Galangin: A food‐derived flavonoid with therapeutic potential against a wide spectrum of diseases

Galangin is an important flavonoid with natural activity, that is abundant in galangal and propolis. Currently, various biological activities of galangin have been disclosed, including anti‐inflammation, antibacterial effect, anti‐oxidative stress and aging, anti‐fibrosis, and antihypertensive effect. Based on the above bioactivities, more and more attention has been paid to the role of galangin in neurodegenerative diseases, rheumatoid arthritis, osteoarthritis, osteoporosis, skin diseases, and cancer. In this paper, the natural sources, pharmacokinetics, bioactivities, and therapeutic potential of galangin against various diseases were systematically reviewed by collecting and summarizing relevant literature. In addition, the molecular mechanism and new preparation of galangin in the treatment of related diseases are also discussed, to broaden the application prospect and provide reference for its clinical application. Furthermore, it should be noted that current toxicity and clinical studies of galangin are insufficient, and more evidence is needed to support its possibility as a functional food.

270.2369, melting point of 214-215 C, is a common food-derived flavonoid, can be isolated from propolis and galangal (Fang et al., 2019).
In order to obtain comprehensive understandings into the natural sources, pharmacokinetics, and bioactivities of galangin, the literatures from the recent 17 years (2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020)(2021)(2022) collected from PubMed and Web of Science were reviewed.The initial search results showed approximately 689 articles in these databases, but after sorting based on themes, 95 articles were finally obtained that are featured in this review.This paper presents the first systematically review of the natural origin, pharmacokinetics, bioactivities, and therapeutic potential of galangin in multiple diseases with a view to promoting its development as a functional food.

| NATURAL SOURCES OF GALANGIN
Galangin is a natural flavonoid that comes mainly from propolis and the roots of Alpinia officina rum Hance (Rampogu et al., 2021).
F I G U R E 1 The pharmacological activities of galangin and its role in various diseases.
WANG ET AL.Galangin is a 3-hydroxyflavone, and the structural characteristics of the flavonoid parent nucleus determined the poor water solubility, which limited the clinical application of galangin to a certain extent.

| PHARMACOKINETICS OF GALANGIN
Robert et al. used the monolayer model of CaCo-2 cell to research the absorption and metabolism of galangin.They found that galangin is absorbed by differentiated CaCo2 cells and rapidly produce a lot of glucuronic ester and sulphate conjugates.Then, these conjugates leave the cell to the apical (luminal) and basolateral (serosal) sides, with glucuronic ester and sulfate preferentially exiting the lateral and apical compartments, respectively (Barrington et al., 2009).Besides, Fadhilah Jailaniab & Gary Williamson found that soybean, olive, and corn oils inhibit transport and binding of galangin in intestinal cells (Jailani & Williamson, 2014).Further study found that galangin is biotransformed through phase I and phase II metabolic pathways in rats, such as oxidation, hydrogenation, O loss, and conjugation reactions.And the metabolites of galangin include chrysin, apigenin, and kaempferol, all of which have outstanding biological activities (Zhao et al., 2022).In addition, long-term administration of galangin may alter the activity of CYP450 enzymes.Galangin induced the enzyme activities of CYP1A2, CYP2B3, CYP3A1 and inhibits the activity of CYP2C13 in rat liver, which suggests that galangin has great potential in improving oral drug bioavailability (Ma et al., 2019).At present, studies on the bioavailability of galangin are lacking, and it needs to be further studied.

| Anti-inflammation
Inflammation, the response of body to tissue damage such as physical injury, ischemic injury, infection, or other types of trauma, is a common pathological process (Soliman & Barreda, 2022).Immunosuppressive regulatory T cells (Tregs) can be induced to differentiate by tolerant dendritic cells (TolDCs), which strongly suppress the immune response.So, regulation of TolDCs is a good option to prevent or treat various inflammatory diseases (Morante-Palacios et al., 2021).Song et al. reported that galangin could induce Th cell differentiation to immunosuppressive Tregs by inducing the differentiation of tolerogenic DCs, which provides new opinions into the molecular mechanism of the anti-inflammatory effect of galangin on dendritic cells (Song, Kim, et al., 2021).In addition, galangin has a splendid inhibitory effect on over-obvious inflammation.Mast cells are closely related to allergic inflammatory reactions such as asthma and atopic dermatitis (Mendez-Enriquez & Hallgren, 2019).Kim et al. reported that galangin could block histamine release and the expressions of proinflammatory cytokines, c-JNK, p38, and NF-κB in mast cells.These results suggested galangin can down-regulate mast cell derived allergic inflammatory response (Kim et al., 2013).In short, galangin could exhibit outstanding anti-inflammatory activity in vitro, and the underlying mechanism may be related to regulate NF-κB and MAPK signaling pathways.

