Ganoderma lucidum Polysaccharides in Liver Protection: Mechanisms and Therapeutic Potential

The liver is the body’s central organ for metabolism and detoxification, and its dysfunction is closely associated with a variety of conditions, including drug-induced liver injury, alcoholic liver disease, non-alcoholic fatty liver disease, viral hepatitis, and liver fibrosis. In recent years, with increasing research on natural products for functional foods and therapeutic development, Ganoderma lucidum (Reishi mushroom), a traditional medicinal fungus, has attracted considerable attention for its polysaccharide components and their hepatoprotective effects. Accumulating experimental and clinical evidence indicates that G. lucidum polysaccharides exhibit multiple mechanisms of action, including immunomodulation, antioxidant activity, anti-inflammatory effects, and antifibrotic properties, offering promising strategies for the prevention and management of liver diseases.

Keywords: Ganoderma lucidum polysaccharides; hepatoprotection; liver injury; antioxidant; antifibrotic; mechanism of action

1. Introduction

The liver, as the central organ of metabolism, plays essential roles in material transformation, detoxification, and immune defense. However, it is highly susceptible to damage from factors such as alcohol consumption, drug abuse, viral infection, and metabolic disorders, which can lead to conditions including fatty liver, hepatitis, liver fibrosis, and even cirrhosis. Current hepatoprotective drugs often have limitations, including single-target mechanisms and notable adverse effects with long-term use—for example, glycyrrhizin formulations may cause sodium and water retention, while tiopronin can induce gastrointestinal discomfort. In this context, identifying hepatoprotective compounds from natural products with high efficacy and low toxicity has become a research focus. Ganoderma lucidum, a traditional medicinal fungus with a history of over two millennia in China, contains polysaccharides that exhibit multiple bioactivities, including immunomodulatory, antioxidant, and anti-inflammatory effects, with minimal side effects. These characteristics have made G. lucidum polysaccharides increasingly valued in liver protection research. Recent advances in isolation and purification techniques, coupled with molecular biology approaches, have clarified the chemical structures, hepatoprotective mechanisms, and clinical application potential of these polysaccharides. This review systematically summarizes current knowledge on G. lucidum polysaccharides, providing a reference for their further development and application in hepatoprotection.

2. Plant Sources and Physicochemical Properties of Ganoderma lucidum Polysaccharides

Ganoderma lucidum, belonging to the family Polyporaceae, is one of the most representative species among traditional medicinal fungi. Its polysaccharides are widely distributed in the fruiting body, spores, and mycelium, with the majority of research focusing on polysaccharides extracted from the fruiting body. These polysaccharides are chemically complex, typically composed of monosaccharide residues such as glucose, galactose, mannose, fucose, and xylose, linked through various glycosidic bonds, forming diverse backbone and branched structures. G. lucidum polysaccharides generally exhibit high molecular weight and good water solubility, with some displaying viscous or colloidal properties. These physicochemical characteristics not only influence their absorption and distribution in vivo but also underlie their broad spectrum of biological activities, providing the material basis for their antioxidant, immunomodulatory, and hepatoprotective effects.

3. Multifactorial Causes of Liver Dysfunction

The liver is exposed to multiple potential sources of injury during its central roles in metabolism and detoxification, and cumulative damage over time can lead to functional impairment. Alcoholic liver disease (ALD) is commonly caused by chronic excessive alcohol consumption; ethanol metabolism generates acetaldehyde and reactive oxygen species that directly damage hepatocyte structure and inhibit fatty acid oxidation, leading to lipid accumulation and inflammatory responses, which may ultimately progress to fibrosis or cirrhosis. Non-alcoholic fatty liver disease (NAFLD) is primarily associated with metabolic syndrome. High-calorie diets combined with sedentary lifestyles disrupt hepatic lipid metabolism, promoting fat accumulation within hepatocytes and triggering chronic inflammation and fibrotic processes. Drug-induced liver injury (DILI) typically occurs during prolonged or combined medication use, as reactive metabolites produced during hepatic drug metabolism can induce oxidative stress and hepatotoxicity. Viral infections, including hepatitis B and C, also represent significant causes of liver injury; these viruses directly infect hepatocytes and elicit persistent immune responses, damaging liver architecture, impairing synthetic and detoxification functions, and potentially leading to chronic liver disease. Overall, liver dysfunction is often the result of multiple interacting factors, encompassing metabolic, toxic, infectious, and immune-mediated mechanisms.

4. Hepatoprotective Mechanisms of Ganoderma lucidum Polysaccharide

4.1 Regulation of Inflammatory Pathways

Inflammation plays a central role in liver injury and disease progression. Studies indicate that G. lucidum polysaccharides can suppress excessive pro-inflammatory signaling, reducing the release of cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), while increasing anti-inflammatory mediators like IL-10, thereby alleviating hepatic inflammation. Moreover, these polysaccharides inhibit the overactivation of Kupffer cells, limit infiltration of inflammatory cells into hepatic tissue, and reduce the cascade of inflammatory responses.

