NAFLD represents the hepatic manifestation of a cluster of conditions linked to metabolic dysfunction. The prevalence of NAFLD on a global scale tends to go up (Friedman et al., 2018). Globally, the estimated prevalence of NAFLD stands at approximately 25%, with the highest rates observed in the Middle East and South America, and the lowest in Africa. In North America and Europe, NAFLD is commonly associated with central obesity, accounting for approximately 83% of affected patients. However, it is noteworthy that in Asia, a significant proportion of NAFLD patients, known as “thin NASH” individuals, exhibit normal body mass index (BMI), despite the lower BMI threshold for defining overweight in Asia (BMI > 23) compared to North America and Europe (BMI > 25) (Pereira et al., 2015). NAFLD is characterized by the accumulation of fat (steatosis) in more than 5% of hepatocytes, occurring concurrently with metabolic risk factors, particularly obesity and type 2 diabetes. Notably, NAFLD is distinguished by the absence of excessive alcohol intake (≥30 g per day for men and ≥20 g per day for women), as well as the absence of other chronic liver diseases (Byrne and Targher, 2016). NAFLD encompasses a spectrum that spans from isolated steatosis, in which fat accumulates in the liver without significant progression, to the more severe condition known as non-alcoholic steatohepatitis (NASH). NASH is distinguished by the presence of hepatocellular injury, inflammation, and fibrosis, and is characterized by a progressive clinical course. Left untreated, NASH may lead to the development of cirrhosis, with its associated complications including hepatocellular carcinoma.

PP have shown the potential to alleviate the effects of NAFLD by inhibiting hepatocellular injury, inflammation, and fibrosis. The underlying mechanism is closely associated with the regulation of energy metabolism mediated through signaling pathways such as AMPK and MAPK. Radix Hedysari polysaccharide, Polygonatum sibiricum polysaccharides, and Astragalus mongholicus polysaccharides have been reported to ameliorate disorders in lipid metabolism, regulate hepatic lipid content, and improve liver inflammation and damage by modulating the phosphorylation levels of AMPK (Sun et al., 2014; Huang et al., 2021; Zhou et al., 2021; Zhong et al., 2022). Up to now, APS has been widely used in poultry and animal feed, with the function of improving the utilization of nutrients and promoting animal growth. The application of APS in the human is mainly to prevent and treat cardiovascular diseases. Additionally, the MAPK cascade plays a role in regulating NF-κB gene expression through redox mechanisms. ASP has been shown to mitigate Caspase-3-dependent apoptosis through the involvement of the Caspase-8 and JNK-mediated pathway. Moreover, ASP inhibits the activation of IL-6/STAT3 and NF-κB signaling pathways (Wang et al., 2016). Furthermore, emerging evidence supports the significant involvement of the gut microbiota in the development and progression of NAFLD. This study contributes novel findings by demonstrating the potential of Astragalus mongholicus polysaccharides to alleviate hepatic inflammation and reduce lipid accumulation in NAFLD. These beneficial effects are achieved through the modulation of the gut microbiota composition and the SCFA-GPR signaling pathways (Zhong et al., 2022). Moreover, Poria cocos polysaccharides have demonstrated the potential to mitigate the disruption of the gut–vascular barrier, the translocation of endotoxins induced by a high-fat diet, and inhibit intestinal pyroptosis. These effects are mediated through the regulation of key factors, including PARP-1 and the administration of pyroptosis inhibitors, such as MCC950 (Ye et al., 2022). Walnut green husk polysaccharide has the potential to enhance the composition and diversity of the gut microbiota, as well as increase the abundance of beneficial bacteria (Wang et al., 2020). Long-term and repetitive inflammation is a contributing factor in the advancement of NAFLD. In the progression of NAFLD, inflammation, fibrosis, autophagy, and apoptosis interact and exacerbate one another. Gynostemma pentaphyllum polysaccharides have been shown to inhibit the expression of Toll-like receptor 2 (TLR2) and downregulate the expression of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, as well as the pro-inflammatory cytokines TNF-α and IL-1β. These polysaccharides have the potential to improve non-alcoholic steatohepatitis (NASH), possibly through the modulation of gut microbiota and the TLR2/NLRP3 signaling pathway (Yue et al., 2022). Angelica sinensis polysaccharide (ASP) has garnered significant attention due to its notable hepatoprotective effects. Previous research has demonstrated that ASP exerts therapeutic effects on NAFLD through the regulation of lipid metabolism via the propionate/ERRα pathway (Luo et al., 2023). Furthermore, ASP has the capacity to enhance the expression of PPARγ and key liver insulin signaling proteins, such as IRS-2, PI3K, Akt, p-Akt, and GLUT2. Moreover, ASP has been shown to increase the levels of the anti-apoptotic protein Bcl-2 while concurrently reducing the expression of the pro-apoptotic protein Bax. This multifaceted action of ASP not only provides protection against hepatic damage but also offers promising therapeutic benefits in the context of liver health (Wang et al., 2016). Gynostemma pentaphyllum polysaccharides is a pure natural plant with medicinal value, which has broad application prospects in food, health, and drug. At present, the utilization is only for crude products, and research on it is limited to preclinical studies. Various studies have been done for discovering the anti-NAFLD activity of plant polysaccharides in Figure 1. Table 1 gives an overview of some studies performed in NAFLD.