| Antibacterial effect
Staphylococcus aureus (S. aureus) is a common foodborne pathogenic microorganism that causes skin and visceral infections, such as folliculitis, pneumonia, sepsis, pseudomembranous enteritis (Chang et al., 2020).Nowadays, as S. aureus develops resistance to antibiotics, searching for new antibacterial agents is urgent.Galangin (50 mg/ml) showed obvious antibacterial activity against 4-quinolone-resistant strains S. aureus.Notably, 4-quinolones do not affect the resistance of S. aureus to galangin.The antibacterial mechanism of galangin may be related to the inhibition of topoisomerase IV enzyme (Cushnie & Lamb, 2006).Further studies have shown that galangin could cause bacterial cells to cluster together, which may indicate that the plasma membrane of the cell is a target for galangin (Cushnie et al., 2007) (Ouyang et al., 2018).
The coagulation ability is a distinguishing feature of coagulasepositive S. aureus isolates, which is caused by coagulase (CoA) and von Willebrand factor binding protein (vWBP) (Goetz et al., 2017).Jin et al. reported that galangin bound to trP-64 and LEU-69 amino acid residues on vWBP to inhibit vWBP activity.Further studies found that treatment with galangin improved survival while reduced bacterial load and inflammation in the lungs of mice induced with 30 μl (4 Â 109 CFU) of S. aureus compared with untreated mice (Jin et al., 2022).
Klebsiella pneumoniae (K.pneumoniae) is a ubiquitous opportunistic pathogen of the human upper respiratory tract and intestine, which can cause severe lung damage.Galangin (10 μM/L) remarkably reduced the binding ability of primary replicative DnaB helicase of K. pneumoniae to dATP, thus inhibiting the replication of K. pneumoniae (Chen & Huang, 2011).In brief, galangin has a favorable effect on drug-resistant bacteria and the underlying antibacterial mechanism is worthy of further study.

| Anti-oxidative stress and aging
Reactive oxygen species (ROS) is an outgrowth of aerobic metabolism, which plays an essential role in regulating a variety of cell signaling and homeostasis.Excess ROS can cause an imbalance in the antioxidant system, which may cause damage to DNA, RNA, proteins, and cell membranes (Mittler, 2017).Aging is a systemic response to the gradual accumulation of cell and tissue damage, leads to deterioration of homeostasis.It was previously reported that ROS is intricately connected to ageing and life span (Mladenov et al., 2023).Human skin aging is a gradual process, regulated by internal and external factors, both of which are closely related to the increased production of ROS production (Liu et al., 2023).Lee et al. reported that galangin could promote the up-regulation of Nrf2 by upregulating deacetylase silent information regulator 1 (Sirtuin1) and lysine residues of PPARγ coactivator-1α (PGC-1α), thereby reducing ROS generation and alleviating dermal aging induced by H 2 O 2 /UVB in human dermal fibroblast injury models.Besides, in vivo experiments showed that galangin at 12 and 24 mg/kg significantly inhibited epidermal hyperplasia and skin senescence induced by ultraviolet radiation and activated SIRT1/ PGC-1α/NRF2 signal transduction in UVB-induced skin photoaging of C57BL/6J mice (Lee et al., 2022).Furthermore, galangin also protected human keratinocytes from UVB-induced oxidative damage.
Hewage et al. reported that galangin could efficiently remove free radicals and reduced UVB-induced human keratinocytes damage.
Galangin inhibited UVB radiation-induced apoptosis of HaCaT cells by restoring mitochondrial polarization and down-regulating apoptosis proteins (Madduma Hewage et al., 2015).Further studies found that galangin relieved UVB-induced oxidative stress in HaCaT cells by activating ERK/AKT-Nrf2 pathway and elevating the expression of GSHsynthesizing enzymes (Madduma Hewage et al., 2017).These results suggested that galangin could reduce the damage of ROS on cells through the Nfr2 pathway, thereby delaying aging.
Type I and III collagens are the main components of ECMs that give support and strength to the dermis of skin, and their disruption can lead to the wrinkling and sagging characteristic of aging skin.TGF-β is a potent cytokine that promotes dermal collagen synthesis (Shin et al., 2019).Lee et al. reported that galangin could up-regulate TGF-β, promote the activation of Samd2/3/4 complex, and finally activate type I and III collagen, thereby reducing H 2 O 2 -induced senescence of HS68 cells (Lee et al., 2021).In addition, the IGF-1 signaling pathway has been implicated in controlling aging in humans (Anisimov & Bartke, 2013).
Wen et al. reported that galangin could alleviate the aging of HS68 cells induced by H 2 O 2 through promoting IGF-1R pathway and suppression of NF-κB activation, reducing pro-inflammatory protein level, as well as promoting collagen formation (Wen et al., 2017).Recently, they found that galangin reversed H 2 O 2 -induced upregulation of senescence markers, such as age-related p53, p21, and p16 in HS68 cells (Wen et al., 2020).Taken together, these findings demonstrated that galangin could alleviate skin aging induced by external factors via reducing oxidative stress, inflammatory response, and promoting collagen synthesis.

