S-Adenosyl-L-methionine (SAMe) is a molecule of significant importance for cell survival and function in all living organisms. It is recognized as the principal methyl donor reagent for methylation reactions. Considering the critical role of methylation in sustaining the normal cell function and maintaining the various cellular processes, any alterations in SAMe metabolisms can bring profound influence in cell growth, differentiation and normal function. SAMe is also the precursor of glutathione (GSH) (Lu, 2000). Since the structure been first unveiled in 1951 (Cantoni, 1951), studies investigating the biological function of SAMe have not been stopped. SAMe participate in tremendous physiological process and is recognized as the most important cofactor only second to adenosine triphosphate (ATP).

SAMe is involved mainly in three biological pathways: trans-methylation, trans-sulfuration and polyamine synthesis (Lu, 2000; Ouyang et al., 2020). More than 90% of the formed SAMe molecules are consumed to sustain methylation reactions (Ouyang et al., 2020). Liver is the major site for SAMe synthesis and degradation and have the fundamental role in the homeostasis of SAMe. In patients with liver disease, the intracellular SAMe is inadequately produced. But this inadequacy can be compensated from exogenous SAMe administration. Due to its crucial role in physiological processes and beneficial effect for hepatocyte, SAMe is widely used in liver disease including hepatitis, non-alcoholic fatty liver disease (NAFLD) and cholestasis. Its therapeutic effect is also proved in patients with neurological diseases, arthritis and cancer. Guidelines from Society for maternal and fetal medicine, European Association for the Study of the Liver and Chinese Medical Association all recommend the application of SAMe in the management of ICP(European-Association-for-the-Study-of-the-Liver, 2009; Obstetrics-Group-of-Obstetrics-and-Gynecology-Branch-of-Chinese-Medical-Association, 2015; Royal-College-of-Obstetricians-and-Gynaecologists, 2022). SAMe is also frequently applied in other types of cholestatic disease, including neonatal cholestasis and cholestasis caused by NAFLD (Virukalpattigopalratnam et al., 2013; Zeng et al., 2021). Evidence from both animal models and clinical trials revealed that exogenous administration of SAMe raised the GSH levels and ameliorated liver injuries (Mora et al., 2018; Brzački et al., 2019). In spite of its widely accepted therapeutic effects, the exact kernel mechanism of its function remains to be explored since SAMe is involved in so many critical cellular processes. But there is no doubt that the intracellular trans-methylation and trans-sulfuration processes are modulated due to the supplementation of exogenous SAMe.

Studies regarding the hepatoprotective effects of SAMe are summarized in (Supplementary Tables S1, S2) (Frezza et al., 1984; Frezza et al., 1990; Ribalta et al., 1991; Nicastri et al., 1998; Binder et al., 2006; Wang and Shen, 2012; Zhang et al., 2015; Jiang et al., 2019; Li and Xiao, 2019; Fanying et al., 2023). In this table, studies on the comparison between SAMe with placebo and SAMe in combination with UDCA are presented. Considering the first line medication for ICP is still UDCA, we did not analyze studies comparing the treatment effects between SAMe with UDCA. From these studies, we can see that in recent years, SAMe is usually applied with the combination of UDCA and seldomly used alone as the monotherapy for ICP patients. Compared with placebo, SAMe is found to be effective in reducing liver transaminases in studies conducted in the 1980s–1990s. Results from the combination use of SAMe plus UDCA indicated the combination therapy provided better maternal and fetal prognosis. Results from meta-analyses summarizing the treatment of ICP in recent decade demonstrated that UDCA-SAMe combination therapy is considered to have better hepatoprotective effects than either UDCA or SAMe monotherapy (Zhou et al., 2014; Zhang et al., 2016).