ALD encompasses a range of liver conditions resulting from excessive alcohol consumption. These conditions include liver steatosis, steatohepatitis, hepatitis, cirrhosis, and HCC. The progression of ALD is primarily influenced by the duration and quantity of alcohol intake, while genetic, epigenetic, and environmental factors also contribute. Chronic alcohol use is a prominent cause of morbidity and mortality on a global scale, impacting over 200 disease and injury outcomes (Rehm et al., 2017; European Association for the Study of the Liver, 2018). According to the World Health Organization (WHO), there are approximately 2.3 billion current consumers of alcoholic beverages, with around one billion categorized as heavy intermittent drinkers. Among alcohol-attributable conditions, cirrhosis of the liver obtains the highest score, followed by road injuries and other digestive diseases (Saito et al., 2018). Alcohol is widely acknowledged as a carcinogen, being associated with the development and progression of various types of cancer. Furthermore, alcohol consumption has been firmly linked to the advancement of liver-specific diseases, including chronic viral hepatitis and hepatocellular carcinoma (Dolganiuc, 2015; Sahlman et al., 2016; Ganesan et al., 2020).

The liver assumes primary responsibility for ethanol metabolism. When excessive alcohol is consumed, the liver incurs substantial tissue damage as a result of both oxidative stress and the accumulation of acetaldehyde and lipopolysaccharide (LPS) (Meroni et al., 2018; Kong et al., 2019). ALD encompasses various conditions linked to alcohol consumption, such as early-stage asymptomatic ALD characterized by fatty liver or steatosis, steatohepatitis, advanced forms including alcoholic hepatitis and cirrhosis, as well as the development of HCC(Thursz et al., 2019).

Inflammation is a crucial risk factor associated with the progression of ALD, serving as a prerequisite for the development of fibrosis, cirrhosis, and HCC. Activation of Toll-like receptor 4 (TLR4) triggers NF-κB signaling, leading to the production and release of pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). Chronic alcohol consumption increases the levels of TNF and IL-6 in both animal models and human liver biopsy samples. Notably, patients with acute alcoholic hepatitis exhibit significantly elevated circulating levels of TNF and IL-6, which have been implicated in disease severity and the onset of multiorgan failure (Seitz et al., 2018).

PP exhibit notable anti-inflammatory properties, and recent studies have indicated that Aloe vera polysaccharides (AVP) can ameliorate ALD. AVP achieves this by upregulating AMPK-α, PPAR-α, and IκB-α, while simultaneously downregulating TLR-4 and MyD88 (Cui et al., 2014). Additionally, Aloe vera polysaccharides have been found to reduce hepatic inflammation by inhibiting the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. Moreover, they improve hepatocyte apoptosis by inhibiting the CYP2E1/ROS/MAPKs signaling pathway (Jiang et al., 2022). Lycium barbarum polysaccharide was found to regulate the NLRP3 inflammasome pathway, effectively inhibiting hepatic inflammation in the context of ALD. Moreover, it was observed that Lycium barbarum polysaccharide primarily ameliorated ALD through the SCD1-AMPK-CPT pathway, subsequent to ERα (Xiao et al., 2014; Wang et al., 2018). The activation of PPAR-γ signaling by water-insoluble polysaccharide treatment effectively reduces inflammation in colonic epithelial cells and promotes a hypoxic state, which aids in suppressing the excessive growth of fungi and Proteobacteria in the gut. This mechanism holds promise for alleviating ALD (Sun et al., 2020). A polysaccharide known as PFP-1, obtained from the fruiting body of Pleurotus geesteranus, has exhibited the ability to mitigate oxidative stress and inflammatory responses. This effect is achieved through the activation of Nrf2-mediated signaling pathways and regulation of the TLR4-mediated NF-κB signaling pathways, presenting a potential therapeutic strategy against ALD (Song et al., 2021). Additionally, research has indicated that the lipid-lowering impact of ASP may stem from its dual inhibition of lipid synthesis and CD36-mediated lipid uptake. The antioxidative properties of ASP can be attributed to its ability to reverse alcohol metabolic pathways, transitioning from cytochrome P450 2E1 (CYP2E1) catalysis to alcohol dehydrogenase (ADH) catalysis. Overall, this study establishes the direct involvement of ASP in lipid metabolism and elucidates its mechanism of action in reducing reactive oxygen species (ROS), thus positioning it as a potential therapeutic agent for the treatment of alcoholic fatty liver disease (AFLD) (He et al., 2022). The polysaccharides derived from Echinacea purpurea, known as EPPs, exhibit significant free radical scavenging activity in vitro, and have demonstrated the ability to ameliorate alcohol-induced liver injury through the activation of Nrf2/HO-1 pathways in vivo (Jiang et al., 2021; Jiang et al., 2022). These findings highlight the remarkable potential of PP in effectively regulating abnormal biochemical indices associated with ALD. Figure 2 and Table 2 give a summary of a few reports that PP against ALD.