4.2 Activation of Antioxidant Defense

G. lucidum polysaccharides protect hepatocytes by scavenging excess reactive oxygen species (ROS) and enhancing endogenous antioxidant systems. They have been shown to upregulate the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), while reducing oxidative stress markers such as malondialdehyde (MDA) and lactate dehydrogenase (LDH). These effects mitigate oxidative damage to hepatocyte membranes and mitochondria. Additionally, G. lucidum polysaccharides can activate the Nrf2/HO-1 signaling pathway, inducing the expression of antioxidant proteins and further enhancing cellular protection.

4.3 Anti-Fibrotic Effects

Activation of hepatic stellate cells (HSCs) is a key step in liver fibrosis development. G. lucidum polysaccharides have been shown to inhibit persistent HSC activation, reducing α-smooth muscle actin (α-SMA) and type I collagen accumulation, thereby preventing excessive extracellular matrix deposition. They also enhance the activity of matrix metalloproteinases (MMPs) and maintain the balance with their inhibitors (TIMPs), facilitating collagen degradation and potentially slowing or reversing fibrosis progression.

4.4 Promotion of Hepatocyte Metabolism and Regeneration

Recent studies suggest that G. lucidum polysaccharides can improve hepatocyte energy metabolism, stabilize mitochondrial membrane potential, reduce ROS production, and promote ATP synthesis, playing a protective role in metabolic liver disorders such as non-alcoholic fatty liver disease. Furthermore, they stimulate hepatocyte DNA synthesis and accelerate regeneration; in partial hepatectomy mouse models, polysaccharide treatment doubled the hepatocyte proliferation index and shortened liver regeneration time. Additionally, these polysaccharides enhance the activity of hepatic detoxification enzymes, including cytochrome P450 isoforms, facilitating the metabolism of alcohol, drugs, and other toxic substances, thereby reducing the accumulation of harmful intermediates.

5. Safety Evaluation of Ganoderma lucidum Polysaccharides

5.1 Animal Toxicity Studies

Existing animal studies indicate that G. lucidum polysaccharides exhibit good safety and tolerability at conventional doses. In acute toxicity studies in mice, a single oral dose of 5 g/kg did not produce observable mortality or toxic symptoms. In long-term oral administration studies in rats, daily doses of 1 g/kg for 90 consecutive days did not result in abnormal liver or kidney function or histopathological changes, suggesting a high level of safety for prolonged use.

5.2 Clinical Safety Observations

Clinical studies have demonstrated that oral administration of 1–2 g/day of G. lucidum polysaccharide preparations for 8 weeks in adults did not cause significant changes in hematological parameters or liver and kidney function markers. A few participants reported mild gastrointestinal discomfort or rash, but no serious adverse effects were observed. These findings indicate that G. lucidum polysaccharides are generally safe at commonly used doses, providing experimental and clinical evidence for their application in food and pharmaceutical development.

6. Evidence from Studies

G. lucidum polysaccharides have demonstrated significant hepatoprotective effects across various liver injury models. For instance, in a carbon tetrachloride (CCl₄)-induced mouse model of liver injury, oral administration of polysaccharides reduced serum alanine aminotransferase (ALT) levels by approximately 45% and aspartate aminotransferase (AST) levels by about 40%. Histological analyses revealed marked attenuation of hepatocyte necrosis and inflammatory infiltration. In D-galactose-induced aging-related liver injury in rats, G. lucidum polysaccharides decreased levels of lipid peroxidation products, such as malondialdehyde (MDA), while enhancing antioxidant enzyme activities including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), thereby improving hepatic antioxidant capacity. In vitro studies further support these protective effects. In hepatocyte injury models induced by hydrogen peroxide (H₂O₂), G. lucidum polysaccharides treatment markedly improved cell viability, reduced intracellular reactive oxygen species levels, and restored mitochondrial function. 

7. Conclusion and Future Perspectives

As the primary bioactive component of Ganoderma lucidum, polysaccharides have shown multiple hepatoprotective effects in models of alcoholic liver injury, non-alcoholic fatty liver disease, and hepatic fibrosis, with a favorable safety profile, highlighting their potential as natural hepatoprotective agents. However, their complex structures, unclear mechanisms of action, and poorly defined structure–activity relationships remain major challenges, while clinical studies are limited by small sample sizes and short follow-up durations. Future research should focus on structural elucidation and synthetic biology approaches to identify key active moieties and underlying molecular mechanisms; large-scale, multicenter clinical trials to establish standardized dosages; and investigations into synergistic effects with other compounds and strategies to improve bioavailability, thereby facilitating their translation into functional foods and pharmaceuticals.

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