Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Mechanistic study of Hederagenin against liver injury by inhibiting AIM2-mediated PANoptosis via the JAK2/STAT3 signaling pathway.
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Zhang Qinqin, Dai Haoyang, Cui Tianyi, Chen Suiqing
Аннотация
BACKGROUND: Acute liver injury (ALI) is a severe liver disease induced by various factors, including hepatitis viruses and drug toxicity. Severe and persistent ALI can eventually progress to multiple organ failure in the absence of effective intervention. At present, existing treatments for liver injury fail to provide effective and safe long-term management. Therefore, it is urgent to develop new anti-liver injury drugs.
PURPOSE: This study aimed to investigate whether Hederagenin (HD) alleviates ALI and to elucidate the mechanism underlying the protective effect of HD against liver injury.
METHODS: The intervention efficacy of HD on ALI was assessed using HE staining, TUNEL staining, ROS detection, immunofluorescence, ELISA, and biochemical assays. RNA-seq and proteomic analysis were performed to identify the potential target pathways. Differential gene expression between controls and patients with liver injury was analyzed using the GSE14668 and GSE38941 datasets retrieved from the GEO database. Western blot, qRT-PCR, molecular docking, and immunofluorescence, together with pharmacological inhibitors and agonists, were further applied for verification both in vitro and in vivo.
RESULTS: HD was found to significantly alleviate liver injury in mice, including attenuating pathological injury, improving liver function indices and reducing inflammation levels. Subsequent RNA-seq and proteomic analysis results indicated that the protective effect of HD against liver injury was related to the JAK/STAT signaling pathway and PANoptosis. In the GSE14668 and GSE38941 datasets, AIM2 expression was upregulated in liver tissues from patients. By employing the JAK2/STAT3 inhibitor AG490 and the JAK2/STAT3 agonist α7nAChR-JAK2-STAT3 agonist 1, the results demonstrated that HD ameliorated liver injury by regulating the JAK2/STAT3 signaling pathway. Following that, our study found that AIM2 was the downstream target of the JAK2/STAT3 pathway. Using the AIM2 inhibitor ODN TTAGGG and AIM2 overexpression, the protective effect of HD against liver injury was verified to be associated with AIM2-regulated PANoptosis.
CONCLUSION: HD exerted a certain ameliorative effect on ALI. In addition, HD protected against liver injury by inhibiting AIM2-mediated PANoptosis through the JAK2/STAT3 signaling pathway.
PURPOSE: This study aimed to investigate whether Hederagenin (HD) alleviates ALI and to elucidate the mechanism underlying the protective effect of HD against liver injury.
METHODS: The intervention efficacy of HD on ALI was assessed using HE staining, TUNEL staining, ROS detection, immunofluorescence, ELISA, and biochemical assays. RNA-seq and proteomic analysis were performed to identify the potential target pathways. Differential gene expression between controls and patients with liver injury was analyzed using the GSE14668 and GSE38941 datasets retrieved from the GEO database. Western blot, qRT-PCR, molecular docking, and immunofluorescence, together with pharmacological inhibitors and agonists, were further applied for verification both in vitro and in vivo.
RESULTS: HD was found to significantly alleviate liver injury in mice, including attenuating pathological injury, improving liver function indices and reducing inflammation levels. Subsequent RNA-seq and proteomic analysis results indicated that the protective effect of HD against liver injury was related to the JAK/STAT signaling pathway and PANoptosis. In the GSE14668 and GSE38941 datasets, AIM2 expression was upregulated in liver tissues from patients. By employing the JAK2/STAT3 inhibitor AG490 and the JAK2/STAT3 agonist α7nAChR-JAK2-STAT3 agonist 1, the results demonstrated that HD ameliorated liver injury by regulating the JAK2/STAT3 signaling pathway. Following that, our study found that AIM2 was the downstream target of the JAK2/STAT3 pathway. Using the AIM2 inhibitor ODN TTAGGG and AIM2 overexpression, the protective effect of HD against liver injury was verified to be associated with AIM2-regulated PANoptosis.
CONCLUSION: HD exerted a certain ameliorative effect on ALI. In addition, HD protected against liver injury by inhibiting AIM2-mediated PANoptosis through the JAK2/STAT3 signaling pathway.