Objective To investigate the mechanism of Jiedu Huayu Granules for the treatment of acute liver failure (ALF) based on the JAK/STAT signaling pathway. Methods Sixty specific pathogen⁃free SD rats were randomly divided into four groups as follows: normal control group, Traditional Chinese Medicine group, model group, or tofacitinib group, with 15 rats in each group. Except for the normal control group, the ALF rat model of the remaining three groups was prepared by using D⁃galactosamine hydrochloride and lipopolysaccharide. Three days before modeling, the normal control group, model group, and tofacitinib group received intragastric administration of distilled water, while the Traditional Chinese Medicine group received intragastric administration of Jiedu Huayu Granules solution (with concentration in 0.3 g/mL) once daily. One hour before modeling, the tofacitinib group received an intraperitoneal injection of tofacitinib. At 24 hours after modeling, the rats were anesthetized, and blood was collected to detect prothrombin time (PT) and levels of serum ALT, AST, and total bilirubin. Liver tissues were collected for the HE staining and TUNEL staining. The mRNA expressions of JAK2 and STAT3 in liver tissues were detected by real⁃time fluorescent quantitative PCR, and the protein expressions of JAK2, STAT3, phosphorylated JAK2 (p⁃JAK2), and phosphorylated STAT3 (p⁃STAT3) were detected by employing the Western blot. Results Compared with the normal control group, the model group exhibited elevated PT, levels of serum ALT, AST, total bilirubin, and blood ammonia, as well as elevated TUNEL⁃positive rate (P<0.05). Compared with the model group, both the Traditional Chinese Medicine group and the tofacitinib group yielded decreased PT, levels of serum ALT, AST, total bilirubin, and blood ammonia, as well as decreased TUNEL⁃positive rate, with the tofacitinib group showing lower PT, serum ALT level, and TUNEL⁃positive rate as compared with the Traditional Chinese Medicine group (P<0.05). The HE staining results revealed that in the normal control group, hepatocytes were radially arranged around the central vein with clear hepatic lobule structure and no significant necrosis, whereas the model group displayed massive, submassive, and bridging necrosis, severe degeneration of surviving hepatocytes, disordered hepatocyte arrangement, hemorrhage, collapse of hepatic sinus mesh stent, and extensive inflammatory infiltration. Both the Traditional Chinese Medicine group and the tofacitinib group expressed as milder hepatocyte necrosis, more surviving hepatocytes, and less inflammatory infiltration as compared with the model group. Compared with the normal control group, the model group exhibited elevated mRNA expressions of JAK2 and STAT3 in liver tissues. Compared with the model group, both the Traditional Chinese Medicine group and the tofacitinib group yielded decreased mRNA expressions of JAK2 and STAT3 in liver tissues, with the tofacitinib group displaying a lower STAT3 mRNA expression as compared with the Traditional Chinese Medicine group (P<0.05). Compared with the normal control group, the model group demonstrated elevated protein expressions of JAK2, p⁃JAK2, STAT3, p⁃STAT3, as well as p⁃JAK2/JAK2 and p⁃STAT3/STAT3 ratios in liver tissues. Compared with the model group, the tofacitinib group exhibited decreased protein expressions of JAK2, p⁃JAK2, STAT3, p⁃STAT3 and p⁃STAT3/STAT3 ratio, while the Traditional Chinese Medicine group depicted decreased protein expressions of p⁃JAK2 and p⁃STAT3 in liver tissues (P<0.05). Conclusion Jiedu Huayu Granules can inhibit over⁃activation of JAK/STAT signaling pathway, reduce inflammatory responses, ameliorate liver function, exerting hepatic protection effect through inhibiting expressions of JAK2, STAT3 and their phosphorylated form.

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