INTRODUCTION:

Recent pharmacological studies have shown that myricetin (MYR) possesses a variety of biological properties, such as anti-inflammatory, anticancer, antibacterial, antiviral, and anti-obesity actions, as well as protective benefits on the cardiovascular system, against neurological disorders, and damage, and shields the liver from possible harm^1–10. The cellular machinery is always under stress during cancer metastasis because a vast number of interactions are occurring across a broad molecular landscape^11–13. A comprehensive understanding of the sequence of concurrent molecular activities taking place in tumour cells is necessary to develop an effective medication and delivery system^14,15. Due to a number of issues, the cancer treatment regimen now in use is highly hazardous to healthy cells as well as tumours^16–19. According to studies, naturally occurring phytochemicals may be used therapeutically to treat long-term illnesses in people^20–22. The phytochemicals target human long non-coding RNAs (lncRNAs) using RNA interference technology. The most widely distributed lncRNAs are PVTI, HI9, ROR, NEAT1.

These lncRNAs are influenced by a variety of phytochemicals, such as resveratrol, sulforaphane, curcumin, and epigallocatechin gallate (EGCG). Patients may also receive a combined therapy consisting of traditional chemotherapy drugs and phytochemicals to increase the effectiveness of the treatment^23,24. Numerous natural sources contain the isoflavonoid MYR, which has been shown in several studies to have antioxidant and free radical scavenging qualities^25,26.

MYR has not yet received market approval as a novel medication. Furthermore, individuals are increasingly interested in discovering natural remedies to fortify the body rather than utilizing chemical medications that are more hazardous and prone to negative effects; this has incentivized experts to advance their studies on MYR.

Figure 1. Structure of Myricetin

PATHWAYS INVOLVED IN CANCER:

PI3K/AKT and associated mTOR pathway

The PI3K/Akt-related kinase [PIKK] pathway is extended by mTOR, a serine/threonine protein kinase. mTOR is the catalytic subunit of two different protein complexes: mTOR complex 1 [Mtorc1] and Complex 2²⁷. mTOR is one of the most important regulators of mammalian metabolism and physiology. In order to control cell growth and proliferation, mTOR signalling is engaged in gene transcription and protein synthesis²⁸. The cell signalling pathway PI3K/Akt is in charge of several processes in a cell, such as growth, survival, proliferation, and differentiation²⁹. The cytoprotective role of MYR is reported in various studies but in different cancer. MYR interact with Akt and directly inhibits the kinase activity of Akt. Biochemically speaking, MYR tries to remove ATP in order to attach to Akt³⁰. Furthermore, it has been documented that MYR inhibits PI3K expression in both in vitro and in vivo investigations^31,32. MYR is also involved in the down-regulation of epidermal growth factor receptor (EGFR) to target the PI3K/Akt signalling pathways³³. Through their interaction and inhibition of PI3K and Akt phosphorylation, MYR disrupts mTOR signalling activity^34,35. MYR is also involving to control the activity of p70s6k1(effector of mTOR pathway)³⁶. It is reported that the SIRT3 can also suppresses the action of Akt via LKB1/AMPK pathway and MYR can up-regulating the protein level of SIRT3 (negative regulator of Akt) through which MYR stop the signal transduction of Akt^37,38.

Nuclear factor-kappa (NF-kB) beta pathway:

Nuclear factor kappa beta (NF-kB) is an essential pathway for cell survival. This is the pathway which is initiated by TNF-alpha molecules. Though this molecule has the capacity to drive Apoptosis but also TNF molecules can skip the apoptosis and drive cell survival pathways in the form of inflammation by activation of IAP proteins (inhibitors of Apoptosis protein) from there apoptosis is skipped and the cell leads towards the NF-kB pathway or cell survival pathway. The NF-kB pathway regulates the fate of cells toward growth or death and is primarily in charge of inflammatory responses. MYR either directly or indirectly modulates NF-κB signalling³⁹. Lipopolysaccharide (LPS) is a strong inducer of inflammation. MYR suppresses the TLR4-MyD88-NF-κB signalling pathway and the AKT/IKK/NF-κB pathway in LPS-induced mastitis and lung inflammation designs, which in turn reduces the synthesis of inflammatory markers such as TNF-α, IL-6, and IL-1β. As a result, inflammation is decreased^40,41. By controlling IκB/NF-Kb, MYR can also lower the levels of oxidative stress and inflammatory cytokines^42,43. It reduces its activity and prevents related downstream NF-κB signals from being activated⁴⁴. MYR may repair LPS-induced cardiomyocyte H9c2 injury by reducing inflammation since it enhances MALAT1 expression, inhibits NF-κB and IκBα phosphorylation, and lowers MCP-1 and IL-6 expression⁴⁵. By inhibiting Akt, mTOR, IκB/NFκB, and cytokines and chemokines produced in keratinocytes, MYR prevents the activation of COX-2. Finally, MYR inhibits TNF-α and UV light-induced skin inflammation^45,46.