The liver is highly susceptible to drug toxicity during clinical treatment due to its first-pass effect in gastrointestinal nutrition metabolism. Drug-induced liver injury is estimated to affect around 14–19 cases per 100,000 individuals (Andrade et al., 2019). Although asymptomatic elevated liver enzymes are the most common presentation, drug-induced liver injury constitutes the primary cause of acute liver failure in many Western countries, accounting for over 50% of cases. It can manifest at either excessive or therapeutic doses, potentially as consequence of direct intrinsic drug hepatotoxicity or idiosyncratic (unpredictable) hepatotoxicity (Hoofnagle and Bjornsson, 2019).

DILI is an infrequent condition that occurs irrespective of drug dose, route, or duration of administration. Moreover, idiosyncratic DILI does not represent a single homogeneous disease, but rather a range of rare disorders presenting diverse clinical, histological, and laboratory characteristics. The pathogenesis of DILI remains incompletely elucidated, with various factors contributing to its development and progression (Fontana, 2014). Intrinsic hepatotoxins, such as acetaminophen, typically exhibit dose-dependent behavior and can be studied using reproducible animal models to understand the underlying pathways leading to hepatocyte injury. Conversely, most cases of DILI observed in clinical practice are considered “idiosyncrasies” because they lack a clear correlation with the dose, route, or duration of administration, which makes them specific to each patient. PP play a significant protective role in mitigating drug-induced liver damage. In addition to the direct toxic effects of drugs, oxidative stress can occur as a result of drug metabolism, leading to the generation of ROS. These ROS can interact with proteins, causing changes in their functional and structural characteristics, and form neoantigens. ROS are responsible for initiating lipid peroxidation, leading to the formation of lipid peroxidation byproducts, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Various studies have demonstrated the potential of PP in improving ROS levels associated with DILI. Notable examples include Jujube polysaccharides, Seabuckthorn berry polysaccharide, and Periploca polysaccharide (Liu et al., 2015; Athmouni et al., 2018; Wang et al., 2018). Periploca polysaccharides have shown significant reductions in MDA content and protein damage in liver tissue, along with improvements in liver function parameters (alanine transaminase, ALT; aspartate aminotransferase, AST; bilirubin). Furthermore, Periploca polysaccharides have demonstrated the ability to enhance the activities of hepatic antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPx; GSH) as a protective response against cadmium chloride (CdCl₂)-induced toxicity in male Wistar rats (Athmouni et al., 2018). Schisandra polysaccharide exhibited a significant reduction in ALT, AST, TNF-α, and IL-1β levels, leading to the alleviation of hepatic pathological alterations in the mouse model. Additionally, it demonstrated protective effects on liver injury-associated enzymes and factors, including a notable decrease in MDA levels and GSH depletion, downregulation of Bax/Bcl-2 expression, inhibition of cleaved caspase-3 expression, as well as upregulation of p-AMPK, p-Akt, GSK 3β, Nrf 2, and HO-1 proteins in the liver tissues of the mouse model (Che et al., 2019). The hepatoprotective effect of Echinacea purpurea polysaccharide against APAP-induced DILI was observed. This effect was associated with a decrease in autophagy-dependent oxidative stress, inflammation, and apoptosis. Moreover, the observed protective mechanism involved Parkin-dependent autophagy (Yu et al., 2022). ASP pretreatment demonstrated significant attenuation of Caspase-3-dependent apoptosis through the Caspase-8 and JNK-mediated pathway. Furthermore, ASP inhibited the activation of IL-6/STAT3 and NF-κB signaling pathways in ConA-induced liver damage in mice (Wang et al., 2016). Moreover, ASP exhibits potential as a hepatoprotective agent for the management of acetaminophen (APAP)-induced liver injury by increasing glutathione (GSH) levels and inhibiting hepatic apoptosis (Cao et al., 2018). Notably, ASP has also shown efficacy in alleviating chronic liver fibrosis by inhibiting HSC activation via the IL-22/STAT3 pathway (Wang et al., 2020). Broussonetia papyrifera polysaccharide demonstrated hepatoprotective properties against APAP-induced liver injury. It effectively attenuated liver apoptosis, enhanced antioxidant capacity, and improved the liver’s detoxification ability towards APAP (Xu et al., 2022). Several studies have been conducted to investigate the efficacy of plant polysaccharides on the treatment of drug-induced liver damage in Figure 3 and Table 3.

