Journal of ethnopharmacology · 2026
Natural glycosides from Cistanche deserticola alleviate hepatic ischemia-reperfusion injury via a cAMP-mediated signaling pathway.
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Yang QiWei, Huang Tao, Chen HaoQi, Cao Xi, Zhu WenFeng, Peng YiShan, Yu Lin, Zhao QiYi, Wang Li, Wang XiaoWen, Wang GenShu
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche deserticola Y.C. Ma (Orobanchaceae), traditionally prescribed in Chinese medicine to "tonify the kidneys, nourish the essence, and moisten the intestines," has long been used to treat disorders related to kidney deficiency, such as fatigue, impotence, infertility, and senile constipation. Modern pharmacological studies have further documented its hepatoprotective potential. Total glycosides extracted from C. deserticola (GCs) represent the major bioactive constituents and may provide novel therapeutic strategies for hepatic ischemia-reperfusion injury (HIRI), a severe complication of hepatic surgery and transplantation.
AIM OF THE STUDY: This study aimed to evaluate the protective effects of GCs against HIRI and to elucidate the molecular mechanisms underlying their hepatoprotective activity, with a focus on the cyclic adenosine monophosphate (cAMP)-exchange protein directly activated by cAMP 2 (EPAC2)-RAS-related protein 1 (Rap1)-Hippo-Yes-associated protein (YAP)-c-Jun N-terminal kinase (JNK) signaling axis.
MATERIALS AND METHODS: A murine model of segmental HIRI and mouse liver organoid models subjected to hypoxia/reoxygenation (H/R) were used to assess the protective effects of GCs. Hepatocyte apoptosis, autophagy, oxidative stress markers, and signaling pathway activation were evaluated in vivo and in vitro. Genetic knockdown experiments targeting EPAC2, Rap1, YAP, and JNK were performed to validate the mechanistic involvement of these signaling molecules.
RESULTS: GCs significantly attenuated HIRI-induced hepatic damage, as indicated by reduced apoptosis and enhanced autophagy in hepatocytes. Mechanistically, GCs increased cAMP levels, upregulated EPAC2, and activated Rap1, which in turn inhibited Hippo kinases mammalian sterile 20-like kinase 1 (MST1) and large tumor suppressor kinase 1 (LATS1), promoted YAP nuclear translocation, and facilitated YAP-JNK interaction. These events enhanced autophagy and conferred cytoprotection. Knockdown of EPAC2, Rap1, YAP, or JNK abolished the hepatoprotective effects of GCs. Liver organoid experiments further confirmed improved structural integrity and survival under H/R stress following GCs treatment.
CONCLUSIONS: GCs protect against HIRI by activating the EPAC2-Rap1-Hippo-YAP-JNK axis to promote autophagy and suppress apoptosis. These findings provide mechanistic insight into the hepatoprotective actions of GCs and support their evidence-based ethnopharmacological use as a promising therapeutic approach for ischemic liver injury.
AIM OF THE STUDY: This study aimed to evaluate the protective effects of GCs against HIRI and to elucidate the molecular mechanisms underlying their hepatoprotective activity, with a focus on the cyclic adenosine monophosphate (cAMP)-exchange protein directly activated by cAMP 2 (EPAC2)-RAS-related protein 1 (Rap1)-Hippo-Yes-associated protein (YAP)-c-Jun N-terminal kinase (JNK) signaling axis.
MATERIALS AND METHODS: A murine model of segmental HIRI and mouse liver organoid models subjected to hypoxia/reoxygenation (H/R) were used to assess the protective effects of GCs. Hepatocyte apoptosis, autophagy, oxidative stress markers, and signaling pathway activation were evaluated in vivo and in vitro. Genetic knockdown experiments targeting EPAC2, Rap1, YAP, and JNK were performed to validate the mechanistic involvement of these signaling molecules.
RESULTS: GCs significantly attenuated HIRI-induced hepatic damage, as indicated by reduced apoptosis and enhanced autophagy in hepatocytes. Mechanistically, GCs increased cAMP levels, upregulated EPAC2, and activated Rap1, which in turn inhibited Hippo kinases mammalian sterile 20-like kinase 1 (MST1) and large tumor suppressor kinase 1 (LATS1), promoted YAP nuclear translocation, and facilitated YAP-JNK interaction. These events enhanced autophagy and conferred cytoprotection. Knockdown of EPAC2, Rap1, YAP, or JNK abolished the hepatoprotective effects of GCs. Liver organoid experiments further confirmed improved structural integrity and survival under H/R stress following GCs treatment.
CONCLUSIONS: GCs protect against HIRI by activating the EPAC2-Rap1-Hippo-YAP-JNK axis to promote autophagy and suppress apoptosis. These findings provide mechanistic insight into the hepatoprotective actions of GCs and support their evidence-based ethnopharmacological use as a promising therapeutic approach for ischemic liver injury.