There are abundant varieties of natural CM resources in China, which is worthy of further development and utilization. For example, Figure 2 only shows the distribution of some CM for liver disease in the main producing area (also named “Daodi” producing area). Among them, many of the common CM have shown anti-liver disease activity, see Table 1. In addition, the pharmacological effects of CM on liver disease are summarized in Figure 3.

Lipid uptake, esterification, oxidation, and fatty acid secretion all occur in hepatocytes. These processes are regulated by hormones, nuclear receptors, and transcription factors to maintain liver lipid homeostasis (Nguyen et al., 2008). If the balance of liver lipid metabolism is destroyed, the lipid will accumulate abnormally in the liver. Excessive lipid accumulation will lead to liver steatosis, insulin resistance and the development of fatty liver disease, and even induce oxidative stress, causing inflammation, cytotoxicity and aggravating liver injury. Therefore, maintaining normal lipid metabolism is an important function of the liver (Ding, H.-R. et al., 2018; Li, X. et al., 2019).

Many CMs have shown good effects in regulating lipid metabolism, such as Radix Bupleuri, Pericarpium Citri Reticulatae, Rhubarb, Polygonum Multiflorum, Coptis Chinensis, Artemisia Annua, Flos Lonicera and Radix Sophorae Tonkinensis. The results showed that the serum high-density lipoprotein cholesterol (HDL-C), TC and low-density lipoprotein cholesterol (LDL-C) levels of c57BL/6 mice were reduced by Citrus reticulata Blanco peel extract. The author further revealed that 0.2 and 0.5% of the extract could effectively prevent the micro fatty degeneration and excessive accumulation of lipid droplets in the liver (Ke et al., 2020). Rheum Palmatum L. can continuously reduce the accumulation of excess fat and the expression of lipogenic genes in the liver of male Sprague-Dawley rats induced by a high-fat diet. Concomitantly, increased phosphorylation of adenine monophosphate activated protein kinase (AMPK) and acetyl-CoA carboxylaze was observed (Yang, M. et al., 2016). In addition, Sophorae Tonkinensis water extract and Polygonum Multiflorum Thunb. extract alleviate nonalcoholic liver disease by enhancing hepatic carnitine palmitoyltransferase 1A activity to promote fatty acids β-oxidation, and regulating the protein response to lipid metabolism and expression in the liver to reduce lipid accumulation (Jung et al., 2020; Zhao et al., 2020).

It is worth mentioning that relevant studies of hepatic lipid metabolism were also conducted in fish. Addition of 200–400 mg/kg Radix Bupleuri extract to the daily diet of hybrid grouper fish can reduce the expression of lipogenesis-related genes, such as diacylgycerol acyltransferase 2, glucose-6-phosphate dehydrogenase, malic enzyme 1 and diacylglycerol kinase alpha (Zou et al., 2019). Lonicera japonica extract can effectively reduce the levels of LDL-C, triglyceride (TG) and total cholesterol (TC) in the serum of grass carp as well as the expression of lipogenic genes acc1, fas, SREBP1 and PPARγ, and increase the expression of liposoluble genes CPT1, ATGL, LPL and PPARα (Meng et al., 2019).

Inflammation is the basis of a variety of physiological and pathological processes, mainly induced by infection and tissue damage (Medzhitov, 2008). When natural antioxidants are out of balance, the free radicals produced by different organisms and environments can further lead to various inflammation-related diseases (Arulselvan et al., 2016). As we all know, there are many kinds of cytokines involved in the inflammatory response. For example, TNF-α, IL-1β, and IL-6 play a pro-inflammatory role, by contrary, TGF-β, IL-4, IL-10, and IL-13 can inhibit the occurrence and progress of inflammation. There is evidence that the inflammatory mechanisms of the liver are essential for maintaining the homeostasis of the tissues and organs. When the inflammatory mechanisms are out of balance, the hepatic pathological process will be drived, such as chronic infection, autoimmunity, and malignant tumor (Robinson et al., 2016). FSE, Gentianae Macrophyllae extract, and Aloe vera can reduce inflammatory liver injury by reducing the serum concentration of TNF-α, IL-1β, IL-6, NF-κB, and other cytokines (Zhao et al., 2017; Cui et al., 2019; Hu et al., 2020a; Klaikeaw et al., 2020). Moreover, Radix Bupleuri extract and Schisandra Sphenanthera extract can directly inhibit the mRNA expression of TNF-α, IL-1β, and IL-6 to protect the liver (Chen et al., 2019; Jia et al., 2019). In addition, Angelica Sinensis Supercritical Fluid CO2 Extract can significantly inhibit D-galactose-mediated expression of inflammatory cytokines, such as iNOS, COX-2, IKBα, p-IκBα, and p65, protecting the liver and kidney tissues (Mo et al., 2018).

