Editorial Note: Bicyclol (4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2-hydroxymethyl-2'-methoxycarbonylbiphenyl) is a derivative of Schisandra chinensis, a traditional Chinese medicine. In recent years, it has demonstrated remarkable efficacy and safety in the treatment of liver diseases. As research progresses, its potential applications have expanded beyond liver-related conditions. A recent study by Dr. Chao Sun’s team from the Department of Gastroenterology at Tianjin Medical University General Hospital, published in European Journal of Pharmacology, provides a comprehensive review of current research on bicyclol. The paper systematically summarizes its biological activities, mechanisms of action, pharmacokinetics, toxicity profile, and potential future directions for research.Bicyclol, derived from Schisandra chinensis, has been widely used in the treatment of various liver diseases since its approval by China’s National Medical Products Administration as a hepatoprotective drug. Viral hepatitis remains a major global public health challenge, with China having the highest number of chronic hepatitis B virus (HBV) infections worldwide (Liu, 2009). As a novel synthetic drug, bicyclol has been shown to improve liver function and inhibit viral replication, making it a common prescription for patients with viral hepatitis (Yao, 2005). Over time, research has clarified its therapeutic roles in metabolic dysfunction-associated fatty liver disease (MAFLD), hepatocellular carcinoma (HCC), acute liver failure (ALF), liver fibrosis, and drug-induced liver injury (DILI). Additionally, clinical studies have demonstrated its favorable safety profile (Zhang et al., 2016a).
In recent years, researchers have extended their focus beyond liver diseases, exploring the potential therapeutic applications of bicyclol in non-hepatic conditions. Studies have suggested that bicyclol exerts protective effects on the cardiovascular, pulmonary, and renal systems and mitigates ischemia/reperfusion (I/R) injury in the liver (Cui et al., 2013; Shih et al., 2005; Zhang et al., 2013, 2014; Zhao et al., 2002). Moreover, bicyclol has shown promise in treating acute lung injury, idiopathic pulmonary fibrosis (IPF), renal dysfunction, renal cell carcinoma (RCC), and cardiomyopathy. These findings have deepened our understanding of its pharmacological mechanisms, highlighting its ability to exert anti-inflammatory effects, regulate different forms of cell death, and combat intracellular and extracellular stress. However, there remains a lack of comprehensive analysis on its therapeutic pathways, which could provide insights into optimizing drug administration and developing novel broad-spectrum organ-protective agents. Given its low bioavailability and solubility, further studies are needed to identify its active metabolites and the role of other hepatoprotective components in Schisandra chinensis (Chen et al., 2023a; Hu et al., 2020; Huang et al., 2022; Luo et al., 2024; Ma et al., 2024). Additionally, real-world studies incorporating clinical practice and drug combination therapy are essential to fully elucidate its therapeutic potential.
Pharmacokinetics of Bicyclol
The evaluation of bicyclol’s metabolites and metabolic enzymes is crucial for assessing its efficacy and toxicity, providing guidance for rational drug combinations in clinical practice (Chen et al., 2023a; Hu et al., 2020; Huang et al., 2022). CYP3A4 and CYP2C19 have been identified as the primary enzymes responsible for bicyclol’s bioactivation (Chen et al., 2023a; Luo et al., 2024). Due to CYP3A-mediated metabolism and P-glycoprotein efflux, bicyclol exhibits low bioavailability (Tan et al., 2008a). However, in ALF rat models, reduced CYP3A metabolism resulted in increased bioavailability (Tan et al., 2008b).
Interestingly, the hepatoprotective effects of bicyclol exhibit sex-specific differences, potentially linked to heat shock transcription factor 1 (HSF1) and heat shock protein 70 (Hsp70) responses (Chen et al., 2015). Testosterone has been shown to inhibit glycogen synthase kinase-3β (GSK3β) activity while promoting HSF1 transcription. Administration of testosterone and GSK3β inhibitors has been found to restore the hepatoprotective effects of bicyclol in females.