RAF/RAS/MAPK/ERK pathway:

The Ras/Raf/MAPK/Extracellular-signal-regulated kinase (ERK) cascade is a cabalistic signalling pathway of living system. Depending on the type of signal received, this pathway entangles a variety of molecular entities and modifies the genetic expression linked to a cell's development, advancement, prevention, or induction of apoptosis^47,48. Raf/MEK/ERK are directly impacted by MYR, which modifies their kinase activity. In an ATP-noncompetitive way, it binds to Raf and inhibits its function to phosphorylate its downstream molecules⁴⁹. In a similar manner, MYR causes an EGF stimulus by interfering with MEK1's kinase activity and inhibiting ERK phosphorylation⁵⁰. Additionally, it lowers the amounts of p38-MAPK protein, as shown by several immunoblotting tests⁵¹. The modulation of MYR in certain disorders, the Raf pathway also influences the molecules and related signalling cascades. For example, in cancers, MYR attacks the VEGF expression by the direct inhibition of MKK1 and MKK4. Using in silico docking, the investigation showed that MYR attaches to MKK4's ATP-binding location⁵². The ability of MYR to control MMPs has been used in research on anti-aging, immunological illness, and cancer therapy^49,53,54.

JAK-STAT pathway:

One important mediator of cancer progression is JAK-STAT signalling, which can be activated through a variety of mechanisms, including the upregulation of cytokine expression. It can also function as a tumour intrinsic driver of cancer growth through metastasis or as a modulator of immune control⁵⁵. The JAK-STAT pathway is essential for controlling immunological responses and cell inflammation, and it uses NF-κB signalling to carry out its intended function⁵⁶. Numerous cancers have been linked to STAT3 activation in different studies. These include blood cancers (such as leukaemia) and solid cancers (such as bladder, breast, medulloblastoma, colon, and cervical cancers)⁵⁵. MYR interacts with JAK1 inhibits it, which as a result suppresses the activity of the phosphorylated STAT3 molecule⁵⁷. The attenuation of the STAT3 molecule has also been beneficial in cholangiocarcinoma⁵⁸.

Nrf2 pathway:

In contrast to JAK-STAT, TNFα, and NF-κB signalling, the Nrf2 pathway functions to reduce oxidative stress-induced inflammation and cytotoxicity⁴⁴. MYR promotes Nrf2 activity while reciprocally suppressing NF-κB function⁵⁹. MYR inhibits the ubiquitination-mediated degradation of the Nrf2 pathway, which causes Nrf2 to accumulate in the cytoplasm⁶⁰. MYR is also involved in the accumulation of Nrf2 translocation in nuclei, which activates ARE and increases the production of ARE-associated genes^60,61. Activation of the Nrf2-associated HO-1 gene, which in turn inhibits pro-inflammatory cytokines and boosts the synthesis of the anti-inflammatory cytokine IL-10⁶².

TNF- ALPHA signalling pathway

One important cytokine implicated in inflammation, immunology, tumour growth, etc. is tumour necrosis factor alpha (TNFα)⁶³. The main association between inflammation-based cytotoxicity and TNFα signalling in cells⁶⁴. A variety of structural proteins, including lipopolysaccharides (LPS), which are bound by Toll-like receptors (TLRs) and which actively generate inflammatory cytokines, can cause this release. Toll-like receptors are involved in the development of the innate immune response. MYR directly targets TNFα and interferes with the start of the TNFα/TNFR signalling cascade, which causes the Akt, mTOR, and NF-κB pathways to be down-regulated. It also inhibits the AKT/IKK pathway, which includes the NF-κB pathway, and reduces the synthesis of these inflammatory cytokines^1,40. When a cell undergoes TNF signalling pathway the TRAF-2 protein activates a special protein IKK (Inhibitor of Nuclear Factor Kappa-B-Kinase Subunit Alpha) through activation of RIP, the IKK molecule inhibits IKBA as a result NF-kB is released to cause cell survival by corporating inflammation; MYR inhibits the phosphorylation of NF-κB and IκBα, and thus it reduces inflammation through inhibition of gene expression⁶⁵.