Toll-like receptor4 (TLR4)-myeloid differentiation factor 88 (MyD88)-NF-κB signaling pathway is a key pathway in the physiologic and biochemical reactions of diseases. It widely exists in various tissues and cells, which is one of the important signaling pathways that mediate the expression of inflammatory factors (Wu et al., 2017). As one of the important pathways associated with inflammatory response and hepatic fibrosis, its activation can lead to the release of downstream inflammatory factors and induce the production of TNF-α, IL-1β, and IL-6. Hu et al. found that FSE could improve the inflammatory state of liver fibrosis through the TLR4-MyD88-NF-κB pathway (Hu et al., 2020a). Jia et al. found that RBE could inhibit TLR4-MyD88-NF-κB signaling pathway to reduce H₂O₂-induced liver inflammation in tilapia (Jia et al., 2019). Another study showed that GME could also attenuate ALD by inhibiting the phosphorylation of JNK and p38 to inhibit the initiation of inflammation (Cui et al., 2019).

The molecular mechanisms of the CM alleviating liver diseases through inflammatory pathways are shown in Figure 4.

Zou et al. found that adding 200–800 mg/kg RBE to the diet of hybrid grouper could effectively reduce the serum ALP, ALT, AST, and LDH contents. In addition, it could down-regulate the expression of apoptosis-related genes (caspase-9), and up-regulate the antioxidant genes (CAT) and immune-related genes (MHC2, IKKα, and TGF-β1) (Zou et al., 2019). Tan et al. reported that dietary supplementation of Lycium barbarum extract (0.50–2.00 g/kg) could effectively increase IL-10 and TGF-β1 mRNA levels in the liver of HFD-fed hybrid grouper (Tan et al., 2019). In addition, Ginkgo biloba extract not only improves the hepatic antioxidant status of HFD-fed hybrid grouper, and maintains normal liver histology and preserves liver function, but also up-regulates the expression of immune-related genes (MHC2 and TLR3) (Tan et al., 2018).

Some CM have inhibitory effects on hepatitis virus and can assist the treatment of patients with viral hepatitis. Some studies have shown that most of the terpenoids isolated from Flos Lonicerae can inhibit the secretion of HBsAg and HBeAg, as well as the DNA replication of HBV (Ge et al., 2019). In addition, Yang et al. found that the methanolic extract of Rhizoma Coptidis could block the attachment of HCV and the entry/fusion with host cells, which effectively inhibited the infection of pseudoparticles of HCV in Huh-7.5 cells, and hindered the infection of several HCV genotypes (Hung et al., 2018).

Currently, Western medicine and therapies are the main treatment strategies for liver cancer, but the overall prognosis of liver cancer patients is still very poor. Under such circumstances, it is extremely urgent to find a better method for the treatment of liver cancer. CM contains abundant treatment resources and has been used for the prevention of liver cancer for thousands of years. In modern China, CM has also been proven to be an effective method for the treatment of liver cancer. However, the theory of CM prevention and treatment of liver cancer is more widely accepted in China than abroad (Liao et al., 2020). According to relevant data, most CM can show anti-liver cancer effects. Ethanol extract of root of Prunus Persica can significantly inhibit the migration of liver cancer HepG2 cells and the expression of extracellular matrix metalloproteinases, MMP3 and MMP9. It is worth mentioning that it can also inhibit tumor growth in nude mice in vivo (Shen et al., 2017). Artemisia capillaris extract can inhibit the growth, migration and invasion of Huh7 and HepG2 liver cancer cells. This inhibitory effect is closely related to blocking the PI3K/AKT signaling pathway (Yan, Honghua et al., 2018). Jiang et al. further found that the anti-liver cancer effect of Artemisia capillaris extract is also related to the inhibition of the IL-6/STAT3 signal axis (Jang et al., 2017). Futhermore, Zheng et al. found that oral administration of portulaca oleracea extract to male AKR mice for seven consecutive days could contribute to the treatment of liver cancer. The results showed that the serum levels of IL-6, IL-1β, TNF-α and MDA in mice decreased after 7 days of treatment, while the activity of SOD increased. The pathological changes of the liver were significantly alleviated. Meanwhile, portulaca oleracea extract could effectively inhibit PI3K, Akt, mTOR, NF-κB and IκBα, and up regulate the expression of Nrf2 and HO-1. These effects are attributed to the protective effect of Portulaca oleracea extract on liver cancer by regulating PI3K/Akt/mTOR and Nrf2/HO-1/NF-κB pathway (Guoyin et al., 2017).

