonoids can be substantially metabolized by cytochrome P450 monooxygenases in the liver through phase I metabolism following ingestion. Flavonoid metabolism has been shown to involve 18 families of cytochrome genes with a wide variety of isoforms [67]. It is proposed that phase II conjugating enzymes, including urine‐5′‐diphosphate glucuronosyltransferases (UGTs), sulphotransferases, and catechol‐O‐methyltransferases (COMTs), constitute the principal metabolic pathways; consequently, the products of phase I metabolism‐derived oxidation are generally considered secondary metabolites [68]. Plasma and urine are the primary sources of glucuronide conjugates. There are not many studies on luteolin metabolism, hence the field's understanding is still unclear.

Three unique luteolin glucosides as well as luteolin aglycone were isolated using green pepper leaves and administered to rats in the study conducted by Hayasaka et al. [69]. Luteolin aglycone was administered to individuals. The principal findings indicated that luteolin‐3′‐O‐sulfate was predominant in human plasma after the administration of luteolin aglycone, while in rats, luteolin aglycone was mainly metabolized to luteolin glucuronide [37, 69].

Two potential mechanisms were proposed after the role of luteolin's glucuronidation along with methylation pathways in rats was examined [36]. In the first, UGTs glucuronidate luteolin to produce luteolin‐7‐glucuronide, luteolin‐4′‐glucuronide, and luteolin‐3′‐glucuronide, the latter of which is the most prevalent in rat bile and plasma. According to the second possible pathway, COMTs will first methylate luteolin to chrysoeriol and diosmetin, and UGTs will then glucuronidate it to the corresponding chrysoeriol as well as diosmetin glucuronides. Because COMTs and UGTs convert metabolites to one another, both glucuronidation as well as methylation of luteolin were compensating each other, with glucuronidation being the predominant pathway [70].

4.1.3. Strategies to Improve Luteolin Bioavailability

Due to substantial first‐pass digestion by phase II enzymes, luteolin's low bioavailability is one of the main obstacles to its therapeutic application [71]. Many delivery methods, likewise lipid carriers and nanoformulations, have been created and studied against the problem.

A team of researchers evaluated the bioavailability of a solid nanostructured lipid carrier as well as a liquid microemulsion formulation of luteolin in rats [72]. Both formulations enhanced luteolin's oral bioavailability, but the microemulsion produced superior outcomes. Additionally, microemulsion was shown to have a greater concentration of solubilized medication, indicating rapid absorption and good bioavailability. Additionally, luteolin's solubility, bioavailability, as well as efficiency were improved by complexing it with phospholipid matrix (LPC). For example, rats treated with LPC showed a greater reduction in ear and paw edema than rats administered with pure luteolin [73]. Later, by focusing on the liver's inflammatory regions, the same study team showed that oral administration of LPC to albino rats reduced hepatic damage more successfully than luteolin‐treated rats [40]. Similarly, compared to free luteolin, liposome encapsulation has been shown to have strong anticancer activity against colorectal carcinoma cells (CT26) [53]. In order to create luteolin micelles with better water dispersion and prolonged drug release, luteolin was further coated with the amphiphilic copolymer poly (ethylene oxide) monomethyl ether‐poly (lactide‐co‐glycolide) (MPEG‐PLGA) [74]. Polyethylene glycol 4000 has recently been used to create luteolin solid dispersion (LT‐SD) using a variety of concentrations and techniques [75]. The earlier investigations show that various formulation techniques may improve luteolin's effectiveness, most likely by making it more soluble at the target sites and, as a result, more bioavailable.

Recent breakthroughs in flavonoid‐based nanomedicine have proven that nanoformulation technologies considerably improve the therapeutic efficacy of flavonoids by overcoming poor water solubility, fast metabolism, and restricted bioavailability [76]. Luteolin's stability, controlled release, tumor accumulation, and cellular uptake are all improved by a variety of nanocarriers, such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, and micelles. The enhanced induction of apoptosis, inhibition of cell proliferation, suppression of angiogenesis and metastasis, and modulation of important molecular signaling pathways like PI3K/Akt, NF‐κB, MAPK, STAT3, and Wnt/β‐catenin demonstrate the superior anticancer activity of nanoformulated luteolin [77]. Furthermore, functionalized nanoformulations enable targeted distribution to tumor sites while avoiding systemic toxicity, hence boosting the translational potential of luteolin for cancer therapy. These results are in line with recent developments for flavonoid‐based nanoformulations, emphasizing the increasing significance of combining enhanced bioavailability with molecular targeting to optimize therapeutic results [78].