Polyene phosphatidylcholine (PPC), a major bioactive ingredient of essential phospholipids, have fundamental roles in maintaining the hepatocyte membrane fluidity and function (Li et al., 2021). The major component of PPC is phosphatidylcholine (PC). PC is the key component of organelle membranes and cell membrane. Polyunsaturated fatty acids such as linolenic acid and oleic acid are rich of PPC. By providing the endogenous phospholipids, the damaged liver cell and organelle membrane are repaired by PPC. The membrane function is restored and the fluidity and stability of cell membrane are increased, these mechanisms can protect hepatocyte from the variety of detrimental factors (Committee-of-the-treatment-with-polyenphosphatidylcholine-in-patients-with-liver-diseases, 2017). PPC is also proved to promote liver function restoration by recovering oxidative balance (Cao et al., 2016). Because of its function in repairing cell membranes and maintaining the integrity of biofilm. Recent studies suggest that PPC can be used as an anti-inflammatory drug (Pan et al., 2017; Feng et al., 2020).

PPC has been used vastly in the treatment for hepatitis, liver steatosis, NAFLD, alcoholic liver disease and drug-induced liver injuries. A multicenter retrospective study including 6,052 patients with various liver disease (8% Hepatitis B Virus (HBV) infected) demonstrated that PPC efficiently decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in patients with liver diseases regardless of the status of HBV infection. High-dose PPC resulted in a stronger effect than low-dose PPC(Xu et al., 2022). PPC has better hepatoprotective effect than glutathione or magnesium isoglycyrrhizinate even in patients with hepatic carcinoma (Li et al., 2022). In a prospective study including 2,843 adult patients with newly diagnosed NAFLD complicated with cardiometabolic comorbidities, PPC is found to improve the ultrasonographic features of NAFLD in these patients (Maev et al., 2020).

Three clinical trials focusing PPC in ICP are presented in (Supplementary Tables S1, S2) (Li and Yan, 2014; Jie et al., 2017; Zhu et al., 2022). All of the three trials proved the beneficial effects of PPC, the serum transaminases in ICP pregnancies were decreased and PPC did not cause adverse events for the fetus. Animal studies reveal consistent findings. Karaman. et all used a rat model of biliary obstruction. They found supplementation with polyunsaturated phosphatidylcholine alleviated the severity of liver damage and fibrosis in biliary obstructed rats (Karaman et al., 2003). Improvement in bile lipid secretion might be another underlying mechanism for the beneficial effects of PPC for ICP. Research from murine models found that supplementation with phosphatidylcholines promote the bile lipid secretion. They found phosphatidylcholines were required in the bile secrete process to form vesicles enriched in cholesterol. The protective effect of phosphatidylcholines could possibly be originated from the activation of multidrug export pump 1 (MDR1), which protects the hepatocyte by returning hydrophobic toxic bile components to the bile (Muller and Jansen, 1998; Chanussot and Benkoël, 2003).

Glutathione (GSH) is a thiol-containing tripeptide consisting of L-glutamate, cysteine, and glycine. GSH and its related enzymes, such as glutathione S-transferase (GSH-St) and glutathione peroxidase (GPx) are important antioxidants of human body that arrest toxic electrophilic xenobiotics and eliminate free radicals (Wu et al., 2004; Lv et al., 2019; Lai et al., 2020). Reduced glutathione is the major form of glutathione and is predominately distributed in the cytosol of mammalian cells. GSH is involved in several cellular metabolic activities and play important roles in maintaining the biochemical balance and physiological function. In mitochondria, GSH is oxidized to glutathione disulfide by GPx. During the oxidation process of GSH to glutathione disulfide by GPx, H₂O₂ is reduced to H₂O. This catalytic process promotes the conversion of toxic peroxides to nontoxic hydroxyl compounds. By decomposition of H₂O₂, the detrimental effect of the peroxide is eliminated, and the structure and function of cell membranes are maintained (Wu et al., 2004; Lv et al., 2019). GSH in the nucleus is important in the cell cycle (Markovic et al., 2007). In endoplasmic reticulum (ER), the GSH/glutathione disulfide ratio is in a very high level to keep a highly oxidizing environment, in the condition of which the normal function of ER can be maintained (Cao and Kaufman, 2014).