Therefore, MYR contributes to cytoprotection by inhibiting TNFα, which destroys signal transduction via all of these pathways. MYR also affects the TNFα adaptor protein, TRAF6. It suppresses the downstream phosphorylation cascade and encourages TRAF6 ubiquitination⁵⁹.

ROS-Apoptosis signalling pathway:

Strong intrinsic stimuli known as reactive oxygen species (ROS) play a role in the process of stress-induced cell death. Therefore, ROS is essential for controlling the primary apoptotic pathways that are regulated by the endoplasmic reticulum, death receptors, and mitochondria⁶⁶. The Tumour Suppressor Protein P53 is activated by ROS at lower concentrations. By causing cell cycle arrest, this P53 plays a critical role in controlling the regulation of cell stress and promoting DNA repair for either cell survival or apoptosis. ROS activates the P53 protein in cases of cell apoptosis or extremely severe cell damage. This P53 then triggers apoptosis by downregulating pro-survival proteins like Bcl-2, Bcl-Xl, and IAPs and upregulating pro-apoptotic genes that are crucial for controlling the intrinsic pathway of apoptosis, such as Bax, Bid, Puma, and Noxa⁶⁷. MYR causes tumour cells to produce more ROS, which in turn causes the cell to undergo apoptosis. Research has shown that MYR causes oxidative stress, which raises the amount of ROS in cells, stimulates lipid peroxidation, depletes glutathione, and causes JAR and JEG-3 cells to undergo apoptosis. In order to produce anti-cancer actions, MYR causes ROS to accumulate in cancer cells⁶⁸.

DRUG INTERACTIONS OF MYRICETIN:

MYR generally interacts with the enzymes at the hepatic level.

Interaction with CYP2C8:

The metabolism endogenous chemicals, such as the synthesis of epoxyeicosatrienoic acid (EETs), which are thought to be signalling molecules against cancer hallmarks, depends heavily on the enzyme CYP2C8. In an in vitro investigation, MYR demonstrated a significant suppression of CYP2C8 in human liver microsomes with the use of the CYP2C8-catalyzed amodiaquine-N-deethylation enzyme⁶⁹.

Myricetin and cytochrome P450 (CYP):

Cytochrome P450 consist of a large heme enzyme super family, which are responsible for catalyzing the oxidative transformation of various range of organic substances mainly it is responsible for the metabolism of xenobiotics⁷⁰. MYR has been found to inhibit human Cytochrome P450(CYP) enzymes and is an inhibitor of P-gp in KB/MDR cell line⁷¹.

Myricetin interacts with hUGTS

A class of enzymes known as UDP-glucuronosyltransferases (UGTs) aids in phase II metabolism and is helpful in the metabolism of endogenous fatty acids, including metabolites of arachidonic acid, some opioids, and antiepileptic and antiviral medications⁷². Now MYR contributes in food-drug interaction with UDP-glucuronosyltransferase (UGT), studies has shown MYR displayed a broad-spectrum inhibition against the human UGTs, it has shown strong inhibitory effects against UGT1A1, 1A3, 1A6, 1A7, 1A10 while moderate inhibition against and 2B7⁷³.

PATHWAYS INVOLVED IN CANCER:

PI3K/AKB/PKB signalling

In response to external cues, the Akt signalling route, also known as the PI3K-Akt signalling system, is a signal transduction mechanism that enhances growth and survival. Phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) are important proteins involved. PI3K is phosphorylated and a cell surface receptor is activated upon initial stimulation by one of the growth factors. The second messenger, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), is created when activated PI3K phosphorylates lipids on the plasma membrane. Through contact with these phosphoinositide docking sites, the serine/threonine kinase Akt is drawn to the membrane for complete activation shown in (figure 1)⁷⁴. By phosphorylating a variety of intracellular proteins, activated Akt regulates downstream reactions such as angiogenesis, growth, proliferation, migration, and cell survival. The route is extremely conserved and found in all higher eukaryotic cells. The PI3K/AKT pathway is highly responsible for cell growth and cell proliferation. When MYR introduced it inhibit the phosphorylation PI3K, in result, PIP2 is not converted in to PIP3 and AKT/PKB protein doesn’t formed, thus MYR stop the PI3K/AKT pathway and shows its anti-cancer properties⁷⁵.