5. Advanced Formulation Strategies to Enhance Translational Feasibility

Luteolin, polyphenolic molecule, exhibits anti‐inflammatory, anti‐allergic, and anticancer properties. According to recent research, luteolin exhibits anticancer activity against various cancers, including those of the lung, head and neck, colon, liver, cervix, prostate, breast, and skin [13]. These properties have been linked to the induction of apoptosis, suppression of metastasis, and inhibition of angiogenesis [13]. The findings of the aforementioned research suggest that further testing of luteolin's chemo‐preventive potential in human subjects is warranted [79]. However, due to its low water solubility, it is very difficult to administer intravenously or intraperitoneally and has very low bioavailability after oral administration [80]. Despite luteolin's high potency and usefulness, its rapid renal excretion and limited systemic absorption restrict its use in medicine. These adverse pharmacokinetic features hinder its therapeutic translation despite its strong anticancer activity by causing inadequate drug concentrations at tumor locations after traditional dosing [81]. Nanotechnology offers a solution to this issue by encapsulating this chemical in nanoparticles or creating intelligent materials to deliver two or more medications to the intended location. In addition to encapsulating different medications, nanomaterials offer methods for effectively delivering the agents to target areas, overcoming endothelium and epithelial barriers, and releasing them in the appropriate ratio, all of which improve therapy efficacy [82]. By increasing aqueous solubility, preventing premature metabolism, extending systemic circulation, and boosting tumor accumulation via the enhanced permeability and retention (EPR) effect and, when appropriate, active ligand‐mediated targeting, nanoformulations improve the pharmacokinetic and pharmacodynamic profile of luteolin. Higher intratumoral medication concentrations are made possible by these advancements, which also reduce systemic toxicity and raise the therapeutic index [34].

Additionally, in lung and head and neck cancer xenograft models, polymer‐encapsulated luteolin nanoparticles showed superior tumor growth suppression, indicating better systemic transport and therapeutic impact [82]. The most effective drug delivery method for enhanced oral medication delivery is thought to be nanostructured lipid carriers (NLCs) [83]. Cationic charged mucoadhesive polymers can be used to modify the surfaces of NLCs to produce unique mucoadhesion with absorption‐enhancing properties. This allowed it to further inhibit the growth of tumor cells in pancreatic cancer and encourage apoptosis. Several molecular studies demonstrated the effectiveness of the LUT‐NPs dealing in terms of tumor regression in an in vivo evaluation using a xenograft pancreatic cancer model [37]. By increasing luteolin's solubility, bioavailability, systemic exposure, and tumor‐specific accumulation, lipid‐based nanocarriers (such as liposomes and nanostructured lipid carriers) and polymeric nanoparticles show the most translational potential among the different delivery platforms. This increases luteolin's in vivo anticancer efficacy when compared to the free compound. To identify patient categories most likely to benefit from luteolin‐based therapy, however, standardized formulations, improved dosing techniques, thorough safety review, and biomarker‐guided clinical studies will be necessary for successful clinical translation [34]. Advanced nano‐delivery strategies have been listed out in Table 2.

TABLE 2.

Advanced nano‐delivery strategies for enhancing the translational potential of luteolin in cancer therapy.

