Licorice belongs to the genus Glycyrrhiza, and radix glycyrrhizae (RG) is the dried roots and rhizomes of licorice. Licorice is commonly used as a natural sweetener and in herbal medicine. It mainly acts as a supplement in Western countries, for products such as herbal teas, soft drinks, and tobacco products. However, it is regarded as a medicine in Asia. Licorice is utilized to relieve pain, phlegm, spasms, cough, and dyspnea. The abundant active ingredients in licorice demonstrate efficacy in many different biological and physiological functions. To date, more than 300 bioactive compounds have been identified in licorice, including ~100 types of triterpenoid saponins and sapogenins, and ~300 kinds of phenolic compounds ^[1][17]. However, it has been found that the cultivated geographical area, the state of plant maturity, environmental conditions (including the pH of the soil, temperature, and weather), harvesting, and processing all affect the content of the bioactive compounds in licorice ^[2][18]. For example, the triterpenoid saponins in licorice, especially glycyrrhizic acid (GL; approximately 1.84% to 9.82% of licorice, depending on the sources and methods of extraction), are the major constituents and bioactive ingredients of licorice ^[3][4][5][19,20,21]. Flavonoids (approximately 1.78% to 4.82% of licorice, depending on the sources and methods of extraction) are the other main bioactive compound found in licorice, including isoliquiritigenin (ISL), isoliquiritin, and liquiritigenin, etc. ^[3][6][19,22]. In the 2010 edition of the Chinese Pharmacopoeia, GL and isoliquiritigenin were selected as the biomarkers for licorice, and it is stated that their content should exceed 2% and 0.5%, respectively ^[7][23]. Interestingly, rwesearchers found that these two major compounds (GL and ISL) appear in many studies related to chemotherapy, which will be discussed further in a later section.

Licorice can be simply categorized into three Glycyrrhiza species: Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L., and Glycyrrhiza inflata Bat. ^[8][24]. In China, G. uralensis, G. glabra, and G. inflata are considered equivalent, and are combined and utilized as licorice without discrimination in the 2015 edition of the Chinese Pharmacopoeia. However, the morphological characteristics of the three Glycyrrhiza species show differences in the root, rhizome, seed, fruit, and inflorescence, as well as in the leaf and stem height. It is difficult to identify these licorice species accurately based only on their root or rhizome morphology ^[9][25].

There are significant differences between the species, which were established by the analytical methods of numerous studies aimed at separating and quantifying the active ingredients in licorice samples. These studies report that different licorice species have species-specific markers (Table 1); for example, the content of major flavonoids (liquiritin, liquiritigenin, and isoliquiritin) in G. uralensis is higher than that in G. glabra, and glycycoumarin only exists in G. uralensis ^{[10][11][12][13][14]}[26,27,28,29,30]. Glycyrrhizin, 50 times sweeter than sugar and especially suitable for children, is evenly distributed in the three species ^[13][29]. The amount of isoliquiritigenin (2′,4′,4-trihydroxychalcone, ISL), one of the major bioactive compounds in licorice, is higher in G. uralensis than in G. glabra and G. inflata. ^[15][16][31,32].

Glycyrrhiza Species	Region	Specific Content	Ref

[39,40,41]. Moreover, preoperative gargling with a licorice solution reduces postoperative sore throat, thus, revealing its analgesic properties ^[34][42]. The clinical trials of licorice are summarized in Table 2.

Name	Disease/Disorder	Dose/Duration	Trial				Location/ Identifier No.	Ref
			Patient (	n	)	Experiment Group			Control Group	Outcome
Glycyrrhiza uralensis (Glycyrrhiza radix)	China
		Extract of	G. glabra	Northeastern Far east Russia	Radiotherapy Head or neckOwning the highest content of flavonoids (liquiritin, liquiritigenin, and isoliquiritin). Glycycoumarin only represented in	G. uralensis	.	Oral 100 c.c/Bid 2 weeks	[10][11][12][13][14][	n17]	[26,27,28,29,30,43]
		= 37	Extract of		G. glabra	Placebo		(radiotherapy)	Prevent oral mucositis	IRCT201203012464N4 Iran Tehran University of medical science
Licorice extract	Randomized Double-blind	Oral 1 g/Tid	n	= 236	+licorice extract	Sugar water	Pain relieving	NCT02968823	[34]	[42]
Licorice	Dyspepsia	380 mg/Bid 4 weeks	n	= 120	+licorice	N.A.	Improved	H. pylori	eradication	IRCT2014061718124N	[28][29]	[36,37]
Glycyrrhizin	Alcohol consuming	Oral 0.1–0.3% 12 days	n	= 24	+Licorice	Placebo (alcohol)	Hepato-protection	N.A.	[30]	[38]