Recent Perspectives of Myricetin:

The MTOR pathway is the most important pathway in the case of cancer. This pathway is responsible for the regulation of cell growth and cell proliferation. Once AKT/PKB proteins get activated its block the TSC-1 and TSC-2 protein in result RHEB proteins gets activated and RHEB further activate the MTOR protein. MTOR can inhibit Autophagy through the inhibition of ULK-1 complex and furthermore it activates the p70S6K (effector of MTOR) which inhibit the eEF2K which leads to activation of eIF4B and p70S6K also involved in the phosphorylation of S6, both S6 and eIF4B are involved in protein synthesis. Myricetin inhibits the kinase activity of Akt through direct interaction. It competes with adenosine triphosphate (ATP) for binding with Akt on a biological level^78,79. Furthermore, myricetin has been shown in both in vitro and in vivo experiments to target PI3K expression. Additionally, it targets the PI3K/Akt pathway by downregulating the epidermal growth factor receptor (EGFR). Myricetin also prevents the activation of downstream molecular pathways in cancer by targeting PI3K and Akt. Through its interaction and inhibition of PI3K and Akt phosphorylation, it disrupts mTOR activation. Moreover, myricetin also affects the expression of p70s6k1, an effector of the mTOR pathway. It is demonstrated that myricetin regulates the PI3K/Akt/mTOR pathway to cause autophagy-mediated apoptosis in human colorectal cancer cells. Moreover, myricetin inhibits signal transduction via the Akt/mTOR pathway by increasing SIRT3 (Akt negative regulator) protein levels. Additionally, SIRT3 inhibits Akt through the LKB1/AMPK pathway^47,80.

MYR has been clinically investigated to treat diabetes in conjunction with several phytochemicals. During the course of a 4-week clinical investigation, Blueberin and the dosage of MYR administered was 250mg. 300mg total, made up of 50mg of MYR and blueberry leaves. every day. This trial with a placebo found that Blueberin and MYR together effectively decreased levels of plasma sugar in people with type 2 diabetes. When blueberin was used, plasma sugar levels were lowered from between 143±5.2 and 104±5.7mg/L. Additionally, Blueberin was discovered to lower the levels of glutamyltransferase (GGT), alanine aminotransferase (ALT), and AST in the serum reduced the C-reactive protein (CRP) levels as well. which might eventually stop inflammation⁸¹. Emulin, a combination of MYR, quercetin, and chlorogenic acid, has been shown to lower blood glucose levels in people with type 2 diabetes. Forty participants in the Emulin clinical trial had blood sugar fasting (BSF) levels ranging from 126 to 249 mg/mL⁸². In addition to its function in diabetes, MYR has been investigated for its potential as a chemopreventive agent and as a signalling and cell proliferation inhibitor⁸³. A meta-analysis of 5073 lung cancer patients revealed that MYR and other flavonoids could lower their risk of developing lung cancer by 30–40%⁸⁴.

Bioavailability of Myricetin:

MYR is a weak acidic, lipophilic substance that functions best at a pH of 2.0. It has a low aqueous solubility (16.60g/ml), which renders it insoluble in the GI tract and limits its effectiveness when taken orally⁶⁸. Optimal gut absorption and solubility are the two obstacles that prevent medications from being helpful in treating cancer, even with clinical advancements in human health and cancer treatment. Additionally, a drug's effectiveness depends on its concentration and mode of delivery⁴⁷. Some recent researches attempted to improve the efficacy of MYR by the drug delivery designing system based on Nanotechnology⁸⁵. At two oral dosages of 50 and 100mg/kg, MYR's oral bioavailability is only roughly 9.62% and 9.74%, respectively, suggesting that it has low absorption capabilities. Additionally, the gastrointestinal environment and numerous other factors can readily affect the stability of MYR⁸⁶.

Pharmacological Effect of Myricetin in Different Cancer:

Prostate Cancer:

Prostate cancer (PCa) ranks sixth globally in terms of cancer-related mortality among men and is the second most common malignancy to be diagnosed. The bark and leaves of the bayberry are rich in the flavonoid MYR, which has been linked to a decreased risk of prostate cancer and other malignancies, according to epidemiological studies. The proviral integration site for Moloney murine leukaemia virus-1 (PIM1), a Ser/Thr protein kinase of the PIM family, is a proto-oncogene protein that is overexpressed in PCa. PIM1 plays a role in carcinogenesis, castration resistance, and PCa metastases. Additionally, PIM1 facilitates the phosphorylation and surface expression of CXCR4, supporting the CXCL12–CXCR4 axis and significantly accelerating the development and metastasis of cancer. Comparative molecular field and cell-free crystallographic investigations revealed that MYR binds to PIM1's ATP-binding pocket and further suppresses its kinase activity. In PCa cells, MYR selectively disrupted the PIM1/CXCR4 connection and inhibited PIM1, hence causing apoptosis and anti-metastasis^87–89.