In an effort to improve its pharmacokinetics, Ryu and Yoo (2012) reported that pre-microemulsified formulations of bicyclol enhanced its bioavailability. Additionally, the development of poly(lactic-co-glycolic acid) (PLGA) nanoparticles enabled sustained and targeted drug release (Yan et al., 2015). Two active metabolites of bicyclol, M2 and M3, have been successfully synthesized on a gram scale (Ma et al., 2024). Yang et al. (2019) demonstrated that bicyclol did not exhibit significant clinical drug interactions with commonly used medications such as pioglitazone, metformin, fenofibrate, and atorvastatin.
Toxicity of Bicyclol
Bicyclol is considered a safe and effective hepatoprotective agent. Liu et al. reported that administration of bicyclol at different doses (150, 200, and 600 mg/kg) in rats and dogs did not result in significant toxicological changes (Liu et al., 2005a). In chromosomal aberration assays, bicyclol exhibited a half-maximal inhibitory concentration (IC50) of 200 μg/mL for Chinese hamster lung cell growth. The oral median lethal dose (LD50) for both mice and rats exceeded 5 g/kg. Studies evaluating the mutagenic and teratogenic potential of bicyclol demonstrated no related toxicity even at high doses (1 g/kg) (Liu et al., 2005a). Additionally, bicyclol methyl ether, a major impurity of bicyclol, showed no genotoxicity in vitro and exhibited no embryotoxic effects on zebrafish embryos (Zhang et al., 2019). Clinical studies further confirmed that bicyclol improves alanine aminotransferase (ALT) normalization rates without causing significant renal impairment or hematological abnormalities (Pan et al., 2007; Wang et al., 2021). Overall, no significant toxicity has been observed with bicyclol.
Therapeutic Applications of Bicyclol
1. Bicyclol in the Treatment of MAFLD
With rising obesity rates, the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) has increased significantly. MAFLD is a chronic liver disease that, in its advanced stages, can progress to liver fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), while also increasing the risk of cardiovascular disease and type 2 diabetes. Currently, no definitive pharmacological treatment for MAFLD is available (Konerman et al., 2018).
A meta-analysis involving 1,008 patients showed that bicyclol effectively improves liver function markers (ALT and AST) and lipid profiles (triglycerides and total cholesterol) in MAFLD patients (Li et al., 2020). Bicyclol combined with berberine has demonstrated synergistic therapeutic effects in MAFLD (Geng et al., 2022; Li et al., 2022a). Co-administration with fenofibrate further reduces intrahepatic triglyceride and cholesterol levels while mitigating fenofibrate-induced liver injury (Zhu et al., 2015).
Bicyclol exerts hepatoprotective effects by correcting dysregulation of the peroxisome proliferator-activated receptor alpha (PPARα) pathway and reducing oxidative stress markers, such as serum amyloid A-1, glutathione S-transferase Mu 1, and A1 (Wu et al., 2023; Yu et al., 2009b). Additionally, bicyclol downregulates endoplasmic reticulum (ER) stress-related biomarkers, including glucose-regulated protein 78, C/EBP homologous protein, activating transcription factor 6 alpha, and inositol-requiring enzyme 1 alpha. This suggests that bicyclol protects the liver by alleviating ER stress-induced apoptosis (Jia et al., 2022; Zhen et al., 2015).
Furthermore, bicyclol reduces the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 by inhibiting the NF-κB and MAPK signaling pathways, thereby improving MAFLD outcomes (Zhang et al., 2016b; Zhao et al., 2021c). Clinical studies indicate that bicyclol lowers serum transaminase levels, hepatic lipid accumulation, and inflammation while improving glucose metabolism and insulin resistance. This effect is achieved through inhibition of inflammatory cytokines (IL-1β, TNF-α), insulin signaling, and gluconeogenesis-related pathways such as phosphoenolpyruvate carboxykinase (PCK), PPARγ coactivator-1 alpha (PGC-1α), and Akt (Li et al., 2021).
Therapeutic Applications of Bicyclol
2. Bicyclol in the Treatment of Viral Hepatitis
Viral hepatitis is primarily caused by infection with hepatitis viruses, with China being a high-prevalence region for chronic hepatitis B (CHB). Despite widespread vaccination programs for hepatitis B over the past decades, the global incidence of the disease remains high. Current clinical treatments have limitations, including long treatment durations, adverse effects, and high costs (Lok et al., 2016).
