Due to its various biological activities, astaxanthin has been used to prevent and treat various systemic diseases in vivo. In recent years, researchers have confirmed that astaxanthin is important in preventing acute liver injury, alleviating insulin resistance and NAFLD, liver fibrosis, and liver cancer.

Liver Fibrosis

Liver fibrosis is a key link in chronic liver diseases such as viral hepatitis and fatty liver deterioration. Without effective intervention, 75–80% of these diseases can develop into cirrhosis, which seriously endangers human health. The synthesis of extracellular matrix (ECM) induced by activation of hepatic stellate cells (HSCs) and the transformation of myofibroblasts (MFs) are the key factors in hepatic fibrosis. The reversibility of these factors also provides an important research target for the reversal of hepatic fibrosis. The mechanism of liver fibrosis is complex, involving the regulation of histopathology, cytology, cytokines, and their molecular levels. Studies have confirmed that astaxanthin plays an anti-fibrotic role via its antioxidant, apoptotic, lipid peroxidation, and autophagy activities.

Astaxanthin inhibited the activation of resting HSCs and restored the resting state of activated HSCs in mice. Astaxanthin also decreased reactive oxygen species (ROS) production and increased the expression of nuclear factor erythroid 2-related factor 2 (NrF2), the main transcription factor in endogenous antioxidant defense. Therefore, the protective effect of astaxanthin on hepatic fibrosis may be attributed to its enhanced antioxidant capacity. Astaxanthin could restore the activity of catalase (CAT) and superoxide dismutase (SOD) in rats with carbon tetrachloride (CCl4)-induced liver fibrosis and prevent liver fibrosis induced by CCL4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system.

The transforming growth factor (TGF)-β/Smads pathway is a key pathway in the induction of ECM formation during hepatic fibrosis. Astaxanthin has been shown to inhibit ECM formation through the TGF-β1/Smad3 pathway in the human HSC cell line LX-2. There are many downstream influencing factors, and apoptosis and autophagy are two programmed cell death pathways directly related to the survival status of HSCs in hepatic fibrosis. On the one hand, astaxanthin can induce apoptosis of LX-2 cells by regulating mir-29b, which mainly inhibits Bcl-2 and increases the expression levels of Bax and Caspase-3, thus playing a role in preventing liver fibrosis.

On the other hand, astaxanthin significantly improved liver fibrosis induced by CCL4 and bile duct ligation (BDL) in mice. It can also reduce the expression of TGF-β1 and autophagy by inhibiting the level of nuclear factor (NF)-κB, which inhibits the activation of HSCs and the formation of ECM. Its effectiveness is related to the release of energy by autophagy through lipid droplet degradation, thus providing favorable conditions for the activation of HSCs.

In addition, histone acetylation, as an epigenetic model, participates in the activation of HSCs and liver fibrosis. The histone deacetylase 9 (HDAC9) level in primary biliary cirrhosis of the liver was significantly higher than that in normal liver, and other liver pathologies showed high expression of HDAC9. Accordingly, The level of HDAC9 in primary activated HSCs increased significantly, while HDAC9 knockout in LX-2 cells decreased the expression of the fibrosis gene induced by TGF-β1. Astaxanthin significantly inhibited the activation of HSCs by down-regulating the expression of HDAC9. HDAC3 and HDAC4 may also inhibit the activation of HSCs by astaxanthin.

The use of astaxanthin is often limited due to its lack of stability and water solubility. Astaxanthin-Han aggregates (AHAna) were prepared by adding astaxanthin to hydrophilic hyaluronan nanoparticles (HAn) and used these aggregates in rat models of liver fibrosis with good results. In addition, liposomes were used to encapsulate astaxanthin, achieving improved stability. In conclusion, astaxanthin has significant anti-fibrosis effects, but the mechanism requires further investigation.

Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by excessive fat deposition in hepatocytes, excluding alcohol and other specific liver-damaging factors, and mainly includes non-alcoholic steatohepatitis (NASH). NAFLD is an important metabolic syndrome that can increase mortality in obese and diabetic patients. Presently, NAFLD’s pathogenesis is complex and related to many factors, such as insulin resistance, oxidative stress, inflammatory mediators, and cytokines. Currently, there are no effective targeted drugs for the treatment of NAFLD, and treatment includes diet therapy and lifestyle adjustment, liver protection and lipid-lowering, and insulin sensitization. Astaxanthin has many effects and may play an effective role in preventing the pathogenesis of NAFLD from many aspects.