Delivery system	Composition	Targeting strategy	Enhanced anticancer effects	Cancer model	Ref.
Polymeric nanoparticles	Zein‐loaded luteolin nanoparticles	Passive targeting	Increased cytotoxicity, prolonged release, improved solubility, and apoptosis	Colon cancer cells (SW480)	[84]
Solid lipid nanoparticles (SLNs)	Stearic acid, Tween 80	Passive targeting	Enhanced antitumor efficacy, regulated release, and stability	Prostate cancer (PC‐3)	[41]
PEG–PPS polymeric nanoparticles	PPS (ROS‐responsive hydrophobic polymer) + PEG (hydrophilic)	Release of ROS in response to the tumor microenvironment	Tumor cells are more cytotoxic than normal cells.	Melanoma (SK‐MEL‐28 cells )	[85]
Polymeric NPs conjugated with folic acid	Folic acid + polymer nanoparticles	Active targeting via folate receptor mediators	2.5‐fold increased cytotoxicity, extended retention, and improved internalization of cells	Breast cancer (4T1 cell line)	[86]
Polymeric nanoparticle (nano‐luteolin)	Water‐soluble luteolin encased in a polymer matrix (hydrophobic luteolin)	Passive targeting via enhancement of systemic delivery	Tumor growth in the xenograft model was significantly inhibited in comparison to free luteolin, and Tu212 cells showed reduced IC20 (4.13 µM vs. 6.96 µM for free luteolin).	Head and neck squamous cell carcinoma (Tu212), lung cancer (H292), and SCCHN xenograft mice model	[87]
PEG‐based micelles	Micelles of MPEG‐PCL	Passive targeting	Circulation time increased by 21 times; Cmax rose from 7.73 to 92.7 mg/L.	Breast cancer In vivo model(rat)	[88]
Nanostructured lipid carriers (NLCs) coated with chitosan (CS) and luteolin (LTN)	Chitosan‐coated luteolin enclosed in nanostructured lipid carriers	Mucoadhesive and permeability‐enhancing passive targeting (mediated by chitosan)	Compared to uncoated NLCs and free luteolin, there was a notable increase in dose‐ and time‐dependent cytotoxicity, enhanced gastrointestinal stability, intestinal penetration, antioxidant activity, and entrapment efficiency (up to 95.37%).	Cell lines for breast cancer (MDA‐MB‐231, MCF‐7)	[89]
PD‐L1‐specific stealth Liposome/PLGA nanoparticles (L‐PD‐SP/Ls)	PLGA polymer core loaded with luteolin, surface‐modified with PD‐L1 antibody, and mixed with lipids (DOPC, DSPE‐PEG)	Active targeting	Increased cellular uptake in comparison to non‐targeted NPs; far more HepG2 cell growth inhibition than free luteolin and non‐PD‐L1 NPs; decreased Bcl‐2 expression and elevated LDH release	Hepatocellular carcinoma (HepG2 cell line)	[90]

6. Pharmacokinetic and Safety Profile of Luteolin

Along with bioavailability and efficacy, safety is crucial for any molecule used for therapeutic purposes. Flavonoids have an excellent safety profile and are generally safe to eat. When administered orally or intravenously at certain dosages, luteolin is a safe substance with no adverse effects [91]. Notably, 100 mg/kg of luteolin did not cause significant liver or renal toxicity, suggesting a favorable safety profile for luteolin that is in line with other studies. The research showed that luteolin's LD50 was 460 mg/kg [92]. Despite luteolin's promising nutritional and health benefits, it exhibits poor intestinal absorption, low water solubility, and poor biodistribution. Numerous studies have detailed the metabolism, absorption, and excretion of luteolin [93].

Luteolin has low intestinal absorption, poor water solubility, and inferior biodistribution despite its encouraging nutritional and medicinal promise [94]. Luteolin is rapidly absorbed and extensively metabolized after oral treatment, according to pharmacokinetic studies. For instance, luteolin and its glycosides were rapidly absorbed in rats given Chrysanthemum morifolium flower extract; luteolin monoglucoside and luteolin monoglucuronide were found in plasma [65]. Peak plasma concentrations (0.76 ± 0.27 µM) were found at one hour after injection. According to these results, luteolin is absorbed in both its aglycone and glycosylated forms and goes through phase II metabolism. The main circulating forms of luteolin that may be relevant to human exposure are luteolin monoglucoside, luteolin, and luteolin monoglucuronide [95].