| Anti-fibrosis
Fibrosis is a restorative or reactive process characterized primarily by the formation and deposition of excessive fibrous connective tissue, resulting in progressive structural remodeling of almost all tissues and organs.(Weiskirchen et al., 2019).Liver fibrosis can be induced by diversified pathological factors, such as viruses, alcohol, and drug abuse (Zhang et al., 2022).Wang et al. reported that galangin was able to suppress hepatic fibrosis induced by carbon tetrachloride in rats, which may be related to scavenging oxygen free radicals, reducing lipid peroxidation, and inhibiting the activation and proliferation of hepatic stellate cells (Wang et al., 2013).In addition, pulmonary fibrosis (PF) is an end-stage change of pulmonary disease which leads to death from respiratory failure.There are increasing evidences indicate that epithelial-mesenchymal transition is closely related to PF (Hewlett et al., 2018).Wang et al. reported that galangin significantly alleviated bleomycin-induced PF in mice.Treating with galangin inhibited the expression of vimentin and α-smooth muscle actin (α-SMA), increased the expression of E-cadherin in lung tissue.In addition, galangin could reduce bleomycin-induced inflammatory cell activation such as CD4 + CD69+, CD8 + CD69 + T cells and dendritic cells, thereby reducing inflammatory cells in lung tissue of mice (Wang et al., 2020).Furthermore, myocardial fibrosis is one of the main manifestations of myocardial remodeling, which can lead to heart failure and death (Ren et al., 2022).Thangaiyan et al. reported that pretreatment with galangin decreased heart rate, lipid peroxidation and upregulated the blood pressure in ISO-induced rats.Galangin inhibited ISO-induced up-regulation of TNF-α, IL-1β, NF-κB, and other proteins, thus alleviating cardiac inflammation and oxidative stress.In addition, pretreatment with galangin could inhibit the expression of ISO-induced fibrosis-related genes in rats, such as MMP-2, Fibronectin, and a-SMA (Thangaiyan et al., 2020).Therefore, these results implied that galangin could relieve fibrosis of organs through inhibiting the expression of fibrosis-related genes and reducing oxidative stress.

| Antihypertensive effect
Hypertension is an important risk factor for cardiovascular disease and organ damage.Impaired endothelial function, reduced nitric oxide (NO) synthesis, and sympathetic hyperactivity are important factors leading to elevated blood pressure.(Humphrey, 2021).Chaihongsa et al. reported that galangin could significantly reduce blood pressure and sympathetic excitation, increase plasma nitric oxide levels, and improve endothelium-dependent vasodilation injury in L-NAMEinduced hypertensive rats.Furthermore, galangin inhibited the upregulation of TNF-R1, p-NF-κB and VCAM-1 in l-name rat aorta tissue and reduced the decrease of TNF-α in plasma, which showed that galangin can lower blood pressure through relieving oxidative stress and inflammatory response (Chaihongsa et al., 2021).Further research found that galangin could reduce hypertension, renin-angiotensin system activation, cardio-renal injury, and oxidative stress caused by renal artery stenosis in rats, and the underlying mechanism was related to the expression of cardiac AT1R, TGF-β1, Col I proteins, renal AT1R/Nox-4 and Nrf-2/HO-1 proteins (Chaihongsa et al., 2022).
Thus, galangin might be a potential antihypertensive agent.

| Anti-cancer effect
At present, numerous evidences illustrated that galangin exerts outstanding anti-cancer activities, which could suppress cancers in digestive system, respiratory system, reproductive system, nervous system, motor system, and so on.More importantly, these studies partially revealed the underlying mechanisms, covering inducing tumor cell apoptosis, regulating tumor cell cycle, promoting tumor cell autophagy, and inhibiting tumor cell invasion, which greatly promotes the possibility of developing galangin as a novel anticancer drug or functional dietary supplement.The anti-cancer pathways of galangin have been portrayed in Figure 2.

| Cancer in the digestive system
Liver cancer is a major health problem, with more than 850,000 cases worldwide each year.This tumor is currently one of the leading causes of cancer death worldwide.Hepatocellular carcinoma (HCC) is the most common tumor among all primary liver cancers, accounting for 90% of cases (Llovet et al., 2021).12-O-tetradecylphosphowave-13-acetate (TPA), a diester, is a potent tumor promoter of the signal transduction enzyme protein kinase C (PKC).PKC isoforms are closely related to tumor proliferation, metastasis, and invasion (Isakov, 2018).
Further studies showed that galangin induced autophagy of hepatocellular carcinoma cells by deacetylating endogenous LC3 through SIRT1 (Li, Wang, et al., 2016).In addition, regulating long non-coding RNA (lncRNA) is another pivotal mechanism of galangin in treating HCC.LncRNA H19 has been found to promote cancer cell proliferation and metastasis in solid tumors (Ghafouri-Fard et al., 2020).Zhong et al. reported that galangin significantly decreased the expression of lncRNA H19 in MHCC97H cells, which induced the expression of p53 (Zhong et al., 2020).The Warburg effect is an important metabolic feature of tumors, which can help cancer cells produce energy more quickly, and thus grow and expand more rapidly (Zhou et al., 2021).In vitro Wang et al. reported that galangin reduced glucose uptake and lactic acid production of HCCs by inhibiting Warburg effect (Wang et al., 2017).Besides, endoplasmic reticulum (ER) stress is closely related to apoptosis.Su et al. reported that galangin induced endoplasmic reticulum stress by upregulating the protein levels of GRP94, GRP78, and CHOP and increasing the concentration of free cytoplasmic Ca 2+ , thus inducing apoptosis of HCCs in vitro (Su et al., 2013).In brief, galangin could play an anti-liver cancer effect by inducing apoptosis, autophagy, and endoplasmic reticulum stress in liver cancer cells.(Zou et al., 2020).These results demonstrated that galangin could induce apoptosis and inhibit proliferation, migration, and invasion by regulating MAPK, PI3K/Akt, and PTEN/AKT signaling pathways.
In addition, studies proved that galangin displays a promising therapeutic effect on gastric cancer.Kim et al. reported that galangin promoted apoptosis of human gastric cancer cells by downregulating caspase-3/À9 activation, cleavage of PARP, ERK1/2, and JNK in vitro.
Further study proved these effects are mediated by an interaction of ubiquitin carboxy-terminal hydrolase isozyme L1 (Uch-L1) and glutathione S-transferase P (GSTP) (Kim et al., 2012).In addition, Liang et al. reported that galangin selectively inhibited the cell viability of gastric cancer cells, but had no significant effect on normal gastric mucosal epithelial cells in vitro.Galangin inhibits the proliferation of gastric cancer cells by inactivating JAK2/STAT3 pathway and increasing ROS accumulation (Liang et al., 2021).These results suggested that galangin could exert anti-cancer effect by regulating JAK2/STAT3 and MAPK signaling pathways.
Besides, Sulaiman reported that galangin inhibited HCT-116 cells proliferation by promoting cell cycle stasis in G2/M phase or G1 phase (Sulaiman, 2016).In brief, these studies suggested that galangin might be a candidate for cancer of digestive system.