2. Bioactive Components of Licorice

Licorice root contains a variety of bioactive components, including alkaloids, polysaccharides, polyamines, triterpenes, phenolic acids, flavones, flavans, chalcones, flavonoids, and isoflavonoids. Among them, only a few can be characterized and isolated from licorice. OIn this review, only the components studied for chemoprevention are discussed (See  Table 35), such as glycyrrhetic acid (GA) and chalcone-type derivative isoliquiritigenin (ISL) (Figure 1). Glycyrrhizin demonstrates immunomodulatory actions in vitro, stimulating T lymphocytes for IL-2 production ^[35][188]. An anti-inflammatory effect is associated with glycyrrhizinic and glycyrrhetic acid, via an inhibition of corticosteroid metabolism and production ^[36][189]. To extend the corticosteroid effects, it is broadly classified into immunological and metabolic effects ^[37][190]. From a metabolic perspective, the active form of glycyrrhizin, glycyrrhetic acid, influences energy metabolism and fat distribution by mediating fatty acid oxidation–related genes ^[38][39][191,192]. To emphasize the role of antioxidants, pretreatment with glycyrrhizinic acid could decrease free radicals and increase the level of reduced glutathione (GSH) ^[40][41][193,194]. Licorice extract and glycyrrhizic acid could reduce ROS-mediating p53 activation, and promote p21 expression against cisplatin-induced nephrotoxicity in vitro ^[42][195]. In an animal model, glycyrrhizic acid (GA) and 18β-glycyrrhetinic acid (18βGA) are represented as chemoprotectants, through the modulation of the NF-κB and Nrf2 pathways to reduce cisplatin-induced nephrotoxicity ^[43][196]. Overall, glycyrrhizin has been widely studied for combination chemotherapies involving cisplatin, 5-Fluorouracil, radiation, doxorubicin, paclitaxel, etc. ^{[43][44][45][46][47][48][49][50][51][52][53]}[196,197,198,199,200,201,202,203,204,205,206]. Isoliquiritigenin, one of the major bioactive compounds found in licorice, shares the same basic pharmacologic effects as Glycyrrhiza and exerts more biological activity, especially in its anti-tumor effects ^[54][10]. In a CT-26 murine colon animal model, ISL suppresses cisplatin-induced kidney/liver damage by mediating nitric oxide, lipid peroxidation, and GSH levels ^[55][207]. Based on the antioxidant properties of ISL, it shows a protective effect on cisplatin-induced toxicity, through regulating the oxidative ER stress hormesis. ^[56][208]. In addition, to target the anti-inflammatory effects, ISL also inhibits IL-6, IL-12, and TNF-α production ^[57][209]. Many studies suggest that licorice extract or licorice-derived active components benefit chemotherapy (Figure 13). Table 3 summarizes the licorice components associated with chemopreventive activities, mainly focusing on glycyrrhizin and ISL. However, some components of licorice present unwanted side effects; therefore, Kampo medicine is another option to improve chemotherapy-induced adverse effects.

Licorice and its derivatives exert anti-inflammatory and antioxidant effects, suggesting their potential as chemopreventive or therapeutic agents. For example, licorice can be used for reducing inflammation and allergic responses, as well as preventing liver damage ^[8][25][26][24,33,34]. Licorice extract also acts as a moderate hypocholesterolemic nutrient, and a potent antioxidant agent, to prevent cardiovascular disease ^[27][35]. Clinical data suggest that licorice, or its bioactive components, prevent dyspepsia and hyperlipidemia ^[28][29][36,37]. When taken concurrently with a glycyrrhizin-containing product, licorice is shown to afford hepatoprotection during alcohol consumption ^[30][38]. Three randomized clinical trials claim that Glycyrrhiza acts as a mucoadhesive film, improving oral mucositis during radiotherapy ^[31][32][33]