Considering the fact the liver is the main supporter of total body GSH turnover, which contribute to at least 90% of GSH inflow into the systemic circulation (Lauterburg et al., 1984). Liver dysfunction inevitably lead to the impairment of GSH synthesis, which in turn cause the aggravation of damage to liver due to the inability to scavenge toxic peroxides and free radicals. In cirrhotic patients, the endogenous GSH basal appearance rate have been reported to have a 50% reduction (Bianchi et al., 1997). Supplementation with GSH seems a reliable way to alleviate the reduced GSH level in these patients and improve the antioxidant capacities. Evidence from rat model indicated that administration of oral GSH significantly increased the hepatic GSH level in rats (Vina et al., 1989). However, controversial results were found in the treatment effect of GSH to liver disease. Lai et used oral GSH with vitamin B6 to 61 patients with liver cirrhosis, they found no improvement in liver Child–Turcotte–Pugh scores, the oxidative stress was not reduced (Lai et al., 2020). In an open label, single arm, multicenter study including 34 patients with NAFLD, supplementation of GSH for 4 months lead to significant reduction in serum ALT level. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased (Honda et al., 2017). Another study included 75 patients diagnosed with HBV infection, 25 of them used oral GSH, the effective rate of GSH was 72% (Wang et al., 2008).

As summarized in (Supplementary Tables S1, S2), two Chinese studies investigated the therapeutic function of GSH in ICP patients (Ping et al., 2017; Chundong and Bin, 2022). From this limited evidence, it seems that GSH is an effective and safe medication for ICP. Studies exploring the treatment value and safety of GSH in ICP are still needed.

The Chinese medicinal herbals have been used for centuries and are proved to have the therapeutic effect in various liver diseases. Bicyclol [4,4′-dimethoxy-5,6,5′,6′-bis(methylenedioxy)-2-hydroxymethyl-2′-methoxycarbonyl biphenyl], derived from traditional Chinese medicine Schisandra chinensis (Wuweizi), is an innovative hepatoprotective and anti-inflammatory medication in China. Since its approval by the Chinese Food and Drug Administration in 2004, endeavor to explore its efficacy for clinical application from clinical trials and effort to uncover the underpinning mechanisms from basic research have not been stopped. The therapeutic effects of bicyclol have been proved to be versatile from retrieved literature, including anti-inflammation, antioxidative stress, elimination of free radicals, anti-steatohepatitis, anti-fibrosis and prevention against nuclear DNA damage (Liu, 2009; Li et al., 2020; Zhao et al., 2021; Jia et al., 2022). Bicyclol is also proved to have the regulating function of gut microbiota and prevent ferroptosis (Zhao et al., 2021; Li et al., 2022; Zhao et al., 2022).

The therapeutic effects of bicyclol are investigated in patients with hepatitis, NAFLD and acute drug-induced liver injury. Results from two reviews including randomized controlled trials of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) patients demonstrated beneficial effects of bicyclol (Wu et al., 2006; Yang et al., 2007). A phase IV clinical trial including more than 2000 HBV cases completed 6 months of bicyclol, the normalized rate of serum ALT exceeded 60%, and AST exceeded approximately 50%. In addition, the HBV replication can also be inhibited by bicyclol. After 6 months of treatment, the negative conversion rate of hepatitis B e antigen (HBeAg) was approximately 20%. The therapeutic efficacy was higher in patients at a younger age (Yao et al., 2005). Studies focusing on combination therapy effect of bicyclol and lamivudine revealed that bicyclol is better than lamivudine in reducing liver enzymes in the early stage of treatment (Huang et al., 2005). For patients with HCV, a phase IV clinical trial proved that bicyclol at dosage of 75–150 mg per day for 6 months could reduce the ALT and AST normalized rate by 30%. The negative rate of HCV-RNA was reduced by approximately 20% (Yao et al., 2005). Combined treatment of bicyclol with ribavirin in patients with HCV also showed better efficacy for inhibiting the hepatocirrhosis (Sun et al., 2007). For patients with NAFLD, bicyclol was evaluated in a systematic review included twelve randomized controlled trials (RCTs) involving 1,008 patients (Li et al., 2020). Evidence from this study presents the liver function is significantly improved in either bicyclol monotherapy or combination therapy with another hepatoprotective agent. For patients with acute drug-induced liver injury, evidence from a multicenter randomized trail including 241 patients indicated the therapeutic effect of bicyclol appeared to be convincing without adverse effects, and bicyclol at a higher dosage (150 mg per day) showed higher efficacy (Tang et al., 2022).