In 2007, after studying the effect of astaxanthin supplementation on obese mice fed a high-fat diet. The results showed that astaxanthin inhibited the increase in body weight and adipose tissue caused by the high-fat diet. In addition, astaxanthin also reduced liver weight and triglyceride, plasma triglyceride, and total cholesterol levels. These results indicate that astaxanthin may play an important role in improving lipid metabolism and lays the foundation for future research on the treatment of NAFLD.

The release of inflammatory factors is crucial in the pathogenesis of NAFLD. Astaxanthin significantly reduced M1 macrophages and increased M2 macrophages, reduced liver recruitment of CD4+ and CD8+ and inhibited inflammation in NAFLD. Compared with vitamin E, astaxanthin reduced lipid accumulation, improved insulin signal transduction, and inhibited pro-inflammatory signal transduction more effectively by inhibiting the activation of Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) and NF-κB pathways. Similarly, astaxanthin reduced macrophage infiltration and the expression of macrophage markers in mice inhibited inflammation and fibrosis in liver and adipose tissue. They enhanced the ability of the skeletal muscle to oxidize mitochondrial fatty acids in obese mice.

Peroxisome proliferator-activated receptors (PPARs) play an important role in regulating inflammation. Activated PPAR-α has become a key target in NAFLD as it can improve fatty acid transport, metabolism, oxidation, and inhibiting liver fat accumulation. In addition, activation of PPAR-γ can also regulate gene expression related to lipid synthesis and promote fatty acid storage. Overexpression of PPAR-γ can induce lipid accumulation in the liver. DNA microarray was used to analyze gene expression in the liver of mice fed astaxanthin. It was found that astaxanthin inhibited PPARs. Screening drugs for liver PPARs and their related molecular functions in mice provided a new therapeutic basis for NAFLD. Astaxanthin was administered orally to mice fed a high-fat diet for 8 weeks. It was found that astaxanthin improved liver lipid accumulation induced by a high-fat diet, reduced triglyceride levels in the liver, and decreased the number of inflammatory macrophages and Kupffer cells.

These changes were attributed to the regulation of PPARs by astaxanthin. Astaxanthin activates PPAR-α and inhibits the expression of PPAR-γ and the levels of interleukin-6 and tumor necrosis factor-α in the liver, inhibits inflammation, and reduces fat synthesis in the liver. In addition, astaxanthin also causes autophagy of hepatocytes by inhibiting the AKT-mTOR pathway and decomposes lipid droplets stored in the liver. Compared with N-Acetyl-L-cysteine (NAC) and vitamin C (VC), astaxanthin effectively reduced intracellular lipid deposition.

Additionally, astaxanthin significantly inhibited the expression of fatty acid synthase and acetyl coenzyme A carboxylase, increased SOD, CAT, GPX activity, and glutathione (GSH) in the liver, and significantly reduced lipid peroxidation in the liver. Astaxanthin significantly reduced TAG accumulation in apolipoprotein E knockout mice and increased the expression of NrF2 and its target genes (including SOD 1 and glutathione peroxidase 1). It is very important for the endogenous antioxidant mechanism. Compared with the standard NAFLD antioxidant vitamin E, astaxanthin not only inhibits the expression of lipid-producing genes but also improves the level of liver enzymes; vitamin E only reduces blood lipids.

In clinical trials, a prospective, randomized, double-blind study confirmed the effect of astaxanthin on oxidative stress in overweight and obese adults in Korea. Twenty-three adults with a body mass index >25.0 kg/m2 were enrolled in this study and randomly divided into two dosage groups: astaxanthin 5 mg or 20 mg once a day for 3 weeks. The results showed that the oxidative stress markers, malondialdehyde (MDA), isoprostane (ISP), SOD, and total antioxidant capacity (TAC) were significantly improved. Because of these beneficial effects, astaxanthin should be further evaluated as a new and promising treatment for NAFLD.

Liver Cancer

Hepatocellular carcinoma (HCC) accounts for 70–90% of primary liver cancer, and the complex pathogenesis and genetic polymorphisms restrict the development of HCC therapy and seriously endanger human health. Although progress has been made in clinical research of HCC, the mechanism of invasion and metastasis is still not fully clear. The development of HCC is closely related to many signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, Wnt/β-catenin, NrF2/ARE, and VEGF. Astaxanthin has been shown to play an important role in cancer prevention, inhibition of cell proliferation and metastasis, promotion of cell apoptosis, and enhancement of immunity.

As early as the 1990s, astaxanthin was discovered to inhibit the occurrence and development of HCC by inhibiting the binding of aflatoxin B1 (AFB1) to liver DNA and plasma albumin in the AFB1-induced hepatoma model. Astaxanthin reduced the number and area of liver cancer lesions in rats by regulating the NrF2/ARE pathway in early cyclophosphamide-induced liver tumors and played an important role in preventing the occurrence and development of liver cancer. Astaxanthin promoted mitochondrial apoptosis of CBRH-7919 mouse hepatoma cells and human LM3 and SMMC-7721 hepatoma cells in a concentration-dependent manner. The mechanism was related to JAK1/STAT3, NF-κB P65, and Wnt/β-catenin.