Bicyclol has been shown to significantly inhibit viral replication while maintaining liver function. When combined with adefovir dipivoxil (ADV), bicyclol further reduces serum transaminase levels (Xie et al., 2012). Compared to entecavir, bicyclol demonstrates similar efficacy in ALT normalization and improvement of liver inflammation (Chi et al., 2019). Additionally, bicyclol suppresses HCV replication by reducing the concentration of vesicle-associated membrane protein-associated protein A/non-structural protein 5A (Huang et al., 2019). Its mechanisms of action include downregulating Fas/FasL mRNA expression to reduce TNF-α release (Li and Liu, 2004), regulating iron homeostasis via the Nrf2-glutathione peroxidase 4 axis (Zhao et al., 2022), and upregulating HSP70 and HSP27 to inhibit JNK and NF-κB activity (Bao and Liu, 2008, 2009, 2010a, b; Dai et al., 2016). Furthermore, bicyclol modulates the AMPK-mTOR and MAPK signaling pathways (Zhao et al., 2020).
3. Bicyclol in the Treatment of Acute Liver Failure (ALF)
ALF is characterized by rapid hepatocyte necrosis leading to multiple organ failure, with common causes including viral infections and drug toxicity (Bernal and Wendon, 2013). Bicyclol alleviates inflammatory cascades by reducing TNF-α and IFN-γ levels (Galanos et al., 1979). In liver ischemia-reperfusion (I/R) injury, bicyclol exerts protective effects by scavenging reactive oxygen species (ROS), inhibiting NF-κB activation, and downregulating TLR4 expression (Yao et al., 2009).
4. Bicyclol in the Treatment of Liver Fibrosis
Liver fibrosis represents a critical stage in the progression of chronic liver diseases toward end-stage liver failure. Bicyclol exerts anti-fibrotic effects by inhibiting TIMP-1 expression, enhancing collagenase activity, and reducing TGF-β1 levels (Hu and Liu, 2006; Gu et al., 2010). Additionally, it modulates bile acid metabolism pathways and ameliorates cholestasis via the HMGB1/p62/Nrf2 pathway (Zhao et al., 2021a).
5. Bicyclol in the Treatment of Drug-Induced Liver Injury (DILI)
DILI is one of the most common causes of liver dysfunction in clinical practice. Retrospective analyses indicate that bicyclol significantly improves ALT normalization rates in DILI patients (Wang et al., 2021). In cisplatin-induced liver injury models, bicyclol protects against hepatotoxicity by restoring glutathione (GSH) levels and enhancing antioxidant enzyme activity (Yu et al., 2009a). Among tuberculosis patients, bicyclol reduces oxidative stress and cytokine release by inhibiting CYP2E1 activity (Liu et al., 2017). Cost-effectiveness analyses suggest that bicyclol is one of the most economical therapeutic options for managing anti-tuberculosis DILI (Chen et al., 2018).
6. Bicyclol in the Treatment of Tumor Diseases
Bicyclol inhibits hepatocellular carcinoma (HCC) cell proliferation by modulating the NF-κB, PKC, and MAPK signaling pathways (Sun and Liu, 2006, 2009). In renal cell carcinoma (RCC), bicyclol suppresses tumor growth by inducing cell cycle arrest and apoptosis (Wu et al., 2017).
7. Bicyclol in the Treatment of Pulmonary Diseases
In lipopolysaccharide (LPS)-induced acute lung injury models, bicyclol alleviates pulmonary edema and pathological damage by balancing pro-inflammatory and anti-inflammatory cytokines (TNF-α, IL-1β, IL-10) (Luo et al., 2011). Additionally, it directly binds to MyD88 to inhibit TLR4 complex formation, blocking NF-κB and MAPK signaling pathways (Fu et al., 2024). In silicosis models, bicyclol reduces fibrosis by inhibiting TGF-β1 secretion and the SMAD/JAK2/STAT3 pathway (Liu et al., 2024).
8. Neuroprotective Effects of Bicyclol in Cerebral Ischemia
Bicyclol enhances antioxidant capacity by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, thereby reducing infarct volume and neurological deficits following cerebral ischemia (Zhang et al., 2013, 2014).