Even though luteolin undergoes significant phase II metabolism to produce conjugates of glucuronide and sulfate, it is still unclear how these metabolites contribute to its anticancer effect. After oral treatment, the most common circulating metabolites are glucuronide conjugates, especially luteolin‐3′‐O‐glucuronide, while free luteolin (aglycone) is found in much smaller amounts. The parent aglycone, which is typically thought of as the primary bioactive form responsible for modulating PI3K/Akt, NF‐κB, STAT3, and MAPK signaling, has been assessed in the majority of preclinical anticancer research.Glucuronide conjugates, on the other hand, typically show decreased intrinsic biological activity and cellular absorption. However, luteolin glucuronides may be locally hydrolyzed by β‐glucuronidase, which is abundant in tumor and inflammatory tissues, to replenish the active aglycone, so indirectly contributing to anticancer activity. However, more pharmacokinetic‐pharmacodynamic and metabolite‐specific research is necessary to completely understand the relative contributions of the parent drug and its metabolites to the overall therapeutic effects of luteolin [35].

Luteolin is mostly found in plasma and tissues as glucuronide conjugates, regardless of the form that is supplied [96]. For oral administration in human research, luteolin aglycone, the type that exhibits the maximum absorption in rats, has been chosen. However, luteolin's poor water solubility continues to be a significant drawback, resulting in low oral bioavailability and so limiting its therapeutic efficiency, especially in the treatment of cancer. Due to this low oral bioavailability, researchers have attempted to improve its effectiveness by using nano‐delivery technologies [97].

A recent study assessed the anticancer efficacy of luteolin‐loaded transdermal elastic liposomes (LEL1–LEL12) against MCF‐7 cells for the treatment of breast cancer [98]. Luteolin‐loaded elastic liposomes demonstrated noticeably stronger growth‐inhibitory effects, while both free luteolin and liposomal formulations decreased cell viability in a concentration‐dependent manner. Improved cellular uptake and anticancer activity were demonstrated by the formed luteolin's notable reduction of the IC₅₀ when compared to ordinary luteolin [92].

7. Luteolin in Combination Cancer Therapy

Luteolin (3,4,5,7‐tetrahydroxy flavone) is found in many plants, such as fruits, vegetables, and herbal remedies. Although luteolin exhibits strong anti‐cancer efficacy on its own, it also exhibits a synergistic effect when combined with other anti‐cancer medications. Luteolin causes cytotoxicity in several cancer cells by inducing apoptotic pathways and inhibiting cell survival pathways. By modifying several pathways linked to treatment resistance, luteolin can increase the therapeutic efficacy of traditional anticancer drugs in addition to increasing cytotoxicity. The ERK, JNK, p38, and ERK5 pathways, all of which are essential for cancer cell proliferation, survival, epithelial–mesenchymal transition (EMT), metastasis, and chemoresistance, are all regulated by luteolin, a bioactive flavonoid [99]. While luteolin‐mediated modulation of MAPK signaling has been demonstrated to restore drug sensitivity and improve the effectiveness of conventional anticancer therapies, dysregulation of these signaling cascades contributes to tumor cell plasticity and decreased responsiveness to chemotherapy. Additionally, luteolin reduces survival signaling, promotes apoptosis, and slows the growth of tumors by suppressing important oncogenic signaling pathways such as PI3K/Akt/mTOR, NF‐κB, and STAT3. Additional resistance‐related mechanisms, such as the control of ATP‐binding cassette (ABC) transporters, induction of apoptosis, inhibition of epithelial–mesenchymal transition, suppression of cancer stem cell characteristics, modulation of mitochondrial homeostasis, and remodeling of the tumor microenvironment, have also been shown to be influenced by flavonoids like luteolin. The use of luteolin as a prospective chemosensitizing drug that can overcome therapeutic resistance and increase the efficacy of combination cancer therapy is supported by these pleiotropic activities used together [100].

