Globally, non-alcoholic fatty liver disease (NAFLD) represents the most prevalent chronic liver condition, estimated to affect around 38 % of the world's population (Allen et al., 2023). NAFLD is characterized by macrovesicular fat accumulation in at least 5 % of hepatocytes. Its spectrum encompasses simple steatosis (without significant hepatocyte injury) and non-alcoholic steatohepatitis (NASH), the latter of which may be accompanied by ballooning degeneration of hepatocytes, inflammatory infiltration, and even fibrosis (Gofton et al., 2023; Wei et al., 2024). Approximately 20 % of individuals with NAFLD are expected to progress to NASH, a condition characterized by hepatocellular ballooning, insulin resistance, and lobular inflammation. Over 3–4 decades, 20 % of patients with NASH are likely to develop cirrhosis. Individuals with cirrhosis-related NASH are at risk of developing hepatocellular carcinoma (Samy et al., 2024). Individuals with NAFLD may experience improvement or reversal of the condition through lifestyle modifications, including enhanced physical activity and dietary adjustments (Aerts et al., 2024). A delayed diagnosis often leads to the development of end-stage liver disease, for which the only viable treatment option is liver transplantation (Quek et al., 2023).

Gut-liver axis, describing bidirectional interactions involving gut microbiota composition, intestinal barrier integrity, gut-derived metabolites, and host immunity, is crucial for understanding NAFLD development. Contributing factors such as metabolic dysfunction, dietary habits, and obesity can disrupt gut microbial ecology (Qiu et al., 2023). Studies demonstrate that a one-week high-fat diet (HFD) in mice induces dysbiosis, which promotes damage to the intestinal vascular barrier and facilitates bacterial translocation to the liver (Mouries et al., 2019). Consequently, the liver becomes the primary site exposed to gut-derived microbes, microbial products, and toxins. Furthermore, microbial metabolites including short-chain fatty acids (SCFAs), trimethylamine, and bile acids, may regulate liver lipid metabolism and inflammatory responses by activating host nuclear receptors, such as the farnesoid X receptor and pregnane X receptor (PXR) (Okamura et al., 2020; Ni et al., 2022; Long et al., 2024; Suh et al., 2025). These findings highlight the importance of the gut-liver axis in NAFLD progression and suggest that targeting the gut microbiota and its metabolites could be a potential therapeutic strategy for this disease.

PXR (nuclear receptor subfamily 1 group I member 2, NR1I2) is mainly expressed in liver and gastrointestinal tract (Poudel et al., 2022; Yang et al., 2024). Our previous published reviews have demonstrated that the nuclear receptor family, particularly PXR, plays a crucial regulatory role in the intestinal-liver axis and is involved in NAFLD progression (Ni et al., 2022; Xu et al., 2023). PXR is a key regulator of xenobiotic metabolism (Qiu et al., 2016). Furthermore, PXR activation alters the expression of genes involved in exogenous metabolism, adipogenesis, gluconeogenesis, and bile acid synthesis, all of which have been implicated in NAFLD (Smutny et al., 2022). Notably, a recent study has demonstrated that intestinal PXR exerts a protective effect against metabolic disorders. Activation of intestinal PXR has been shown to reduce obesity and insulin resistance induced by HFD (Zhang et al., 2024). These findings further emphasize the potential value of PXR in the pathophysiology of NAFLD. Given the importance of PXR in regulating NAFLD in the gut-liver axis, further elucidation of PXR-specific mechanisms is necessary.

According to Chinese medicine theory, the excess of dampness, heat, phlegm, and stasis constitute the fundamental pathological mechanisms underlying NAFLD (Liu et al., 2018). Qushi huayu decoction (QHD) is an empirical formula based on the therapeutic principle of dispelling dampness and heat and resolving blood stasis (Supplementary S1). QHD was approved as a patented treatment for NAFLD in 2012 (Patent No.: CN201110056269). Among the constituents identified in rodents, many prototype compounds have previously been reported to exert significant anti-NAFLD activity. Key components include polygonin, rhein, geniposide, and chlorogenic acid (Peng et al., 2018). A randomized controlled trial demonstrated the favorable clinical potential of QHD in NAFLD (Liu et al., 2024). In regulating hepatic lipid metabolism, QHD activates AMP-activated protein kinase while simultaneously suppressing XBP1s, thereby inhibiting hepatic lipid synthesis both in vivo and in vitro (Feng et al., 2013; Tian et al., 2023). Furthermore, current studies have suggested that QHD exerts its effects by reducing hepatic lipid accumulation through fatty acid β-oxidation associated with JAK2/STAT3/CPT-1A (Sun et al., 2022). Our previous studies indicated that gut microbiota modulation is key to therapeutic effect of QHD on NAFLD (Ni et al., 2023). While the role of QHD in the gut-liver axis and whether it mediates the gut-liver axis regulation of NAFLD through PXR is unknown, and further research is required to reveal the potential mechanisms.