In addition, astaxanthin may also regulate nucleoside diphosphate kinase (NPK) nm-23, which is conducive to the correct assembly of cytoskeleton and signal transfer of T protein, thus inhibiting the occurrence of liver tumors. Consistent with the above results, astaxanthin was demonstrated to inhibit cell proliferation and promote cell apoptosis in vitro and in vivo. That astaxanthin mainly blocked the cell cycle in the G2 phase. Abnormal lipid metabolism is an important feature in the occurrence and development of malignant tumors, and obesity is more likely to cause tumors. Fatty acid synthase, which regulates lipid metabolism, has been demonstrated to be elevated in various cancer models after studying astaxanthin’s fatty acid synthase (FASN) regulation in a mouse model. Astaxanthin improved serum adiponectin levels and significantly reduced reactive oxygen metabolites/biological antioxidant potential ratio, thus playing a role in liver tumors of obese individuals.

As mentioned above, animal experiments have demonstrated astaxanthin’s preventive and therapeutic effects on many types of tumors, and its mechanism has been investigated. It has been found that astaxanthin may be related to various signaling pathways, but its specific mechanism is still unclear and requires further study.

Alcoholic Liver Disease

The liver is the main organ in drug metabolism, and some drugs are metabolized only in hepatocytes. Therefore, the intake of toxic substances can easily lead to the accumulation and damage of hepatocytes. Alcoholic hepatitis is mainly caused by direct or indirect inflammation, oxidative stress, erogenous endotoxin, inflammatory mediators, and nutritional imbalance during the metabolism of ethanol and its derivatives. Studies have shown that astaxanthin can alleviate liver steatosis and inflammation caused by ethanol.

In addition, the levels of ROS, pro-inflammatory proteins, and related inflammatory factors were significantly decreased in liver tissue in the drug group, which may be related to the negative phosphorylation of STAT3. Besides inhibiting oxidative stress and inflammation to prevent alcohol-induced liver damage, astaxanthin can also regulate intestinal flora. It may play a potential therapeutic role in alcoholic liver disease-induced bacterial diseases. Similarly, liposomal encapsulation of astaxanthin exerted rapid and direct effects against repeated alcohol-induced liver disease and could boost recovery from liver injuries caused by long-term alcohol intake.

Drug-Induced Liver Injury

Astaxanthin has also been shown to be effective in another drug-induced liver injury. In cell and animal models, astaxanthin significantly reduced liver injury induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and significantly increased the activity of inhibited antioxidant enzymes. In addition, by inhibiting the expression of inflammatory factors such as TNF-α and ROS production, liver injury induced by paracetamol (APAP), concanavalin A (ConA), and lipopolysaccharide (LPS) can be alleviated. The main mechanism of this effect may be related to the inhibition of the MAPK family and NF-κB pathways. Therefore, astaxanthin not only effectively inhibits the occurrence and development of liver fibrosis, NAFLD, and liver cancer but also plays an important role in preventing acute drug-induced injury.

Hepatic Ischemia-Reperfusion

Hepatic ischemia-reperfusion (IR) injury often occurs after hepatectomy, liver transplantation, and shock and can cause severe liver dysfunction. With improvements in economic and living conditions, more patients with end-stage liver disease choose liver transplantation to prolong their lives. Therefore, it is essential to prevent liver IR injury. It is generally believed that such damages are related to ROS, Kupffer cells, inflammatory cytokines, and ROS are key to inducing such injuries. Astaxanthin, a potent antioxidant, has been shown to play an important role in the IR of the cardiovascular system, liver, and kidney.

After 14 days of astaxanthin preconditioning, hepatocyte injury and mitochondrial swelling were lower in IR rats and unprotected groups. It was shown that astaxanthin significantly inhibited the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO). This suggests that astaxanthin improves hepatic IR injury via its antioxidant effect. Scientists subsequently determined ROS and inflammatory factors in a mouse model of IR after astaxanthin preconditioning to determine the role of astaxanthin in scavenging oxidative stress products and examined the relevant mechanisms, which may be related to down-regulation of the activity of the MAPK family-related proteins, thus inhibiting apoptosis and autophagy.

In addition, the apoptosis of hepatocytes induced by hypoxia can also be inhibited by astaxanthin, which further demonstrates that astaxanthin has a protective effect in hepatic IR injury via antioxidation and is a safe and effective treatment method.