In addition, some CM can also achieve protection against liver cancer through various other effects. For examples, Astragalus membranaceus and Curcuma wenyujin promote the normalization of blood vessels in liver tumor endothelial cells by increasing the expression of CD34 and reducing the expression of HIF1a (Zang et al., 2019). Artemisia capillaris leaves can achieve pro-apoptotic effects on liver cancer cells by reducing the expression of XIAP and the release of cytochrome C through mitochondrial membrane potential (Kim et al., 2018). Besides, Ligustrum lucidum Ait. fruit extract can induce apoptosis and cell senescence of human liver cancer cell Bel-7402 by up-regulating p21. All in all, there are abundant resources of CM against liver cancer, which are worthy of our further development and utilization.

A large number of studies have shown that the occurrence of liver diseases is also closely related to endoplasmic reticulum stress and insulin resistance. Scutellaria baicalensis Georgi extract can regulate the endoplasmic reticulum stress and protect the liver by reducing the expression of glucose-related protein 78 (Dong et al., 2016). HFD increased the expression of adipose-derived carbohydrate response element binding protein and endoplasmic reticulum stress genes CHOP, x-box binding protein 1, and glucose regulated protein 78 in male wistar rats, and Ginger extract could restore these changes to normal state (Kandeil et al., 2019). Jung et al. reported that Polygonum multiflfluorum thunb. reduced nonalcoholic steatosis and insulin resistance by regulating the expression of the proteins on lipid metabolism and glucose transport in the liver (Jung et al., 2020).

Recently, the evidence has shown that gut microbiota play an important role in metabolism, immune system, and so on. The changes of gut microbiota and their function can promote the development of acute and chronic liver diseases. In addition, the destruction of intestinal barrier can make microorganisms transfer to the blood, and continuously cause inflammatory reaction, thus promoting liver injury, hepatic fibrosis, cirrhosis, and carcinogenic transformation (Shen et al., 2018; Chopyk and Grakoui, 2020). Rhubarb extract can promote some intestinal bacteria (such as Akkermansia muciniphila and Parabacteroides goldsteinii.) to participate in the intestinal barrier function, and alleviate liver inflammation caused by acute alcohol intake (Neyrinck et al., 2017). In addition, Schisandra chinensis bee pollen could inhibit the expression of LXR-α, SREBP-1c, and FAS genes, and regulate the structure of intestinal microflora in obese mice, so as to achieve the protective effect on MAFLD (Cheng et al., 2019).