Hepatic fibrosis and cirrhosis pose a substantial global health burden, leading to liver failure or HCC, thereby posing a significant threat to human health on a worldwide scale (Yang et al., 2023). Liver diseases pose a substantial global threat to human health, contributing to approximately 2 million deaths annually. Hepatic cirrhosis alone accounts for approximately 50% of all liver disease-related fatalities (Asrani et al., 2019).

Liver cirrhosis is a progressive complication that arises from liver disease, representing a significant advancement in hepatic fibrosis whereby there is a substantial loss of liver cells accompanied by irreversible scarring. Various factors such as viral infections (HBV and HCV), hepatic lipid accumulation, alcohol consumption, and drug toxicity contribute to chronic damage, impairing the functionality of hepatocytes. This, in turn, triggers inflammation and release of inflammatory factors, which promote excessive accumulation of collagen and extracellular matrix (ECM), resulting in the disruption of liver structure and function. Ultimately, this fibrotic process may progress to clinically significant cirrhosis and subsequent hepatic failure. Cirrhosis can be identified as an advanced stage of fibrosis characterized by the development of regenerative nodules within the liver parenchyma, enclosed by fibrotic septa (Pinzani and Macias-Barragan, 2010).

NAFLD and ALD, as well as DILI, contribute significantly to the development of advanced liver conditions, including hepatic fibrosis and HCC. PP have been reported to exhibit a variety of pharmacological effects such as antioxidation, anti-inflammation, and anti-apoptosis, thereby improving hepatic fibrosis. The polysaccharide derived from Talinum triangulare demonstrates remarkable antioxidant activities, effectively reducing the levels of AST, ALT), and MDA in CCl₄-induced liver injuries. Furthermore, it restores the activities of key antioxidant substances, SOD, and reduced GSH, thereby normalizing the liver’s defense mechanisms (Liang et al., 2011). Lycium barbarum polysaccharides have demonstrated effectiveness in reducing hepatic necrosis, serum ALT levels, and cytochrome P450 2E1 expression. Additionally, they restore the expression levels of antioxidant enzymes, decrease nitric oxide levels, inhibit lipid peroxidation, and alleviate hepatic inflammation. These effects are achieved through the downregulation of NFκB activity induced by CCl₄ (Xiao et al., 2012). Amomum villosum polysaccharides exhibited potent in vitro free radical scavenging activities and effectively mitigated oxidative stress-induced liver injury in CCl₄-treated mice by suppressing malondialdehyde formation and enhancing the activities of antioxidant enzymes (Zhang et al., 2013). Seabuckthorn berry polysaccharide (SP) administration significantly ameliorated liver injury in CCl₄-challenged mice, as evidenced by reduced levels of serum ALT, AST, and total bilirubin (TBIL). Moreover, SP treatment enhanced PALB levels, indicating hepatoprotective effects. These beneficial effects were accompanied by increased activities of antioxidant enzymes SOD and GSH-Px, elevated GSH levels, and reduced MDA content, indicating reduced oxidative stress. SP pre-treatment also attenuated the expression of pro-inflammatory cytokines TNF-α and IL-1β, as well as iNOS and NO production induced by CCl₄. Furthermore, SP pre-treatment suppressed hepatic TLR4 expression and inhibited the phosphorylation of p38 MAPK, p-ERK, p-JNK, and NF-κB signaling pathways in CCl₄-challenged mice (Zhang et al., 2017). Stipa parviflora polysaccharides treated rat liver anti-oxidant parameters (SOD, CAT and GPx) were significantly antagonized for the pro-oxidant effect of CCl₄ (Bargougui et al., 2019). Dictyophora polysaccharides (DIP) attenuated liver fibrosis induced by arsenic (As) by reducing hepatic pathological alterations and modulating the levels of serum markers including AST, ALT, total protein (TP), albumin (ALB), and Albumin/Globulin (A/G) ratio, as well as diminishing the concentrations of hyaluronic acid (HA), laminin (LN), procollagen type III (PCIII), collagen type Ⅳ (IV-C), TBIL, and direct bilirubin (DBIL). Moreover, DIP exhibited inhibitory effects on the synthesis of TGF-β1, thereby regulating the expression of connective tissue growth factor (CTGF) and subsequently suppressing the proliferation of fibrinogen and fibroblasts. This led to a reduction in fibroblast transformation into myofibroblasts, thus limiting the synthesis of fibroblasts (Wang et al., 2022). Results of the effects of PP on hepatic fibrosis activity are described in Figure 4 and Table 4.