| Cancer in reproductive system
Ovarian and cervical cancers are among the most dangerous cancers in women worldwide (Ventriglia et al., 2017).Huang et al. reported that compared with normal ovarian cells, galangin preferentially induced apoptosis of ovarian cancer cells in vitro.Galangin treatment increased expressions of cleaved caspase-3, caspase-7, DR5, and Bax via the p53-dependent apoptotic pathway, thereby activating mitochondrial apoptosis and death receptor apoptosis pathways.
In addition, galangin could down-regulate the expression of p-Akt and p-p70S6K, which suggested that interfering with the Akt/p70S6K pathways might be the underlying mechanism of galangin in treating ovarian cancer (Huang et al., 2020).Studies have shown that glyoxalase system can be used as an important molecular target for cancer prevention and treatment (Wang et al., 2022).
Kumar and Tiku reported that galangin could downregulate the activity of glyoxalase-1 and Nrf-2, thereby increasing ROS production and inducing apoptosis of hela cells (Kumar & Tiku, 2018).In short, galangin could induce apoptosis of ovarian and cervical cancer cells through regulating p53, Akt/p70S6K, and Nrf-2 signaling pathways.

| Cancer in respiratory system
Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor with a high incidence in squamous cell carcinoma of head and neck (Johnson et al., 2020).It was proved that galangin can inhibit the growth of laryngeal carcinoma cell.Wang et al. reported that galangin induced laryngeal cancer cells apoptosis through up-regulating caspase-3 expression by regulation of PI3K/AKT/NF-κB in vitro.
Besides, galangin suppressed the transcription and proliferation of cancer cells by reducing PI3K/Akt-regulated mTOR activation.And galangin suppressed laryngeal cancer cell proliferation by inducing autophagy, as evidenced by the upregulation of LCI, LC3II, and Beclin 1 (Wang & Tang, 2017).Galangin also has an inhibitory effect on lung cancer.Devadoss et al. reported that galangin could inhibits pulmonary tumorigenesis in swiss albino mice through modifying xenobiotic enzymes in murine model, such as Cytochrome P450/b5 and NADPH Cytochrome P450/b5 redcutase (Devadoss et al., 2018).These results indicated that galangin might be a potential agent for the treatment of laryngeal squamous cell carcinoma and lung cancer; the underlying mechanisms include inducing apoptosis and autophagy and inhibiting the proliferation of cancer cells.

| Cancer in nervous system
Glioblastoma multiforme (GBM) is a common malignant neuroepithelial tumor of the central nervous system (Mahmoud et al., 2022).Kong et al. reported that galangin could induce pyroptosis by increasing the DNA damage of human glioblastoma multiforme cells via upregulating temporary gasdermin E. In addition, galangin could induce cell autophagy by downregulating MAP1LC3B-II through activating AMPK/ mTOR pathway (Kong et al., 2019).CD44, a transmembrane protein, can induce epithelial-mesenchymal transformation (EMT) and angiogenesis, which play a vital role in glioma growth (Lah et al., 2020).
Chen et al. reported that galangin inhibited the proliferation, migration, invasion, and angiogenesis of glioma cells by inhibiting EMT, angiogenesis, and CD44 expressions in glioma (Chen et al., 2019).In addition, galangin has a therapeutic effect on retinoblastoma, a rare cancer that occurs during childhood.Galangin was reported to suppress the progression of retinoblastoma cells by suppressing proliferation and accelerating apoptosis, as revealed by the upregulation of PTEN and cleaved caspase-3 (Zou & Xu, 2018).These results demonstrated that galangin could trigger apoptosis, autophagy, and inhibiting proliferation of cancer cells, suggesting that galangin might be a promising drug for cancer in nervous system.

| Other types of cancer
Osteosarcoma is derived from primitive osteoblastic mesenchymal cells and is a malignant tumor of mesenchymal tissue, related to excessive proliferation and poor differentiation of osteoblasts (Chen et al., 2021).Liu et al. reported that galangin could induce osteogenic differentiation of human osteosarcoma cells through selectively activating TGF-β1/Smad pathway with the up-regulation of collagen type I, alkaline phosphatase, osteocalcin, and osteopontin (Liu et al., 2017).
Head and neck cancers (HNCs) are the most common malignant tumors in the world, including neck, ear, nose, throat, oral and maxillofacial tumors (Auperin, 2020).Zhu et al. reported that galangin induced significant HNC cells cycle arrest in the G0/G1 phase, and decreased AKT phosphorylation and activation of mTOR and S6 kinases.In addition, galangin promoted the apoptosis of HNSCC (head and neck squamous cell carcinoma) cells by the downregulation of Bcl-2 and Bcl-xL and the up-regulation Bax and cleaved caspase-3 protein (Zhu et al., 2014).
Melanoma is a type of skin cancer, that is developed by the malignant transformation of melanocytes (Teixido et al., 2021).Focal adhesion kinase (FAK) is a bridging protein that regulates adhesion signaling and cell migration.Zhang et al. reported that galangin inhibited tumor growth and metastasis of B16F10 melanoma via inhibiting the expression of FAK (Zhang, Tang, et al., 2013).
In summary, these findings demonstrated that galangin has specific effects on a variety of cancers.However, the underlying mechanisms need to be further investigated in the future.