The main objectives of combination research are to achieve a synergistic therapeutic effect with lower drug doses and to lessen or postpone the formation of resistance [101]. Certain flavonoids, either by themselves or in combination with other substances, have been demonstrated to have antineoplastic effects in vitro and in vivo with minimal toxicity to normal cells, including peripheral blood cells, myeloid cells, and epithelial cells [102]. Anticancer medications target many signaling pathways, including the p38 MAPK/p53 signaling cascade and AKT/mTOR/PTEN, to cause malignant cells to undergo apoptosis [103]. These signaling pathways should be seen as parts of an interconnected oncogenic network rather than as discrete chemical events [104]. To produce coordinated downstream effects like suppression of Cyclin D1, Bcl‐2, Bcl‐xL, VEGF, MDR1, and inflammatory mediators while promoting Bax expression, caspase activation, p53 signaling, and mitochondrial apoptosis, luteolin simultaneously targets several upstream regulators, including PI3K/Akt/mTOR, STAT3, NF‐κB, and MAPK [105].

It has been demonstrated that the core of novel anticancer treatments should be apoptosis. Chemotherapeutic drugs cause DNA damage in cancer cells, which mostly triggers apoptosis via p53‐dependent pathways that involve Bcl‐2 repression and Bax activation [106].

Tumor cell proliferation, angiogenesis, epithelial–mesenchymal transition, metastasis, cancer stem cell maintenance, and treatment resistance are all inhibited by the integrated control of these interrelated pathways, which eventually increases the effectiveness of traditional chemotherapy. Luteolin's development as a pleiotropic adjuvant in combination cancer therapy is supported by its coordinated multitarget mechanism, which sets it apart from single‐pathway inhibitors [107, 108]. Clinical trials, in vitro research, and in vivo investigations have demonstrated that combination medicines are required to treat tumors more successfully because single‐agent therapies are rarely effective against cancer in Table 3 summarizes the mechanism of action of combination therapy with luteolin [28].

TABLE 3.

List of combination anticancer therapy with luteolin.

Combinate agent	Cancer model	Therapeutic efficacy	Mechanism of action	Ref.
Luteolin+ doxorubicin	Hepatocellular carcinoma	Significant enhancement of antitumor efficacy	Reduction of oxidative stress (NO, MDA), stimulation of caspase‐3‐mediated apoptosis, improvement of liver biomarkers (ALT, AST, ALP, AFP‐L3), and restoration of antioxidant defences (GSH, SOD)	[109]
Luteolin+ cisplatin	Colorectal carcinoma	Five out of the seven examined dose combinations showed synergistic cytotoxicity, and lower cisplatin doses increased the mortality of cancer cells.	Mitochondrial malfunction induction, mitochondrial membrane potential loss (Rho123), apoptosis and necrosis activation (Hoechst/PI staining), and cisplatin‐resistant cell sensitisation	[110]
Paclitaxel + luteolin (pH‐sensitive liposomes modified with EA2‐aptamer)	Oesophageal squamous cell carcinoma (ESCC)	Strong synergistic anticancer activity, better tumor targeting and retention, decreased hepatotoxicity caused by paclitaxel, and increased tumor growth inhibition	Targeting CTNNA1 with EA2 aptamer; pH‐triggered drug release in an acidic tumor microenvironment; increased cellular uptake and endosomal escape; disruption of mitochondria and microtubules; activation of antitumor immunity (including dendritic cell maturation, T‐cell infiltration, MDSCs, and Tregs); remodeling of the tumor microenvironment	[111]
5‐Fluorouracil + luteolin	Human colorectal cancer cells HT‐29 (in vitro)	Significant drop in VEGF levels showing anti‐angiogenic activity; ∼10.1‐fold increase in apoptosis relative to control; and significant synergistic growth inhibition	Intrinsic apoptotic signaling activation (≥ p53, Bax, p38 MAPK, PTEN); reduction of survival pathways (Bcl‐2, mTOR, Akt); and prevention of angiogenesis through downregulation of VEGF	[102]
Luteolin + oxaliplatin	Colorectal cancer cells HCT116 and HT‐29 (in vitro); xenograft mice model (in vivo)	Significant tumor reduction in vivo, increased apoptosis, decreased clonogenic survival, and synergistic inhibition of tumor growth	Reduction of survival and stress‐adaptation pathways; amplification of oxaliplatin‐induced apoptotic signaling; and inhibition of AMPK activation	[100]