Polysaccharide is one of the active components of CM. The polysaccharides in CM have a wide range of biological activities in enhancing immunity, antiviral, anti-inflammation, anti-oxidation, and anti-tumor (Chen et al., 2016). Ginkgo biloba leaf polysaccharides and Astragalus polysaccharides can effectively inhibit liver steatosis (Yan et al., 2015; Huang et al., 2017). The polysaccharides from roots of Sophora flavescens can significantly inhibit the HBsAg and HBeAg secretion of HepG2.2.15 cells, and have good anti-HBV activity (Yang et al., 2018). In addition, the polysaccharides extracted from many CM have obvious protective effects on acute liver injury, such as Rhizoma Atractylodis Macrocephalae polysaccharides (Han et al., 2016), Angelica sinensis polysaccharides (Wang, K. et al., 2020), Poria Cocos polysaccharides (Wu, K. et al., 2018), Lycium barbarum polysaccharides (Wei et al., 2020), and Schizandra chinensis acidic polysaccharides (Yuan et al., 2018). Wang et al. reported that Paeoniae Radix Alba polysaccharides inhibited the NF-κB signaling pathway (including the liver infiltration of inflammatory CD⁴⁺ and CD⁸⁺ cells, and the overexpression of inflammatory cytokines IL-2, IL-6, and IL-10) to inhibit the immune inflammatory response in experimental autoimmune hepatitis mice (Wang, S. et al., 2020). Finally, it is also important that APS is the main active component extracted from Astragalus, which has been proved to have a significant inhibitory effect on many types of human solid tumors. A recent study showed that APS could reduce the activity of hepatoma cells and induce the apoptosis of HCC cells in a concentration-dependent manner. The study further showed that the results might be related to inhibiting the expression of Notch 1 in HCC cells (Huang et al., 2016).

Glycosides are a class of compounds formed by linking the sugar or sugar derivative with another non-sugar substance through the terminal carbon atom of the sugar. The studies have shown that most glycosides have good hepatoprotective effects on liver, such as amygdalin, amarogentin, and forsythiaside A (Pan, C.-W. et al., 2015; Tang et al., 2019; Zhang et al., 2017). Chrysophanol 8-o-glucoside, extracted from Rheum palmatum, can significantly inhibit the gene expression of α-SMA and collagen I, and inhibit the phosphorylation of STAT3 by inhibiting the nuclear translocation of p-STAT3, thus alleviating fibrosis and achieving liver protection (Park et al., 2020). What’s more, Gentiopicroside not only protects alcoholic liver disease by improving lipid metabolism imbalance and mitochondrial dysfunction caused by alcohol (Yang, H.-X. et al., 2020; Zhang et al., 2021), but also treats alcoholic liver cancer by regulating the activation of P2x7R-NLRP3 inflammasome (Li, Xia et al., 2018). It is worth mentioning that astragaloside IV can inhibit hepatoma cells by inhibiting multidrug resistance-associated protein 2, and long noncoding RNA ATB (Li, Y. et al., 2018; Qu et al., 2020).

The specific information of polysaccharides and glycosides is shown in Table 2. In addition, the chemical structures of the glycosides with therapeutic effects on liver diseases are shown in Figure 5.

Phenolic compounds are composed of the aromatic rings with one or more hydroxyl groups. They play an important role on oxidative stress in the human by maintaining the balance between oxidants and antioxidants, which are divided into phenolic acids, flavonoids, coumarins, and tannins (Van Hung, 2016). A large number of phenolic compounds in CM have obvious antioxidant capacity, which can reduce the oxidative damage of the liver, such as Lithospermic acid, Chlorogenic acid, Curcumin, Polydatin, and Salvianolic acid C (Chan and Ho, 2015; Koneru et al., 2017; Shi et al., 2016; Wu, C.-T. et al., 2019; Zhong et al., 2016). Yang et al. further found that Chlorogenic acid could reduce the expression of α-SMA, collagen I in the liver tissue and serum TGF-β1 by increasing the mRNA and protein expression of Smad7 and MMP-9, thus alleviating liver fibrosis (Wu, C. et al., 2019). The studies have shown that Curcumin and Polydatin can inhibit lipid accumulation by regulating endoplasmic reticulum stress and the Keap1/Nrf2 pathway (Lee, H.-Y. et al., 2017; Zhao, X.-J. et al., 2018). In addition, Yan et al. demonstrated that Chlorogenic acid could improve liver injury and insulin resistance by inactivating the JNK pathway and inhibiting the autophagy in MAFLD rats (Yan, Hua et al., 2018).