| Diabetes mellitus and its complications
Research has shown that galangin has good a anti-obesity effect, which inhibits pancreatic lipase, lowers blood lipids, and prevents oxidation in Canteen diet-fed rats (Kumar & Alagawadi, 2013).In recent years, considerable evidences have indicated that galangin has promising a therapeutic effect on diabetes mellitus (DM), diabetic retinopathy, diabetic nephropathy, and diabetic cardiopathy, suggesting that galangin may function as dietary supplement for DM and relevant complications.The mechanism of galangal anti-diabetes and its complications is shown in Figure 3.
Diabetes mellitus (DM), featured by persistent hyperglycemia, is a chronic metabolic noncommunicable disease that may impact over 783 million people globally by 2045 (Chen, Qin, et al., 2023).Although the exact pathogenesis is not fully elucidated, studies have shown that suppression of α-glucosidase and non-enzymatic glycation has been shown to be an effective approach to treat T2DM (Hossain et al., 2020).Zeng et al. reported that galangin was a potent α-glucosidase and non-enzymatic glycation inhibitor in vitro.Galangin (27.5 μM/L) effectively inhibited α-glucosidase reversibly through a monophasic process.Moreover, galangin could suppress the formation of non-enzymatic glycosylation intermediates, fructosamine, and α-dimethyl compounds and significantly suppress the formation of late glycosylation end products (Zeng et al., 2019).In addition, Aloud et al. reported that galangin reduced oxidative stress and strengthened the antioxidant capacity in STZ-induced DM rats.Specifically, galangin could reverse the abnormal levels of blood glucose, insulin resistance, lipid peroxidation products, and antioxidant ions in DM rats (Aloud et al., 2017;Aloud et al., 2018).Besides, galangin administration improved STZ-induced changes of glucose homeostasis, glycolytic and gluconeogenic enzyme, decreased plasma glucose and glycosylated hemoglobin in STZ-induced rats (Aloud et al., 2020).In addition, galangin significantly increased the functions of the mitochondrial enzyme and mitochondrial respiratory chain enzyme in rats with high blood glucose (Aloud et al., 2018).Furthermore, dipeptidyl peptidase-4 (DPP-4) is a serine protease on the cell surface target which can be a drug target to decrease blood glucose levels in patients with diabetes (Gilbert & Pratley, 2020).Kalhotra et al. reported that galangin inhibited DPP-4 activity in a concentrationdependent manner in vitro (Kalhotra et al., 2019).This suggests that galangin can reduce blood sugar levels in diabetic patients by inhibiting DPP-4.These results suggested that galangin might be a promising drug for DM, and the underlying mechanisms may be related to its capacity to alleviate oxidative status, improve the carbohydrate metabolism, and maintain glucose homeostasis.and Bax and up-regulating SOD, Bcl-2, and CAT (Abukhalil et al., 2021).In addition, galangin could reduce kidney damage by enhancing insulin sensitivity and suppressing antioxidant stress in dietary model of MS (Sivakumar et al., 2010).And galangin could relieve oxidative stress and inflammation of liver induced by fructose through improving insulin sensitivity and down-regulating TNF-α, IL-6, and NF-κB pathways (Sivakumar & Anuradha, 2011).These results suggested that galangin could improve diabetic cardiomyopathy by reducing oxidative damage, inflammation, and myocardial remodeling.

| Neurodegenerative diseases
Neuroinflammation, marked by the activation of microglia, can give rise to the occurrence of various neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD) (Woodburn et al., 2021).
Acetylcholinesterase (AChE), reversible inhibitor of acetylcholinesterase, has a good effect on the treatment of AD.Guo et al. reported that Galangin could inhibit AChE activity with the inhibitory rate up to 55% and IC 50 was 120 μM (Guo et al., 2010).Furthermore, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a pivotal enzyme in the production of Aβ, and its inhibition is an efficient target for AD treatment (Hampel et al., 2021).Zeng et al. reported that galangin reduced acetylated H3 in BACE1 promoter regions by increasing endogenous HDAC1 induced deacetylation (Zeng et al., 2015).These results suggested galangin might be a potential therapeutic agent for AD.
Ischemic stroke is characterized by vascular occlusion and insufficient blood supply and has a high fatality rate.Li et al. reported that galangin improved the dysneuria and brain infarct and significantly improved the reduced regional cortical blood flow in MCAO rats.
Moreover, Galangin inhibited cell apoptosis by down-regulating Bax, activated caspase-3, and the cleavage of PARP (Li et al., 2012).Interestingly, ferroptosis has recently been shown to be strongly related to the development of stroke.Ferroptosis is an iron-dependent mode of programmed cell death and is strictly regulated by SLC7A11 (Liu et al., 2022).In addition, ferroptosis cell death can be induced by reducing intracellular GSH levels or suppressing glutathione peroxidase 4 (GPX4) (Seibt et al., 2019).Guan et al. reported that galangin reduced the lipid peroxide level and iron content in the brains of I/R gerbils, reduced the number of cell death, and up-regulated SLC7A11 as well as GPX4 expression.These findings suggest that galangin can suppress ferroptosis through increasing SLC7A11 and GPX4 levels, thereby reducing brain injury (Guan et al., 2021).

| Rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic and systemic disease mainly characterized by inflammatory synovitis, and the pathogenesis of RA is closely related to fibroblast-like synovial cells in joint synovium.
Recently, the PI3K/AKT pathway has been identified as an important pathway for RA development (Liu et al., 2021).Deng et al. reported that galangin could induce apoptosis, inhibit cell proliferation of arthritis rheumatoid fibroblast-like synovial cells, and increase cell invasion in rheumatoid arthritis.In the RA rats, galangin alleviated the development of RA by suppressing the levels of TNF-α, IL-1β, and IL-6, p-PI3K, p-AKT, as well as p-mTOR.These findings suggest that galangin alleviates RA progression by inhibiting inflammatory responses and inhibiting PI3K/AKT/mTOR signaling pathways (Deng et al., 2022).Another research found that macrophages play an important role in the progression of RA.Activation of toll-like receptors (TLRs) can promote inflammation by activating macrophages and dendritic cells (Cutolo et al., 2022).Recently, research has found that the JAK/STAT pathway is associated with a variety of inflammation and plays a key role in the regulation of IL-6 in the pathogenesis of RA (Simon et al., 2021).Erusappan et al. reported that galangin decreased the production of NO, TNF-α, IL-1β, and IL-6 in LPS-stimulated RAW 264.7 cells.Besides, galangin reduced the RNA levels of COX-2, IRAK-1, and JAK-1 M in a dose-dependent manner.And galangin significantly down-regulated the expression of JAK-1, IRAK-1, p38, ERK, and P65 (Erusappan et al., 2022).These results illustrated that galangin could exert anti-RA effects by inhibiting IRAK-1/p65/MAPK/ JAK-1, PI3K/AKT/mTOR, and JAK/STAT signaling pathways.

| Osteoarthritis and osteoporosis
Osteoarthritis (OA) is a degenerative disease that is most common in middle-aged and elderly people.Cartilage degradation and chondrocyte dysfunction are important pathological features of osteoarthritis (Chen, Ning, et al., 2023).Huh et al. reported that galangin effectively improved collagen-induced arthritis in mice, which prevents osteoclast bone destruction and osteoclast formation in collagen-induced arthritis mice by attenuating RANKL-mediated activation of JNK, p38, and NF-κB (Huh et al., 2013).In addition, Huang et al. reported that galangin reduced cartilage degradation in the anterior cruciate ligament transection (ACLT) rat.In vitro, galangin reduced the levels of IL-1β, iNOS, COX-2, MMP1/3/13, and ADAMTS5 in chondrocytes of ACLT rats.Moreover, galangin suppressed IL-1β-mediated degradation of collagen II and aggrecan in chondrocytes and observably abrogated IL-1β-induced activation of p-Akt and p-NF-κB in rat chondrocytes (Huang et al., 2021).Thus, it suggests that galangin alleviates osteoarthritis by inhibiting the inflammatory response and reducing the degradation of type II collagen and aggregator.
Osteoporosis is a systemic bone disease caused by the decrease of bone density and bone quality and the destruction of bone microstructure.Osteoporosis is closely related to the overexpression of osteoclasts (Li et al., 2023).Li et al. reported that galangin decreased osteoclast generation from bone marrow-derived macrophages (BMMs) in vitro.During osteoclast formation, galangin downregulated the tartrate acid phosphatase (TRAP), cathepsin K (CtsK), and other osteoclast specific genes.Further study found that galangin inhibited RANKL-mediated ERK, p38, and NF-κB signaling pathways by downregulating p-ERK, p-p38 and p-p65, and stabilizing IκB-α levels in BMMs (Li et al., 2021).All in all, these findings demonstrate that interfering with NF-κB and MAPK signaling pathways is an underlying mechanism of galangin in treating osteoclastogenesis.