8. Biomarkers and Precision Oncology of luteolin in Cancer Therapy

Luteolin increases the susceptibility of cancer cells to therapy‐induced cytotoxicity by inhibiting cell survival pathways such as nuclear factor kappa B (NF‐κB), phosphatidylinositol 3‐kinase (PI3K)/Akt, and X‐linked inhibitor of apoptosis protein (XIAP), and by promoting apoptosis pathways, including those that trigger the tumor suppressor p53 [112]. As per previous research, luteolin prevents tumor formation via mechanistically inducing cell death by upregulating BAX, caspase‐3, and p21 and downregulating PLK‐1, cyclin‐B1, cyclin‐A, CDC‐2, CDK‐2, Bcl‐2, and Bcl‐xL. Additionally, it has been shown to reduce STAT3 activation and promote STAT3 protein degradation in a variety of cancer cells, hence inhibiting STAT3 signaling [113]. Luteolin mainly inhibits STAT3 phosphorylation at Tyr705, which stops STAT3 dimerization and nuclear translocation and lowers STAT3 signaling. This lowers the transcription of STAT3‐dependent oncogenes, such as Cyclin D1, VEGF, survivin, and Bcl‐xL, which are important in proliferation, angiogenesis, immune evasion, and survival. Although there are still few conclusive target‐engagement investigations, experimental research using phosphorylation‐specific Western blot analysis and molecular docking has indicated that luteolin interferes with STAT3 activation [13]. An increased tumor oxidant status is caused by enzymes that produce reactive oxygen species (ROS). Anticancer efficacy is limited by efflux transporter‐mediated resistance to chemotherapy. Additionally, intracellular redox equilibrium is modulated by luteolin. Stress‐responsive kinases like JNK and p38 MAPK are activated when it either scavenges excessive ROS or encourages ROS accumulation above the cellular antioxidant threshold, depending on the tumor context. DNA damage, depolarization of the mitochondrial membrane, and subsequent activation of intrinsic apoptotic pathways are all caused by these signaling events [13]. It has been demonstrated that luteolin inhibits ATP‐binding cassette transporters, including P‐glycoprotein (MDR1/ABCB1), increasing intracellular drug accumulation. Decreased MDR1 expression and activity are thought to be significant indicators of luteolin‐mediated chemosensitisation and multidrug resistance reversal [114]. Mechanistically, luteolin reduces mTOR activation and downstream protein synthesis necessary for tumor growth by inhibiting the phosphorylation of PI3K and Akt. Pro‐apoptotic proteins like Bax and p21 are expressed more when Akt is inhibited because FOXO transcription factors are no longer suppressed. Similarly, luteolin prevents nuclear translocation of the p65 subunit and decreases transcription of anti‐apoptotic genes such as Bcl‐2, Bcl‐xL, XIAP, and survivin by blocking IκB kinase (IKK)‐mediated activation of NF‐κB. In the end, these upstream signaling events cause caspase‐dependent apoptosis and mitochondrial malfunction [115].

The goal of precision oncology is to tailor treatment approaches to the genetic, biochemical, and microenvironmental features unique to each tumor. According to this paradigm, luteolin is a promising multi‐targeted anticancer agent whose effectiveness can be maximized by using sophisticated drug delivery methods, rational combination strategies, and biomarker‐guided patient selection [115]. In contrast to traditional single‐target treatments, luteolin modulates oxidative stress, inflammatory signaling, carcinogenic pathways, and multidrug resistance mechanisms all at once to provide pleiotropic effects. In order to detect tumors driven by PI3K/Akt, STAT3, NF‐κB, EGFR, or MAPK signaling, future precision‐oncology techniques should combine biomarker‐guided patient selection with thorough molecular profiling. Direct target‐validation methods like SPR, CETSA, DARTS, and chemo proteomics are still scarce, despite the fact that many publications show pathway blockage utilizing molecular docking, Western blotting, and gene‐expression analysis. To identify luteolin's main molecular targets and expedite its clinical translation, these strategies will be crucial [116].

