Mycotreatment and liver health: hepatoprotective mechanisms, scientific evidence, and perspectives from integrative medicine

The liver and the complexity of biotransformation

The liver is one of the main organs responsible for the transformation and elimination of endogenous and exogenous substances. Its metabolic activity includes an extremely complex network of enzymatic reactions, transport systems, and conjugation processes that transform numerous molecules, making them more easily eliminated through bile or urine.

Among the key players in the so-called phase I of biotransformation is the cytochrome P450 (CYP) enzyme superfamily. These enzyme systems catalyze oxidation reactions and the chemical modification of numerous drugs and xenobiotics. The process can promote detoxification, but under certain circumstances, it can also generate reactive metabolites that are potentially harmful to hepatocytes. The body's protection therefore depends on the balance between biotransformation, antioxidant systems, phase II reactions, and subsequent elimination. [1,2]

This aspect is important for correctly understanding the relationship between the liver and bioactive substances.

It is therefore not correct to imagine the liver as a simple “filter” in which toxins accumulate and that must be periodically “cleaned”. Biotransformation is a continuous physiological process. When the metabolic load, oxidative stress, inflammation, or other factors exceed the body's adaptive capacities, cellular damage processes can instead occur.

In this context, it becomes interesting to study substances capable of modulating oxidative stress and inflammation, protecting cell membranes, interfering with fibrotic processes, and supporting metabolic homeostasis.

It is precisely on these mechanisms that an increasing part of research on medicinal mushrooms focuses.

From medicinal mushrooms to bioactive molecules

Mycomedicine includes the use of medicinal mushrooms, their fruiting bodies, mycelia, or standardized extracts containing different classes of bioactive molecules.

Among the most studied compounds are:

• beta-glucans and other polysaccharides;
• triterpenes;
• phenolic compounds;
• sterols;
• proteoglycans;
• peptides and other low molecular weight molecules.

However, the chemical composition can vary considerably depending on the species, the part used, the cultivation conditions, the substrate, the extraction process, and the standardization of the product.

This element represents a fundamental point when interpreting scientific studies: a result obtained with a specific extract cannot automatically be transferred to any product containing the same fungal species.

Ganoderma lucidum, for example, has been studied in relation to numerous liver processes, and its biological activities have been associated mainly with polysaccharides and triterpenes. The experimental literature describes possible effects on the oxidative response, inflammation, liver metabolism, and fibrotic processes. [3,4]

However, the evidence is predominantly preclinical and must be distinguished from the results obtained in humans.

Oxidative stress: one of the main targets of research

Oxidative stress represents one of the recurring mechanisms in the different forms of liver damage.

When the production of reactive oxygen species exceeds the capacity of the endogenous antioxidant systems to neutralize them, alterations of cell membranes, proteins, nucleic acids, and mitochondria can occur.

The liver is particularly exposed to this phenomenon precisely because it represents an important metabolic and biotransformation center.

In experimental models, several compounds derived from medicinal mushrooms have demonstrated the ability to modify some indicators of redox status, increasing the activity of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase and reducing some markers of lipid peroxidation.

One of the studied mechanisms concerns the Nrf2-ARE pathway, an important cellular system for responding to oxidative stress. The activation of Nrf2 promotes the expression of numerous genes involved in antioxidant defenses and cellular protection.

However, it is necessary to distinguish the evidence of molecular activation observed in vitro or in animals from a clinical benefit demonstrated in humans.

The first represents a biological rationale; the second requires adequately controlled clinical studies.

Inflammation and hepatocyte protection

Chronic inflammation constitutes a central element in the progression of many liver diseases.

The persistent activation of immune cells and the production of pro-inflammatory mediators can contribute to hepatocyte distress, the alteration of mitochondrial function, and the progressive activation of repair processes.

Some polysaccharides and triterpenes from medicinal mushrooms have shown, in experimental models, the ability to modulate several pathways involved in the inflammatory response.

Ganoderma lucidum, in particular, has been studied in numerous experimental models of liver damage, including models of steatosis, toxic damage, inflammation, and fibrosis. The available literature describes a potentially multifactorial biological action, including the modulation of immune responses, antioxidant activity, and influence on some liver metabolic pathways. [3,4]

This multimodal approach is one of the most interesting aspects of mycomedicine research.