HCC is a prevalent form of primary liver cancer with significant medical implications. It ranks sixth among the most commonly diagnosed tumors worldwide, accounting for 1.100 cases per 100,000 person-years. Moreover, it stands as the third leading cause of cancer-related mortality, resulting in 0.746 million new cases and 0.2012 million deaths. Notably, HCC represents the primary cause of death in individuals with cirrhosis, and its incidence is projected to rise in the coming years (Forner et al., 2018). The incidence of HCC is highest in East Asia and Africa, but there is a growing trend in the United States. In Asia and Africa, 60% of HCC cases are attributed to HBV infection, whereas HCV infection takes predominance in North America, Europe, and Japan. The strongest risk factor for HCC is cirrhosis, with an annual incidence ranging from 1% to 6%. HCC is commonly observed in patients with cirrhosis and is a leading cause of mortality in this population. Alcohol-induced cirrhosis accounts for 15%–30% of HCC cases, varying across geographical regions (Llovet et al., 2021). The polysaccharide derived from Panax notoginseng has demonstrated its potential to extend the lifespan of tumor-bearing mice by enhancing the host immune system while displaying limited cytotoxicity against hepatocellular carcinoma (Liu et al., 2021). Treatment with Dictyophora polysaccharides resulted in a time- and dose-dependent inhibition of HCC-LM3 cell proliferation, accompanied by cell cycle arrest in the G₂/M phase. Moreover, the expression of Bax and caspase-3 exhibited a significant increase following Dictyophora polysaccharides administration (Hu et al., 2020). Dandelion polysaccharide (DP) treatment effectively suppressed the protein levels of crucial angiogenesis-related factors involved in HCC, including HIF-1α, VEGF, p-PI3K, and p-AKT. This suggests that DP holds promise as a potential therapeutic agent for HCC (Ren et al., 2020). Astragalus polysaccharide (APS) has been found to mitigate PD-L1-mediated immunosuppression by targeting the miR-133a-3p/MSN axis, thereby facilitating an antitumor response (He et al., 2022). Additionally, ASP has been explored as a targeted drug carrier for HepG2 tumors via ASGPR, enhancing therapy for liver cancer (Zhang et al., 2019). Treatment with Aconitum coreanum polysaccharide, a potential therapeutic agent for HCC, led to a significant reduction in p-Akt protein levels, while simultaneously increasing p-p38 MAPK protein levels in H22 cells (Liang et al., 2015). Hypoxia promotes epithelial-mesenchymal transition (EMT) and facilitates migration and invasion of HCC cells. However, Basil polysaccharide (BPS) exhibits inhibitory effects on tumor progression and metastasis, including the reversal of EMT via cytoskeletal remodeling under hypoxic conditions. Furthermore, BPS targets hypoxia-inducible factor 1 alpha (HIF1α) to alleviate tumor hypoxia. We observed downregulation of mesenchymal markers (β-catenin, N-cadherin, and vimentin) along with upregulation of epithelial markers (E-cadherin, VMP1, and ZO-1) after BPS treatment, highlighting its potential for HCC therapy in hypoxic conditions (Feng et al., 2019). The application of Ginseng polysaccharide (GSP) mainly includes GSP injection and GSP fermented milk beverage. GSP injection is mainly used as an adjuvant therapy for clinical tumors, reducing the side effects caused by various tumor radiotherapy and chemotherapy, and serving as an immune modulator to improve the immune function. It can also be used to treat acute and chronic hepatitis and various liver injuries, as well as various chronic infections, diabetes, and various immune diseases. Figure 5 and Table 5 give a summary of a few reports on the anti-tumor activity of PP.