| Gastrointestinal diseases
The stomach and intestine are the core of nutrient absorption and the most important organs for digestion.However, a number of pathogenic factors, such as inflammation, bacteria, drugs, and so on, cause gastrointestinal injury.Numerous studies have found that flavonoids can protect gastrointestinal cells from damage caused by drugs and food toxins (Oteiza et al., 2018).Recently, galangin has been found to relieve inflammatory bowel disease and drug-induced gastrointestinal damage, which suggests that galangin may be a promising drug for the therapy of gastrointestinal diseases.
Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin, are commonly used clinical drugs, but long-term use of drugs can cause damage to the intestines (Bindu et al., 2020).
Previous studies have found that sodium dexanhydride sulfate (DSS) activates Src by JNK-dependent mechanism, and Src activation induces epithelial tight junction breakdown and barrier injury (Samak et al., 2015).Fan et al. reported that pretreatment with galangin alleviated indomethacin-induced barrier loss in rat intestinal epithelial cells and promoted the expression of three tight junction proteins, zonula occluden-1, occludin, and claudin-1.In addition, galangin decreased the intracellular Ca 2+ concentration and the phosphorylation levels of JNK and Src induced by indometol, which suggested galangin reduces intestinal damage caused by indomethacin by inhibiting Ca 2+ -mediated JNK/Src activation (Fan et al., 2021).These results suggested that galangin might be a potential therapeutic agent to alleviate NSAIDs induced intestinal injury.
Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease involving ileum, rectum, and colon.Inflammation caused by the abnormal intestinal mucosal immune system plays an important role in the progression of IBD (Yang et al., 2023).Sangaraju et al. reported that galangin inhibited inflammation and oxidative stress by suppressing the levels of COX-2, iNOS, Nrf2, and phosphorylation of NF-κB and Ikk-βα, while increasing HO-1 levels in DSS-induced IBD mice (Sangaraju et al., 2019).Besides, Xuan et al. also reported that galangin pre-treatment suppressed shortening of colon length as well as reduced pathological changes occurring in colon in DSS-induced acute colitis of mice.Galangin reduced the levels of colonic pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, myeloperoxidase activity.Furthermore, galangin pretreatment markedly up-regulated the expression of colonic autophagy related proteins, accelerated the formation of colonic autophagosomes, and ultimately maintained the homeostasis of intestinal system system (Xuan et al., 2020).Further study found that galangin ameliorated DSS-induced histopathological alterations and tissue injury in the colon by down-regulating Toll-like receptor 4 expression and suppressing p65 expression (Gerges et al., 2020).In brief, these phenomena revealed that galangin played a protective part in gastrointestinal tract through inhibiting the inflammatory response and oxidative stress and regulating autophagy.

| Skin diseases
Atopic dermatitis (AD) is a common chronic, relapsing, and inflammatory skin disease, usually characterized by dry, itchy skin, and in severe cases infection of the lesion site (Sroka-Tomaszewska & Trzeciak, 2021).Choi and Kim reported that galangin inhibited mast cell infiltration into the ear and serum histamine levels and the levels of IL-1β, TNF-α, IL-6, IL-32 and interferon IFN-c through suppressing NF-κB and MAPK, thereby alleviating 2,4-dinitrochlorobenzene (DNCB)-mediated AD in rats (Choi & Kim, 2014).Galangin also has a good effect on psoriasis and vitiligo.Huo et al. reported that the quantity of skin basal layer melanocytes and melanin-containing epidermal cells were significantly up-regulated in Hydroquinone-induced vitiligo in male C57BL/6 mice after galangin treatment.In addition, galangin upregulated the levels of tyrosinase and MDA and downregulated the level of cholinesterase in vitiligo mice, which suggested galangin has great potential to treat vitiligo (Huo et al., 2014).Furthermore, Sangaraju et al. reported that galangin significantly increased the levels of SOD, GSH, GR, GST, and catalase, as well as the expression of Nrf2/HO-1, and decreased the levels of COX-2, iNOS, NF-κB in the skin of psoriasis mice (Sangaraju et al., 2021).Furthermore, galangin can inhibit scar formation.Zhang et al. reported that galangin inhibited collagen accumulation and abnormal activation of fibroblasts by inhibiting ALK5/Smad2/3 signaling pathway, which were the two pivotal factors for hypertrophic scar formation (Zhang et al., 2016).
Thus, these findings indicate that galangin enhances the antioxidant and anti-inflammatory effects of skin through controlling Nrf2/HO-1, NF-κB, and MAPK pathways.

| Other diseases
Intriguingly, recent research has also focused on the treatment potential of galangin in asthma, cardiac remodeling, nephritis, non-alcoholic fatty liver disease (NAFLD), acute pancreatitis, and pneumonia.Wang et al. reported that galangin alleviated cardiac hypertrophy and fibrosis response in aortic banding mice and angiotensin II-treated rat cardiomyocytes by inhibiting MEK/ERK and PI3K/AKT activation (Wang et al., 2019).Henry et al. reported that galangin obviously improved airway hyperresponsiveness, inflammation, and goblet cell hyperplasia by upregulating the expression levels of PPARγ in ovalbumin (OVA)-induced asthma mice (Henry et al., 2020).Besides, galangin has been found to mitigate trachea remodeling, collagen deposition through inhibiting the protein levels of TGF-β1, α-SMA, VEGF, and MMP-9 in tracheal remodeling in mice induced by OVA, which likely involves the TGF-β1/ROS/MAPK pathway (Liu et al., 2015).In addition, galangin is a promising agent for non-alcoholic fatty liver disease.
Galangin could reduce the levels of ROS through up-regulating the expressions of the mRNA and protein of Nrf-2 as well as HO-1 in L-arginine-induced severe acute pancreatitis (SAP) in mice and in AR42J cells, thus alleviating oxidative stress (Song, Liu, et al., 2021).
These results indicated that galangin could exhibit outstanding antiinflammatory activity in vivo.
Noticeably, galangin can attenuate organ toxicity induced by antimicrobial and chemotherapy drugs.Huang et al. reported that galangin inhibited cisplatin-induced oxidative stress, inflammation, and cell apoptosis in mice kidney through inhibiting ERK and NF-κB single pathways (Huang et al., 2017).Tomar et al. also found that galangin significantly ameliorated cisplatin induced inflammation and apoptosis in rat kidney by suppressing NF-κB, p38, JNK, and ERK1/2 (Tomar et al., 2017).In addition, galangin prevented Cyclophosphamide induced hepatotoxicity in rat through activating the Nrf2/HO-1 signaling pathway and suppressing oxidative damage, the expression of inflammatory factors (Aladaileh et al., 2019).Besides, galangin can prevent aminoglycosides-induced hearing loss in mice.Kim et al. reported that galangin protected hair cells in the organ of Corti against amikacin-mediated toxicity through inhibiting oxidative stress in cochlear explants (Kim et al., 2016).In a word, these data prove that galangin can prevent the heart, kidney, lung, and liver from toxicity by enhancing anti-inflammatory and antioxidant capacity as well as reducing collagen deposition and cell apoptosis.