It is not necessarily about identifying a single molecule capable of acting on a single target, but about understanding how a complex mixture of metabolites can simultaneously modify multiple cellular processes.

Liver fibrosis and the role of stellate cells

One of the most interesting objectives of research concerns liver fibrosis.

Fibrosis represents a pathological response to chronic damage characterized by the progressive deposition of extracellular matrix. If the process persists, the structure of the liver can be progressively altered up to cirrhosis.

A central role is played by hepatic stellate cells, which, in the presence of persistent damaging stimuli, can transform into extracellular matrix-producing cells.

Among the most studied molecular pathways is the TGF-β/Smad pathway, considered one of the main regulatory systems of fibrogenesis.

Cordyceps sinensis has shown, in experimental models, the ability to interfere with some of the processes involved in the activation of stellate cells and the deposition of matrix. In particular, effects on TGF-β/Smad signaling and the balance between metalloproteinases and their inhibitors have been studied. [5]

Other experimental studies have highlighted a possible effect of Cordyceps mycelium on the liver immune response and the deposition of collagen in fibrosis models. [6]

These results are scientifically interesting because they indicate possible antifibrotic mechanisms, but they do not equate to the demonstration that a Cordyceps-based supplement can stop or reverse fibrosis in a patient.

Ganoderma lucidum: the most studied mushroom in the liver field

Among medicinal mushrooms, Ganoderma lucidum, also known as Reishi or Lingzhi, is probably the one with the largest body of experimental studies related to liver function.

Its main classes of bioactive compounds include polysaccharides and triterpenes.

Preclinical research has examined Ganoderma in models of:

• toxic liver damage;
• steatosis;
• inflammation;
• fibrosis;
• alcohol-associated liver disease;
• viral hepatitis;
• hepatocellular carcinoma.

Several mechanisms have been proposed, including the modulation of phase I and II enzymes, the reduction of oxidative stress, immune modulation, and interference with fibrotic processes. [3,4]

An experimental study also observed that polysaccharides derived from Ganoderma could reduce ALT, AST, and malondialdehyde and increase some antioxidant systems in a mouse model of chemically induced liver damage. [7]

Another more recent line of research has studied Ganoderma spore oil in relation to lipid metabolism and the gut microbiota in experimental models of liver damage. [8]

These results reinforce the biological rationale, but do not yet demonstrate equivalent therapeutic efficacy in humans.

It is significant, however, that a 2025 meta-analysis including 17 randomized studies and 971 participants highlighted that the effects of Ganoderma on the different clinical parameters are variable and that, overall, no significant effects on liver enzymes emerged. The overall quality of the evidence was judged to be very low. [9]

This observation is important: strong biological activity in the laboratory does not automatically mean clinical efficacy.

Cordyceps sinensis and antifibrotic research

Cordyceps sinensis has received particular attention for its possible antifibrotic activity.

In experimental models of liver fibrosis, some of its polysaccharides have shown the ability to interfere with stellate cell activation, TGF-β/Smad signaling, and extracellular matrix balance. [5]

Immunological mechanisms have also been studied through which the mycelium could influence the response of natural killer cells present in the liver and modify collagen deposition. [6]

There is also clinical data, but it is much more limited.

A small randomized study, conducted in patients with chronic hepatitis B and fibrosis, reported reductions in ALT, AST, and some serum markers of fibrosis in the group treated with a preparation containing Cordyceps. Some of the patients who underwent biopsy also showed improvements in the degree of inflammation and the stage of fibrosis. [10]

However, the sample size and study characteristics necessitate caution in interpretation.

The data should therefore be considered a signal of clinical interest, not definitive proof of antifibrotic efficacy.

Agaricus blazei: interesting clinical signals, but evidence still preliminary

Agaricus blazei is another fungus that has been particularly studied in the field of integrative medicine.

A small one-year pilot study observed four patients with chronic hepatitis B treated with 1500 mg per day of extract. At the end of the observation, the mean AST and ALT levels were considerably reduced. However, the same researchers emphasized the need for controlled studies with larger samples. [11]

The result is interesting precisely because it was obtained in humans, but the extremely small sample size makes it impossible to draw general conclusions.

Agaricus blazei also has a substantial body of preclinical literature.