Hepatocellular Carcinoma:

In 2020, hepatocellular carcinoma (HCC) will rank third globally in terms of cancer-related mortality and be the sixth most prevalent type of cancer to be diagnosed. Since HCC progresses quickly and is difficult to diagnose early, most individuals are diagnosed when the cancer is intermediate or advanced. For those individuals, systemic medication and trans-arterial chemoembolization (TACE) are the primary treatment choices. Currently available chemotherapeutic medications, including sorafenib, frequently cause numerous toxicities and induce treatment resistance. For patients with advanced HCC, there is no effective systemic therapy available. Therefore, in order to treat HCC, it is imperative to investigate more effective medications with fewer side effects and low toxicity. One type of naturally occurring flavonoid found in many plants, including fruits, nuts, and vegetables, is MYR. MYR exhibits a range of biological actions, including analgesic, anti-inflammatory, and antioxidant properties. Furthermore, some data indicate that MYR may have anticancer properties against a variety of malignancies, including hepatocellular carcinoma⁹⁰. In HepG2 and Huh-7 cells, MYR caused apoptosis and inhibited cell growth. MYR promoted the phosphorylation and subsequent degradation of YAP, which decreased its expression. By promoting the kinase activity of LATS1/2, MYR suppressed the expression of YAP. The phosphorylation and degradation of YAP caused by MYR were lessened by LATS1/2 knockdown expression using shRNA. Moreover, MYR inhibited YAP and its target genes in vitro and in vivo, sensitizing HCC cells to cisplatin therapy. The discovery that MYR targets the LATS1/2-YAP pathway may aid in the development of innovative preventative and therapeutic approaches for human HCC⁹¹.

Oesophageal Cancer:

MYR stopped apoptosis in the esophageal cancer cell lines and inhibited both invasion and proliferation. RSK2 is bound by MYR via the NH2-terminal kinase domain, it was also found. Moreover, MYR was discovered to inhibit the growth of KYSE30 and EC9706 cells via Mad1 and to induce cell death through Bad. MYR induces apoptosis and reduces the proliferative and invasive capacity of KYSE30 and EC9706 cells via RSK2. These results offer new information about the potential of MYR as an esophageal cancer preventative and therapeutic agent⁹².

Bladder Cancer:

Cell growth rates were dramatically reduced when MYR (40 or 80µM) was used. The bladder cancer cell (T24) underwent a concentration arrest of the cell cycle at the G2/M phase as a result of MYR treatments. The nuclei of the control cells were visible. The cells were exposed to either 40 or 80µM MYR showed a notable amount of nuclear fragmentation, a hallmark of apoptosis. Treatment with MYR at a daily dose of 5 mg/kg demonstrated anticancer effects. In patients with bladder cancer, MYR treatment showed a higher survival rate compared to the control group⁹³.

Breast Cancer:

To assess potential modes of action, the apoptotic effect of MYR was examined in breast cancer cells (MCF-7). When MYR was applied to breast cancer cells, there was a significant increase in the expression of genes linked to apoptosis, such as caspase-3, caspase-8, and caspase-9, as well as the ratio of BAX to Bcl-2, GADD45 and p53. By inducing both intrinsic and extrinsic apoptotic pathways, MYR efficiently induces apoptosis in breast cancer cells. MYR may cause breast cancer (MCF-7) cells to undergo apoptosis by triggering the BRCA1-GADD45 pathway^94–97.

Ovarian Cancer:

One of the most frequent cancer-related deaths among women worldwide is ovarian cancer, which also ranks second in terms of gynaecological cancer-related deaths⁹⁸. The ideal concentration range for MYR's suppression of SKOV3 growth was 1×10-5-1×10-4 M for 24 hours, according to CCK-8 cell viability/cytotoxicity experiments. MYR was not harmful to IOSE-80, non-tumor cells at these concentrations, but it did have a dose-dependent inhibitory effect on SKOV-3 cells. MYR-treated SKOV3 cells had a reduced cell size, a smaller appearance, and a high rate of cell death. Moreover, MYR treatment at 10, 20, and 40 µM significantly reduced the ROS levels in these cancer cells in a dose-dependent way, as well as intracellular MDA while increasing SOD levels. In a dose-dependent manner, MYR therapy significantly reduced the amount of SKOV3 cells penetrating matrigel and moving downward in comparison to controls^99,100.