| DISCUSSION AND FURTHER PERSPECTIVE
Recently, drugs derived from food to treat many diseases are gaining acceptance (Chen, Qin, et al., 2023;Chen, Zhong, et al., 2023).Flavonoids, as a bunch of polyphenolic compounds made in plants as secondary metabolites, are extensively exist in fruits, vegetables, and herbs, which have a wide range of biological activities (Chen et al., 2022).Galangin is a pivotal food-derived flavonoid that have been confirmed to possess forms of bioactivities, including antiinflammation, anti-oxidative stress, antibacterial effect, anti-fibrosis, anti-hypertensive effect, and so on.In view of these bioactivities of galangin, its roles within the interference or treatment of connected diseases have been explored in recent years, and part of the mechanism is explained.(Su et al., 2013), but it inhibited the expression of p38, JNK 150 μm/L in TFK-1 cells (Zou et al., 2020).These findings discovered that the bioactivities of galangin could also be influenced by there is a lack of research on the clinical efficacy of galangin, while natural products have been clinically associated with some potentially serious adverse events in recent years, such as herbal and drug interactions (Izzo et al., 2016).Therefore, high-quality safety studies are still needed to clarify the clinical efficacy of galangin.
In conclusion, galangin has extensive biological activity effects.
Because of its remarkable therapeutic potential for a variety of diseases, it is expected to be developed into new drugs or health products for human services and has important research value and application prospects.
Cholangiocarcinoma (CCA) is a malignant tumor originating from the cells of the bile duct, including intrahepatic and extrahepatic bile duct carcinoma.As we know, miRNAs play important roles in the occurrence and development of tumors, such as cell proliferation, metabolism, and apoptosis (Ali Syeda et al., 2020).Deng et al. reported that galangin up-regulated miR-455-5p expression and targeted PPP1R12A to suppress proliferation, migration, and invasion of CCA cells in vitro, which reduced the activation of MAPK and PI3K/ Akt pathways (Deng et al., 2021).Moreover, Zou et al. reported that galangin inhibited CCA cells proliferation and metastasis and induced cell apoptosis by regulating PTEN/AKT pathway in vitro.Phosphatase and tensin homolog (PTEN) is a recognized cancer suppressor gene that can be targeted for silencing by miR-21.Galangin increased the expression of PTEN by inhibiting the expression of miR-21, leading to a decrease in the phosphorylation level of AKT, which plays a critical role in controlling survival and apoptosis Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes.Studies have already shown that hyperglycemia can give rise to the activation of microglia cells, which are a key cell to regulate inflammation in the retina during DR development (Kinuthia et al., 2020).Zhang et al. reported that galangin reversed 25 mM/L D-glucose-induced blood-retinal barrier (BRB) F I G U R E 3 The mechanism of galangal anti-diabetes and its complications.
damage in BV2 cells by blocking the ERK1/2-ROS-NF-κB/Egr1 pathway to reduce TNF-α expression.Moreover, galangin further rescued TNF-α-induced BRB dysfunction by activating Nrf2 to eliminate oxidative stress damage(Zhang et al., 2019).These results indicated that galangin could alleviate DR through inhibiting ERK1/2-ROS-NF-κB/ Egr1 signaling pathway.Diabetic nephropathy (DN) is one of the most important complications of diabetic patients and has become the second cause of endstage renal disease.Recently, blocking the renin-angiotensin system (RAS) has been found to be effective in the treatment of diabetic nephropathy(Samsu, 2021).Liao et al.  reported that galangin inhibited the oxidative damage of HK-2 cells induced by high glucose through inhibiting RAS activation and phosphorylation of AKT and mTOR, which suggested that targeting the RAS and AKT/mTOR pathways is a possible mechanism of galangin in suppressing oxidative stress of renal cells during DN(Liao et al., 2021).DM is also a risk factor for heart failure, which increases the incidence of heart failure by about 2.5 times.Diabetic cardiomyopathy is characterized by structural and functional impairment of the heart independent of diabetic macrovascular complications, which includes hypertension, coronary artery disease, and atherosclerosis(Murtaza et al., 2019).Metabolic syndrome (MS) is a pathological state of metabolic disorder of substances in the human body, which contributes to the development of cardiometabolic disease and T2DM(Méndez Fernández et al., 2023).Prasatthong et al. reported that galangin could alleviate adipocyte hypertrophy, liver function impairment, and myocardial remodeling in MS rats.Galangin inhibited the levels of IL-6 and TNF-α in cardiac tissues and plasma.In addition, galangin upregulated adiponectin receptor 1 (AdipoR1) and COX-2 and down-regulated NF-κB expression.These results demonstrated that galangin reduces cardiometabolic dysfunction in MS rats by reducing inflammatory responses(Prasatthong et al., 2021).Furthermore,Abukhalil et al.    reported that galangin improved cardiac function in experimental diabetic rat models established by STZ.Galangin reduced cardiac oxidative damage, inflammation, and apoptosis and enhance antioxidant defenses by down-regulating NF-κB, TNF-α, iNOS,