In animal models of toxin-induced liver damage, favorable effects on lipid peroxidation, antioxidant systems, and markers of liver damage were observed. [12]

In this case too, the transition from the experimental model to clinical practice must be carried out with caution.

Grifola frondosa and lipid metabolism

Grifola frondosa, commonly known as Maitake, has been studied mainly for its possible role in lipid metabolism and the relationship between the gut and the liver.

An experimental model of fatty liver disease highlighted the favorable effects of a Grifola heteropolysaccharide on lipid accumulation in the liver, triglycerides, and metabolism associated with the gut microbiota. [13]

These data are particularly interesting because fatty liver disease does not simply represent a passive accumulation of fat.

Liver metabolism is closely linked to insulin sensitivity, adipose tissue, diet, gut microbiota, and the systemic inflammatory response.

Consequently, a substance capable of influencing more than one of these systems could theoretically also produce indirect effects on liver physiology.

However, here too, most of the available evidence remains preclinical.

Mycotherapy and fatty liver disease: from NAFLD to MASLD

The terminology related to fatty liver disease has changed in recent years.

The term NAFLD has been gradually replaced by the definition MASLD – metabolic dysfunction-associated steatotic liver disease, which places fatty liver disease within a context characterized by the presence of cardiometabolic risk factors.

The spectrum of MASLD includes conditions ranging from simple fatty liver disease to MASH, fibrosis, cirrhosis, and hepatocellular carcinoma associated with MASH. [14]

This conceptual change is important because it highlights the systemic nature of the disease.

Visceral obesity, insulin resistance, type 2 diabetes, lipid alterations, sedentary lifestyle, and diet represent elements closely linked to liver health.

The most recent European guidelines therefore place lifestyle modification, physical activity, dietary quality, and the management of metabolic risk factors at the center of MASLD management. [14]

In this scenario, mycotherapy can be studied as a possible complementary intervention, but not as a substitute for nutritional intervention, physical activity, or therapies prescribed by a physician.

The microbiota as a possible bridge between fungi and the liver

Another particularly interesting area of research concerns the gut-liver axis.

The gut microbiota influences bile acid metabolism, intestinal barrier permeability, fatty acid metabolism, and numerous immune signals.

Alterations in microbial composition and function can contribute to the production of metabolites capable of influencing liver metabolism and the inflammatory response.

Polysaccharides from medicinal mushrooms, particularly certain beta-glucans, can interact with the microbiota and the intestinal immune system.

This mechanism could help explain why some effects observed in experimental models are not necessarily due to a direct action on the hepatocyte, but also to a modulation of the gut-liver axis.

Research on Grifola frondosa, for example, has highlighted precisely a relationship between fungal polysaccharides, lipid metabolism, and the gut microbiota. [13]

This is an area that is still evolving, in which future research will need to establish which microbial species, which metabolites, and which fungal components are truly responsible for any clinical effects.

Cytochrome P450: a point to interpret with particular attention

The role of cytochrome P450 deserves an important clarification.

It is correct to state that CYP450 participates in the biotransformation of numerous xenobiotics and drugs and that the formation of reactive metabolites can, under certain circumstances, contribute to liver damage. [1,2]

It is not, however, correct to turn this concept into the statement that a medicinal mushroom should simply “increase” or “support” CYP450 to improve clearance.

The CYP system is much more complex.

An indiscriminate increase in the activity of a given enzyme does not necessarily equate to an improvement in liver health. Some biotransformation processes can indeed generate reactive intermediates, while others promote the elimination of substances.

Furthermore, precisely because some natural compounds can modify the activity of CYP enzymes, drug interactions can occur.

For Ganoderma lucidum, recent experimental studies have highlighted the inhibition of several CYP isoforms by certain triterpenes, with potential interference with drug metabolism. These are mainly preclinical data, but they represent a concrete reason to avoid simplistic interpretations of the relationship between medicinal mushrooms and cytochrome P450. [15]

The scientifically more correct perspective is therefore not to “boost CYP450,” but to study how specific fungal molecules can modulate biotransformation and cellular defense systems, taking into account the possible pharmacological interaction.

Mycotherapy is not a “detoxification” of the liver

The concept of “liver clearance” is very widespread in commercial communication, but from a physiological point of view, it must be used with caution.

The liver is not a reservoir of toxins to be periodically emptied.