Flavonoids, a part of phenolic compounds, also have significant hepatoprotective effects. For example, Isorhamnetin suppresses the TGF-β/Smad pathway and reduces oxidative stress to alleviate hepatic fibrosis (Yang, J.H. et al., 2016), and Wogonin reduces hepatic fibrosis by regulating the activation and apoptosis of HSCs (Du et al., 2019). Quercetin can effectively alleviate MAFLD, which depends on its regulation of intestinal microbiota imbalance and related gut-liver axis activation (Porras et al., 2017). Hesperidin and Oxylin A have significant anti-hepatoma activity (Mo'men et al., 2019; Wei et al., 2017). In addition, Licochalcone A can increase the expression of antioxidant enzymes by reducing the apoptosis, mitochondrial dysfunction, and reactive oxygen production stimulated by tert butyl peroxide and Acetaminophen, thus protecting APAP-induced hepatotoxicity, which is largely dependent on the antioxidant Nrf2 pathway (Lv et al., 2018). What’s more, rutin has a good protective effect on various acute liver injury induced by carbon tetrachloride, lipopolysaccharide, and mercury chloride (Caglayan et al., 2019; Elsawy et al., 2019; Rakshit et al., 2021).

Bacalin, a kind of flavonoid extracted from Scutellaria baicalensis, has significant biological activity, which is widely used in the treatment of liver diseases. The study has shown that bacalin suppresses the production of IL-1β, IL-6, and TNF-α, as well as regulates the TLR4 expression and inhibits the NF-κB activation, protecting the inflammation of chicken’s liver induced by LPS through the negative regulation of inflammatory medium (Cheng et al., 2017). Another study showed that the inhibition of the proliferation, apoptosis, invasion, migration, and activation of HSCs induced by platelet derived growth factor-BB through mir-3595/acsl4 axis is one of the mechanisms of bacalin in anti-hepatic fibrosis (Wu, X. et al., 2018).

The specific information of the phenols and flavonoids is shown in Table 3, and the chemical structures of the phenols and flavonoids are shown in Figure 6.

Terpenoids (isoprenoids) are the most abundant chemical compounds in plants (Tholl, 2015), which has a wide range of biological activities, such as anti-inflammation (Kim, T. et al., 2020), anti-depressant (Agatonovic-Kustrin et al., 2020), anti-cancer (Ateba et al., 2018), and so on. Many studies have shown that terpenoids are also widely used in the treatment of liver diseases. Leucodin is a sesquiterpene lactone isolated from Artemisia capillaris, which can inhibit the inflammatory response of macrophages, and P2x7R-NLRP3-mediated lipid accumulation in hepatocytes (Shang et al., 2018). Saikosaponin-d is an active component isolated from Radix Bupleuri, which can inhibit the COX2 expression through the p-STAT3/C/EBPβ signaling pathway in HCC (Ren et al., 2019). Oleanolic acid (OA) is a kind of triterpenoid widely existing in fruits, vegetables, and herbs. It is liver-specific and can selectively inhibit adipogenesis (Lin, Y.-N. et al., 2018). In addition, OA can regulate antioxidant status, and induce mitochondria-mediated apoptosis and regulate inflammation, which effectively inhibits 7,12-Dimethylbenz[a]anthracene-induced liver cancer (Hosny et al., 2021).

Rhizoma Alismatis is a kind of common CM, which is often used in clinic for adverse urination, edema, diarrhea, and so on. Modern studies have shown that many compounds extracted from Rhizoma Alismatis have hepatoprotective effects. For example, Alisol A 24-acetate, a natural triterpene extracted from Rhizoma Alismatis, can improve NASH by inhibiting oxidative stress, and stimulating autophagy through the AMPK/mTOR signaling pathway (Wu, C. et al., 2018). Meng et al. found that Alisol A 23-acetate could also improve NASH in the mice, which was achieved by the activation of X-like receptor (Meng et al., 2017). Futhermore, Meng et al. found that Alisol A 23-acetate activated FXR to induced the phosphorylation of STAT3 and the expression of its target genes, Bcl-xl and SOCS3. And it reduced the expression of the liver uptake transporter NTCP, and bile acid synthases CYP7A1 and Cyp8b1, as well as increased the expression of the outflow transporters BSEP and MRP2, reducing the hepatic bile acid deposition, which achieved the protective effect on CCl₄-induced hepatotoxicity in the mice (Meng et al., 2015).

The specific information of the terpenoids in the treatment of liver diseases is shown in Table 4, and the chemical structures of the terpenoids with therapeutic effects on liver diseases are shown in Figure 7.