It was shown that treating OVCAR3 and A2780 cells with MYR accelerated apoptosis. Apoptotic signal increased roughly 2.5 times in A2780 cells treated with 25 µM MYR compared to untreated cells, and nearly 4 times in OVCAR3 cells. The results support the idea that MYR-induced cytotoxicity in ovarian cancer cells involves apoptosis. Furthermore, it was shown that, in contrast to untreated cells, MYR-treated ovarian cancer cells expressed significantly more of the pro-apoptotic protein BAX (B-cell lymphoma-2-associated X-protein), and significantly less of the anti-apoptotic protein Bcl-2¹⁰¹.

Pancreatic cancer:

Pancreatic cancer is the fourth most prevalent cause of cancer-related deaths, and it has a very bad prognosis. Finding new treatments is crucial because it is resistant to both new treatment techniques and conventional chemotherapy medications. Research has demonstrated that the flavonoid MYR reduced PI3 kinase activity and caused pancreatic cancer cells to die in vitro by apoptosis. MYR therapy for orthotopic pancreatic cancers in vivo led to tumor regression and a reduction in the spread of metastases. Crucially, MYR proved non-toxic in both in vivo and in vitro settings, highlighting its potential as a pancreatic cancer treatment³².

Gastric Cancer:

Cell contraction, nucleus condensation, and bubble formation in the cell membrane are the hallmarks of apoptosis, a sort of controlled cell death. Apoptosis is a representative anticancer strategy since it can cause mutant cells to become malignant when apoptotic pathways are inhibited (Elmore, 2007). Phosphoinositide 3-kinase (PI3K), an upstream kinase, initiates the signalling pathway that activates protein kinase B (Akt), a serine/threonine kinase that is essential for cell survival and proliferation. When there is an adequate supply of nutrients and energy, AKt can phosphorylate and activate the mammalian target of rapamycin (mTOR) protein, which can then integrate signals from growth factors to stimulate cell development. Numerous cancers, particularly gastric cancer, are linked to an aberrant rise in the PI3K/Akt/mTOR pathway's activity¹⁰². In both in vitro and in vivo investigations, MYR has been shown to target PI3K expression. Additionally, it targets the PI3K/Akt pathway by downregulating the EGFR. Additionally, MYR alters the expression of p70s6k1, an effector of the mTOR pathway. Moreover, MYR inhibits signal transduction via the Akt/mTOR pathway by increasing SIRT3 (Akt negative regulator) protein levels. Additionally, SIRT3 inhibits Akt through the LKB1/AMPK pathway⁴⁷.

CONCLUSION:

Since cancer is a complex illness, the formation and progression of the disease are influenced at the same time by a number of cellular pathways that are essential for cell growth, survival, and proliferation. Cancer treatments that are effective must be able to target several molecular actors involved in various cell signalling cascades. An isofavonoid called MYR is typically found as a glycoside in a variety of berries, vegetables, fruits, nuts, and plants. Additionally, it has been discovered to be a significant component of wine, tea, and a few therapeutic plants. This paper discusses the modulation of cellular pathways by MYR in humans, including PI3K/Akt, nrf signalling, mTOR, Ras/Raf, and JAK/STAT pathways, highlighting its potential as a cancer therapeutic solution. However, its low bioavailability, pH and poor water solubility hinder its clinical use. Research is underway to develop nano-formulations of MYR to improve its bioavailability and absorption. However, clinical trials and human use require significant efforts. Understanding MYR's interaction with non-coding RNAs could lead to smart cancer cell targeting. Nano formulations have shown promise in enhancing bioavailability and efficacy. One possible and potentially effective treatment approach is the addition of MYR to nano formulations. MYR nano formulation's dosage safety will be further investigated, which will advance the drug's clinical use.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank Dr. N. N. Bala and Dr. Arin Bhattacharjee for his valuable resources and opinions.

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Received on 04.05.2025 Revised on 28.06.2025

Accepted on 07.08.2025 Published on 11.10.2025

Available online from October 25, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(4):275-285.

DOI: 10.52711/2321-5836.2025.00044

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