Its function consists in transforming, through highly regulated processes, endogenous and exogenous substances. When the liver is healthy, these processes occur continuously.

When, however, there is liver disease, the clinical goal is not simply to “eliminate toxins,” but to identify and treat the cause of the damage, reduce risk factors, prevent the progression of fibrosis, and preserve liver function.

In the presence of MASLD, for example, lifestyle management represents a fundamental component of therapy. European guidelines recognize the importance of diet, physical activity, and the reduction of metabolic risk factors. [14]

Mycotherapy can therefore be studied within a model of integrative medicine, without attributing to it a role that current clinical evidence does not allow us to support.

An often underestimated problem: quality, standardization, and dosage

One of the main obstacles to the scientific evaluation of medicinal mushrooms is the great variability of preparations.

Two products containing the same species may not be pharmacologically equivalent.

They can indeed differ in:

• the part of the fungus used;
• fruiting body or mycelium;
• growth substrate;
• extraction method;
• solvent used;
• polysaccharide concentration;
• triterpene content;
• presence of beta-glucans;
• standardization;
• contaminants;
• daily dose.

Consequently, it is not enough to read the species name reported on the label to predict the biological activity of the product.

Future clinical research should therefore pay greater attention to the chemical characterization of extracts, the standardization of bioactive principles, and the definition of reproducible biomarkers.

Safety: natural does not automatically mean harmless

The issue of safety must also be addressed with rigor.

It is not correct to claim that medicinal mushrooms are always harmless to the liver.

In fact, there are clinical reports of liver damage associated with preparations containing Ganoderma lucidum and Agaricus blazei. Some cases have been particularly severe, although these are rare reports and not necessarily representative of the risk associated with all commercial preparations. [16–18]

The situation can be complicated by the concurrent intake of other supplements or drugs, the variability of extracts, and the possibility of contamination or adulteration.

It is therefore essential to consider:

raw material quality, extract standardization, correct dosage, drug interactions, and individual clinical conditions.

Particular attention should be paid by people taking drugs with a narrow therapeutic margin, drugs metabolized by CYP450, cancer therapies, anticoagulants, or other medications for which a change in plasma concentration may have clinical consequences.

The appearance of jaundice, dark urine, generalized itching, persistent abdominal pain, severe nausea, or increased transaminases during the intake of a product containing medicinal mushrooms requires medical evaluation and should not be interpreted as a normal “detoxification phase”.

From biological promise to evidence-based medicine

Research on hepatic mycotherapy presents a scientifically interesting but still incomplete picture.

Preclinical data are numerous and indicate several possible mechanisms:

reduction of oxidative stress → modulation of inflammation → cellular protection → regulation of lipid metabolism → interference with fibrogenesis → modulation of the gut-liver axis.

This plurality of mechanisms probably represents one of the most interesting aspects of medicinal mushrooms.

However, evidence-based medicine requires an additional step: demonstrating that these mechanisms produce clinically relevant benefits in people.

To achieve this, adequately powered randomized studies are needed, with well-characterized extracts, standardized dosages, sufficiently long treatment periods, and clinically meaningful outcomes.

A simple reduction in ALT or AST, for example, cannot automatically be considered equivalent to the regression of fibrosis or a reduction in the risk of cirrhosis.

A promising perspective, but one that must be built with rigor

Ganoderma lucidum, Cordyceps sinensis, Agaricus blazei, and Grifola frondosa represent four of the medicinal mushrooms most studied in relation to liver health.

Their bioactive molecules have shown antioxidant, anti-inflammatory, immunomodulatory, and potentially antifibrotic properties, especially in experimental models.

Some small clinical studies have also yielded signals of interest, particularly regarding transaminases and fibrosis markers.

However, the overall level of evidence remains insufficient to consider mycomedicine an independent therapy for liver diseases.

The scientific value of mycomedicine today lies primarily in the search for new bioactive molecules and complementary strategies capable of simultaneously targeting multiple biological mechanisms.

For the future, the standardization of extracts, the identification of the truly active components, the study of drug interactions, and the conduct of larger clinical trials will be crucial.

In this sense, mycomedicine does not represent a shortcut to “detoxify” the liver, but rather an interesting field of research in integrative medicine that can contribute to the understanding of new biological approaches to liver protection.

Bibliographic references

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