To date, there are no clinical trials focusing the application of bicyclol in cholestatic patients. Investigated the bicyclol effects in a cholestatic mouse model (Zhao et al., 2021). They found bicyclol could mitigate liver damage in cholestatic mice by amplifying the levels of hydrophilic bile acid and improve liver histopathological indexes. Bicyclol promoted activation of autophagy by increasing the lipidation of LC3. Their results indicate that bicyclol is a promising therapeutic strategy for cholestasis. The underlying mechanism is possibly through regulation of the autophagy-mediated HMGB1/p62/Nrf2 pathway. Yang found bicyclol could decrease the hepatic transaminases and alleviate the fibrosis index in the rat liver (Yang, 2020). They concluded the alleviating effects of bicyclol for cholestasis was associated with the inhibition of cholesterol 7a-hydroxylase (CYP7A1), which is the rate-limiting enzyme for synthesis of bile acid. As a novel medication derived from traditional Chinese medicine, the underlying mechanism for bicyclol is still elusive. Researches aiming at revealing the mechanisms of bicyclol is still emerging. Clinical trials on the application of bicyclol in cholestatic patients, especially ICP, are urgently needed to pinpoint the potential beneficial effect in this population.

Obeticholic acid (OCA) is a synthetic bile acid derivative and act as a potent agonist of farnesoid X receptor (FXR) (Pellicciari et al., 2002; Kjærgaard et al., 2021). It is the approved medication by the FDA and European Medicines Agency (EMA) for the treatment of patients with primary biliary cholangitis with inadequate response to UDCA (Beuers et al., 2015; Hirschfield et al., 2015; Nevens et al., 2016; Kjærgaard et al., 2021). In 17α-ethynyl estradiol induced ICP mouse model, OCA was found to activate placental, maternal, and fetal hepatic FXR signaling. The glutathione depletion and lipid peroxidation in placenta and fetal liver were attenuated with OCA, the placental protein nitration process was also suppressed. OCA almost completely suppressed the elevation of serum bile acid, ALT, and AST levels and markedly attenuated the necrosis and cytoplasm rarefaction of hepatocytes. The incidence of intrauterine growth restriction in the offspring was decreased by OCA supplementation (Chen et al., 2019). In C57BL/6J pregnant mouse model fed with cholic acid-enriched diet and OCA plus cholic acid enriched diet, OCA supplementation during gestation was found to have no apparent detrimental impact on maternal and fetal morphometry. The fetal hypercholanemia was greatly ameliorated with OCA (Pataia et al., 2020).

Currently, there are no clinical trials on OCA’s therapeutic effect in ICP patients. But the efficacy of OCA has been testified in patients with primary biliary cholangitis and non-alcoholic steatohepatitis and primary biliary cholangitis (Nevens et al., 2016; Kjærgaard et al., 2021; Kulkarni et al., 2021). In a 12-month, double-blind, placebo-controlled, phase 3 trial, 216 primary biliary cholangitis patients were randomized to OCA 10 mg, OCA 5–10 mg and placebo group. Patients in the two OCA groups had greater decreases than those in the placebo group in the ALT level and total bilirubin level (Nevens et al., 2016). In a meta-analysis including seven RCTs of 2,834 patients with non-alcoholic steatohepatitis and primary biliary cholangitis, OCA was found to improve the hepatic fibrosis. But OCA at higher dosage (25 mg) was also associated with higher incidence of pruritus and discontinuation of the treatment (Kulkarni et al., 2021). The pros and cons of OCA in ICP patients should be investigated in future research.