9. Bicyclol in the Treatment of Kidney Diseases
Bicyclol has been shown to ameliorate structural damage in obesity-associated kidney disease by inhibiting apoptosis, fibrosis, and inflammation (Zhang et al., 2024b). In cisplatin-induced nephrotoxicity, bicyclol mitigates damage by restoring GSH levels and enhancing antioxidant enzyme activity (Yu et al., 2009b).
10. Bicyclol in the Treatment of Cardiovascular Diseases
Bicyclol protects cardiomyocytes by inhibiting mitochondrial permeability transition pore opening and reducing ROS production (Cui et al., 2013). In atherosclerosis models, bicyclol improves cholesterol metabolism and inflammation by modulating gut microbiota composition (Li et al., 2022b). Additionally, it mitigates inflammation and fibrosis in diabetic cardiomyopathy (Zhang et al., 2024a).
Conclusion
This review summarizes the molecular mechanisms and clinical efficacy of bicyclol in treating various diseases. Bicyclol exerts therapeutic effects through the regulation of inflammatory pathways, oxidative stress, ER stress, and cell death processes. Future research should focus on improving its bioavailability, evaluating individualized therapeutic responses, and assessing potential risks in combination therapies. The integration of computational biology and artificial intelligence techniques may further expand its clinical applications.
Original Reference:
Liu H, Yang Z, Li J, Zhang J, Sun C. Expanding the horizons of bicyclol in multiple diseases: Mechanisms, therapeutic implications and challenges. Eur J Pharmacol. Published online February 13, 2025. doi:10.1016/j.ejphar.2025.177381.
Expert Profile: Professor Sun Chao
Department of Gastroenterology, Tianjin Medical University General Hospital
Professor Sun Chao is an Associate Chief Physician in the Department of Gastroenterology at Tianjin Medical University General Hospital. He holds a medical degree from Peking University Health Science Center and obtained his MD and PhD degrees in Medicine and Science from Tianjin Medical University. He has also served as a research fellow at Hyogo Medical University in Japan.
Professor Sun is an active member of several prestigious national and international medical associations. He is a national committee member of the 5th CNSLD, a member of the Portal Hypertension Committee of the China Human Health Science and Technology Promotion Association, and a senior member of the Chinese Nutrition Society. He also serves as the Deputy Chairman of the Hepatology Committee of the Tianjin Internet Medicine Science Popularization Association and a standing committee member of the Youth Committee of the Tianjin Sleep Research Society.
As a researcher, Professor Sun has led a National Natural Science Foundation of China (NSFC) project and has contributed to the drafting and editing of four clinical guidelines and expert consensus reports. He is an editorial board member of JCTH (Journal of Clinical and Translational Hepatology), PH&C (a high-impact new journal), and eGastroenterology (as a founding young editorial board member).
His academic contributions have been recognized internationally. He has delivered oral presentations at major global conferences, including EASL (European Association for the Study of the Liver), APASL (Asian Pacific Association for the Study of the Liver), JSH (Japanese Society of Hepatology), and KASL (Korean Association for the Study of the Liver). He has also presented poster sessions at AASLD (American Association for the Study of Liver Diseases) and guided students in poster presentations at ACN (Asian Congress of Nutrition).
Professor Sun has received multiple prestigious awards, including the EASL Full Bursary, APDW Travel Grant, APASL Investigator Award, and KASL Travel Award.
As a corresponding author, he has published nearly 80 SCI-indexed research articles in high-impact journals such as Clinical Nutrition, Briefings in Bioinformatics, Liver International, and Cell Death & Disease. His work has been cited over 1,606 times, with an h-index of 23. His research has been referenced in clinical practice guidelines by ASGE (American Society for Gastrointestinal Endoscopy) and EASL, and his findings on malnutrition have been cited in the New England Journal of Medicine (Impact Factor: 96.3).
Research Focus
Professor Sun’s research primarily focuses on:
• The role of cell death and mitochondrial dysfunction in liver injury
• Body composition abnormalities, malnutrition, frailty, and sleep disorders in cirrhosis and metabolic dysfunction-associated fatty liver disease (MAFLD)
• The impact and intervention strategies of micronutrients in liver diseases
His contributions continue to shape the evolving landscape of hepatology, particularly in metabolic liver diseases and liver injury mechanisms.