9. Clinical Evidence and Ongoing Trials

It has been demonstrated that luteolin causes cell‐cycle arrest and apoptosis in cancer cells by inhibiting important oncogenic signaling pathways, such as the insulin‐like growth factor‐1 receptor (IGF‐1R) axis [117]. Under androgen deprivation, oxidative stress‐related pathways were significantly elevated in an animal model of castration‐resistant prostate cancer (CRPC) [118]. In this setting, luteolin showed a strong anti‐tumor effect by suppressing the production of IGF‐1R protein in the CRPC cell line 22Rv1 and downregulating androgen receptor (AR) signaling and its downstream transcriptional target NKX3.1 [119].

Luteolin (LUT) has been the subject of clinical research with a variety of therapeutic goals. Instead of evaluating luteolin as a stand‐alone anticancer treatment, the majority of these trials assess it as a dietary supplement or as a component of multi‐component formulations. Luteolin's anti‐inflammatory properties were highlighted in a completed clinical trial that showed that administering palmitoylethanolamide (PEA). Furthermore, luteolin was assessed in a randomized clinical trial including patients with hepatocellular carcinoma (HCC) as part of the traditional Chinese medicine formulation FuzhengJieduXiaoji (FZJDXJ) in conjunction with transcatheter arterial chemoembolization (TACE) [119]. When compared to conventional treatment alone, this combination therapy enhanced one‐year overall survival (OS) and progression‐free survival (PFS). Preclinical validation revealed that the AKT/Cyclin D1/p21/p27 signaling pathway was modulated to mediate these advantages. The efficacy of LUT substances in the management and treatment of many illnesses and health problems has been demonstrated by clinical trials [120]. The efficacy of LUT substances in the management and treatment of many illnesses and health problems has been demonstrated by clinical trials [121].

Rather than focusing on direct tumor regression, some small‐scale human research and dietary intervention trials have looked at luteolin‐containing foods or supplements in relation to inflammatory indicators, oxidative stress parameters, and cancer risk regulation. According to previous studies, luteolin consumption is linked to decreased systemic inflammation, enhanced antioxidant status, and regulation of cancer‐related biomarkers. These findings support luteolin's current role as a chemopreventive agent [122].

10. Future Directions and Conclusions

Standardized dosing approaches, biomarker‐guided patient classification, and the clinical translation of luteolin‐based nanoformulations should be the top priorities for future research. Validating its therapeutic efficacy, especially as an adjuvant therapy or chemopreventive drug, requires well‐designed randomized clinical trials. Luteolin shows potential as a component of combination regimens meant to overcome treatment resistance while maintaining patient quality of life because of its multitargeted molecular effects and favorable safety profile. To fully achieve luteolin's potential in precision oncology, issues with bioavailability, formulation scalability, and regulatory approval must be resolved.

Author Contributions

Dipanjan Karati designed the concept and supervised the work. Sreemoyee Mitra and Priya Manna wrote the article. Dipanjan Karati edited the manuscript. All authors checked the manuscript.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Biographies

Sreemoyee Mitra completed her B. Pharm from NSHM Knowledge Campus, Kolkata, and she is currently pursuing my M. Pharm at ISF College of Pharmacy, Moga, Punjab. She has a keen research interest in phytomedicine, cancer biology, formulation development, and drug design. She has published articles in national and international journals.

Priya Manna completed her B. Pharm from NSHM Knowledge Campus, Kolkata, and she is currently working as an assistant professor at Brainware University, Kolkata. West Bengal, India. She has a keen research interest in phytomedicine, cancer biology, formulation development, and drug design. She has published articles in national and international journals.

Dipanjan Karati, M. Pharm, Assistant Professor, Department of Pharmaceutical Technology at School of Pharmacy, Techno India University, Kolkata, West Bengal, India, completed his master's in pharmacy from Bharti Vidyapeeth University, Pune, India. He has 110 publications (reviews, research, and book chapters) in National and international journals. His major areas of research include cancer chemotherapeutics, neurodegenerative disorders, drug development, and characterization.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.