Alkaloids are an important class of natural products, which have a wide range of biological activities, and have been used in folk medicine for many years (Stöckigt et al., 2011). We are surprised to find that alkaloids play an important role in the treatment of liver diseases. Matrine and Oxymatrine are the main active substances extracted from the roots of Sophora flavescens, and are widely used (Yuan et al., 2010). They have significant biological activities against MAFLD, liver injury, and liver cancer (Gao et al., 2018; Shi et al., 2020; Wei et al., 2018; Xu et al., 2018; Zhang, H. et al., 2020). Ligustrazine is an alkaloid extracted from Ligusticum chuanxiong. It not only activates Nrf2 to inhibit hepatic steatosis, but also induces the apoptosis and autophagy of hepatoma cells to exert an anti-hepatoma effect (Cao et al., 2015; Lu et al., 2017). And coptisine exerts an anti-hepatoma effect by activating the 67 kDa laminin receptor/cGMP signal to induce the apoptosis of human hepatoma cells, and the proliferation and migration of HCC cells (Chai et al., 2018a; Zhou et al., 2018).

The specific information of various alkaloids in the treatment of liver diseases is shown in Table 5. In addition, the chemical structure formulas are shown in Figure 8.

In addition to the above compounds, many compounds have the activities of anti-liver diseases, including phenylpropanoids (such as simple phenylpropanoids, coumarins, and lignans), anthraquinones, and volatile oils. Some lignans extracted from CM have been proved to have the effects on improving liver diseases. For example, Gomisin N extracted from Schisandra chinensis not only has protective effects on endoplasmic reticulum stress-induced hepatic steatosis, but also alleviates the liver injury caused by ethanol by improving lipid metabolism and oxidative stress (Jang et al., 2016; Nagappan et al., 2018). Futhermore, Arctigenin can inhibit the proliferation of HepG2 cells and block the autophagy cells that lead to the accumulation of sequestosome 1/p62, so as to achieve the therapeutic effects on liver cancer. It will become a new drug for the autophagy research and cancer chemoprevention. It is worth noting that many anthraquinones in Rhubarb have good activities of anti-liver diseases, including chrysophanol, emodin, rhein, and aloe emodin (Bai et al., 2020; Dong et al., 2017; Kuo et al., 2020; Li, Y. et al., 2019). Cryptotanshinone, the main anthraquinone extracted from Salvia miltiorrhiza Bunge, can protect liver by activating the AMPK/SIRT1 and Nrf2, and inhibiting CYP2E1 to inhibit adipogenesis, oxidative stress, and inflammation (Nagappan et al., 2019). Other bioactive components against liver diseases are shown in Table 6. In addition, the related chemical structures are also shown in Figure 9.

After the above discussion, it is not difficult to find the important position of CM in the treatment of liver diseases. As we all know, CM is a relatively safe class of drugs, but we can’t ignore its toxic and side effects on the liver when we use CM to treat liver diseases. The studies have found that some CM show certain hepatotoxicity. For example, Rhubarb extract had a certain protective effect on the rats with chronic renal failure, but the incidence of mild hepatotoxicity was also observed in normal rats (Wang et al., 2009). Ginkgo biloba extract induced DNA damage by inhibiting the topoisomerase II activity in human hepatocytes (Zhang et al., 2015). Interestingly, the hepatotoxicity of some CM comes from their own hydrolysates. For example, after the intragastric administration of Sophora flavescens extract to the rats, kurarinone glucosides was hydrolyzed into Kurarinone in liver cells, which eventually led to the lipid accumulation and liver injury through a series of actions (Jiang, P. et al., 2017). In addition, the use of herbal products is also a crucial cause of acute liver injury. It has been reported that a 68-year-old woman suffered from acute liver injury caused by aloe, after stopping taking aloe, her liver functions returned to normal levels (Parlati et al., 2017). It is worth noting that the first case of autoimmune hepatitis caused by turmeric supplements has been reported (Lukefahr et al., 2018).