Traditional Chinese medicine (TCM) have been widely used in the treatment of hepatic diseases including NAFLD, hepatitis, cirrhosis, and cholestasis in Asia for centuries. The treatment concept of TCM for hepatic disease is holistic. Advantage from this is a more individualized treatment plan. In China, TCM are widely applied with combination of UDCA for the treatment of ICP (Jiang et al., 2021; Wei et al., 2022). The treatment for ICP mainly focused hepatoprotection and promoting circulation of bile. The frequently used herbs for ICP included Yinchenhao decoction, Lidan Yishen Decoction, Jinying Huayu Decoction, Yin Huang Mixture, Dan Shen (Radix Salvia Miltiorrhiza) etc. The various TCM used could manifest with multiple features and functions in mechanism, including anti-oxidant stress, regulation of lipid metabolism, anti-inflammation, anti-fibrosis and modulation of gut microbiota (Liang et al., 2020; Dai et al., 2021; Wei et al., 2022).

Yinchenhao decoction is a classic TCM for cholestasis. This decoction consists of Artemisia capillaris Thunb, Gardenia, and Rhubarb. Artemisia capillaris Thunb is the most important medicinal material, which is named as Yinchenhao in China. This medicinal plant has over 100 kinds of active chemical components such as coumarin compounds flavonoids and organic acids (Zhang et al., 2013; Huang et al., 2021; He et al., 2023; Yao et al., 2023). The pharmacological activities of Yinchenhao includes anti-inflammatory, anti-fibrosis, and anti-tumor effects (Zhang et al., 2013; Li, 2020). Yinchenhao decoction could downregulate transforming growth factor β1 (TGF-β1), p-Smad3 and extracellular regulated protein kinases 1/2 (ERK1/2) expression in chenodeoxycholic acid activated hepatic stellate cells and increase the cell viability significantly (Cai et al., 2018). The most abundant compounds in Yinchenhao decoction were 7-methoxycoumarin, chrysophanol, deoxychrysoside-8-O-gallic acid salt, emodin, and mussaenosidic acid, which can be detected in the plasma of patients taking Yinchenhao decoction (Yao et al., 2023). With the ability of downregulation the level of hepatocyte apoptosis and alleviate oxidative stress, 7-methoxycoumarin can protect liver injury induced by carbon tetrachloride (CCl4) (Sancheti et al., 2013). Chrysophanol can alleviate the liver fibrosis progress by regulating GPx function and endoplasmic reticulum stress response (Kuo et al., 2020). Mussaenosidic acid can regulate immune function by inhibiting the classical complement pathway, and has antioxidant activity in Fe2+-Cystine induced rat liver damage model (Zhang et al., 2010). Emodin can play hepatoprotective effect by acting as the regulating factor for oxidative stress and autophagy (Zheng et al., 2019; Lee et al., 2020). A network meta-analysis by included 38 RCTs exploring the effect of Yinchenhao in ICP pregnancies. Their results demonstrated that when compared with UDCA used alone, Yinchenhao decoction plus UDCA dramatically reduced the serum levels of bile acid, ALT, and AST (Jiang et al., 2021). Recent clinical trials of Yinchenhao in ICP pregnancies are summarized in Supplementary Tables S1, S2 (Wang et al., 2019; Chen et al., 2020; Xu et al., 2021; Zhu, 2021) (Supplementary Tables S1, S2). Based on the hepatoprotective effects of Artemisia capillaris Thunb, the Yin Huang Mixture is another clinical experiential decoction with the combination of different herbs including Hypericum japonicum Thunb, Eucommia ulmoides Oliver, Rheum officinale Baill, Gardenia jasminoides Ellis, Poria cocos Wolf and Dictamnus dasycarpus Turcz. Animal studies using cholestatic rat model found that the Yin Huang Mixture can reduce bile acid level by upregulating the hepatobiliary transporters multidrug resistance associated protein 2 (MRP2) and bile salt export pump (BSEP) (Liu, Hou, and Zhao, 2018).