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Traditional herbal pair Paeoniae Radix Rubra (roots of Paeonia lactiflora Pall., Chishao in Chinese) and Aconiti Lateralis Radix Praeparata (lateral roots of Aconitum carmichaelii Debeaux, Fuzi in Chinese) are widely used for the treatment of liver diseases, demonstrating clinical efficacy against acute-on-chronic liver failure (ACLF). As the core drug pair representing the "clearing method" and "warming method" in traditional Chinese medicine (TCM), they align with the TCM syndromic characteristics of ACLF, characterized by a mixture of deficiencies and realities. However, the molecular mechanisms underlying the anti-ACLF effects of Chishao - Fuzi herbal pair remain unclear. To reveal the immunoinflammatory status of patients with hepatitis B virus-related ACLF (HBV-ACLF) based on macrophage polarization and to explore the mechanism of action of Chishao - Fuzi herbal pair in regulating macrophage polarization against ACLF. Peripheral blood samples were prospectively obtained from patients with HBV-ACLF, patients with chronic hepatitis B (CHB) in the immunoactive phase and healthy individuals. Flow cytometry, qRT-qPCR, and ELISA were used to reveal the activation status of monocyte-macrophages and the expression differences in related cytokines in the peripheral blood of patients with HBV-ACLF. Then, an ACLF rat model and a macrophage inflammation model in vitro were established. Hematoxylin-eosin staining, immunohistochemical staining, transmission electron microscopy, flow cytometry, western blotting, RT-qPCR, and ELISA were used to observe changes in the expression of M1/M2 macrophage markers and related inflammatory factors after Chishao - Fuzi herbal pair intervention, both in vivo and in vitro. Patients with HBV-ACLF exhibited an imbalance in M1/M2 macrophage polarization, showing a tendency to activate M1 macrophages with high expression of CD86 and iNOS. This imbalance led to an increase in relevant pro-inflammatory factors (IL-1β, IL-6, TNF-α) and a decrease in anti-inflammatory factors (IL-10, TGF-β, VEGF), exacerbating the uncontrolled immune-inflammatory response. Chishao - Fuzi herbal pair intervention improved liver function, coagulation function, and histopathological injury in ACLF rats. It also partially ameliorated endotoxemia and inflammatory injury in ACLF. The mechanism was to restore the immune-inflammatory imbalance and prevent the exacerbation of inflammatory response to liver failure by promoting macrophage polarization toward M2 anti-inflammatory direction, inhibiting M1 macrophage activation, and increasing the levels of anti-inflammatory factors and decreasing pro-inflammatory factors. Chishao - Fuzi herbal pair can reduce the systemic inflammatory burden of liver failure by modulating macrophage polarization and restoring ACLF immune-inflammatory imbalance. This study provides new perspectives and strategies for studying HBV-ACLF immune reconstitution and inflammatory response control. [Display omitted] • This study investigated herbal formula effects on ACLF immune-inflammatory imbalance. • Clinical studies, rat models, and in vitro assays were used for comprehensive analysis. • Observed M1/M2 macrophage imbalance in ACLF, alleviated by Chishao - Fuzi herbal pair intervention. • Chishao - Fuzi herbal pair improved liver function and mitigated inflammatory injury in ACLF. • Chishao - Fuzi herbal pair demonstrates potential in modulating macrophage polarization for ACLF treatment. [ABSTRACT FROM AUTHOR]

'Xiayuxue decoction' (XYXD) is a traditional Chinese medicine compound, composing of three natural medicines: Rheum officinale Baill., Prunus persica (L.) Batsch and Eupolyphaga sinensis Walker. It is derived from the famous traditional Chinese medical classics 'Jingui Yaolue' and has been used for thousands of years. In the Guidelines for the Diagnosis and Treatment of Primary liver Cancer issued by China's Health Commission, XYXD was applied in the treatment of primary liver cancer. To clarify the pharmacodynamic material basis and mechanism of XYXD in the treatment of hepatocellular carcinoma (HCC). Firstly, the active components of XYXD and its distribution in vivo were identified by Ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Then, the effective components and mechanism of XYXD against HCC were explored by network pharmacology combined with cell experiments in vitr o. Furthermore, the anti-HCC effect of XYXD was determined by animal experiments in vivo. Metagenomic sequencing was used to detect its effect in gut microbiota, and targeted metabolism was used to detect the changes of bile acids in the liver. Finally, the related targets of NKT cell immune function activation were detected by RT-qPCR and Elisa. A total of 113 active ingredients in XYXD were identified, and the distribution of active ingredients in blood, liver, tumor, cecum, intestinal contents and feces was clarified. The circulation process and active ingredient group of XYXD were preliminarily clarified. In addition, we found five anti-HCC active ingredients in XYXD through network pharmacology combined with cell experiments in vitro, among which aloe emodin had the most significant effect, and predicted the potential mechanism of XYXD against HCC through NKT cell pathway. Moreover, the inhibitory effect of XYXD on liver tumor growth was clarified by animal experiments in vivo. The mechanism was mainly to promote the production of bile salt hydrolase (BSH) by increasing the abundance of Bacteroides and Lactobacillus , BSH converts conjugated bile acids into primary bile acids, and reduces the conversion of primary bile acids to secondary bile acids by reducing the abundance of Eubacterium , thereby increasing the content of primary bile acids. Primary bile acids trigger NKT cells in the liver to produce interferon-γ to exert anti-HCC immune effects. This study found that the traditional Chinese herbal formula XYXD can trigger the immune effect of NKT cells against HCC by regulating the interaction between gut microbiota and bile acids. [Display omitted] • Study completely analyzed pharmacodynamic material basis of XYXD. • Study identified potential anti-hepatocellular carcinoma compounds of XYXD. • XYXD promotes production of primary bile acids by regulating gut microbiota. • XYXD triggers NKT cells immune function against-HCC through primary bile acids. [ABSTRACT FROM AUTHOR]