The dosage of CM is often closely related to hepatotoxicity. In order to study the hepatotoxicity of Cortex Dictamni, fan et al. used its water extract and alcohol extract to carry out the toxicity experiments in vivo and in vitro. The results showed that high dose of water extract and alcohol extract significantly increased the levels of ALT and AST, absolute and relative liver weight, and the liver-to-brain ratio, and the histological examination of the liver showed the cell enlargement and nuclear contraction. In vitro cell experiment also showed that water extract and alcohol extract reduced the cell viability in a dose-dependent manner (Fan et al., 2018). A single oral dose of 60 g/kg Cortex Dictamni ethanol extract for 24 h resulted in severe hepatocyte necrosis in mice, and the induced liver injury showed a dose and time-dependent manner (Huang et al., 2020). Saikosaponins, a major bioactive component extracted from Radix Bupleuri, enhances the CYP2E1 expression in a dose and time-dependent manner, and induces oxidative stress in vivo and in vitro, leading to liver injury in mice (Li et al., 2017). In another study, the rats were fed with 300, 1250 and 2500 mg kg⁻¹·D⁻¹ Radix Scutellariae Baicalensis ethanol extract for 26 weeks. It was found that the liver tissues of the rats in the high-dose group showed some inflammatory changes mainly characterized by leukocyte infiltration. In addition, there were also some changes in the levels of glucose, electrolyte, and lipid (Yi et al., 2018). It can be seen that the hepatotoxicity of many CM are closely related to the dosage.

In addition, the abuse of CM without the guidance of doctors is also the source of toxic reactions. Because traditional Chinese medical science thinks that “toxicity” refers to the biases of drugs, the toxic components of CM are often the effective components for treating diseases. The key to judging whether CM is toxic or non-toxic is to see whether it is used according to the syndrome. As long as the treatment is besed on the syndrome, toxic drugs are also safe. If the treatment is not for the syndrome, non-toxic drugs may be harmful. It is worth noting that there are also some CM products considered non-toxic or low toxic, which have obvious toxicological effects on different organs in animal and human models (Liu, R. et al., 2020). So it is a great problem to control the toxic and non-toxic boundaries reasonably, and every traditional medical scholar should make efforts to do so.

Most drugs for anti-liver diseases used in clinic are CM compounds, and less clinical research and application involve only one CM or one compound. Table 7 shows some CM (excluding CM compounds) used in the clinical treatment of liver diseases. The purpose is to improve the richness of clinical medication, so that more CM with potential and significant therapeutic effects can be noticed.

Single extract or chemical component of CM showed good activity of anti-liver diseases in clinical research. Artemisia annua L. extract can improve the liver function in the patients with mild to moderate nonalcoholic liver dysfunction, and no obvious adverse reactions were observed in all subjects (Han et al., 2020). Futhermore, Portulaca oleracea extract can improve liver enzyme, blood lipid, and blood glucose in the patients with MAFLD (Darvish Damavandi et al., 2021). It is worth noting that Carcuma longa has a wide range of clinical applications, with a large number of clinical data, suggesting its position in the clinical treatment of liver diseases. To assess the effect of Carcuma longa on MAFLD, 92 MAFLD patients aged 20–60 years were enrolled in a 12-week study. The results showed that Carcuma longa supplement was very useful in controlling MAFLD-related risk factors (Darvish Damavandi et al., 2021). Curcumin, the main active component of Curcuma longa, can increase the serum inflammatory cytokine levels in the patients with MAFLD, which may be partly dependent on the anti-steatosis effect (Saberi-Karimian et al., 2020). In addition, curcumin can improve the quality of life of the patients with liver cirrhosis (Nouri-Vaskeh et al., 2020a). Although the clinical application of Curcuma longa has surpassed other CM against liver diseases, it still fails to solve the problem of its optimal dosage, and the molecular mechanisms on treating liver diseases is unclear. More importantly, in view of the widespread use of Curcuma longa, we need larger, more impartial and high-quality controlled randomized trials to conduct a deeper evaluation.

In the future, more clinical experiments should be studied, which makes more CM into clinical application, and even go to the international stage. There are still many deficiencies in the current clinical research. First, the dosage is single and the sample size is small, which is not good for screening the best treatment dose. Secondly, the existing clinical experiments mainly focus on the study of MAFLD, but there are many kinds of liver diseases. In the future, the research can be expanded to make more patients with liver diseases benefit from CM. Finally, the mechanisms of many CM (especially CM compounds) used in the treatment of liver diseases are not clear. We should further explore the mechanism of action of CM, making its fuzzy mechanism clearer and letting more people accept it.