Ginsenoside Rk2 alleviates hepatic ischemia/reperfusion injury by enhancing AKT membrane translocation and activation
Abstract Hepatic ischemia–reperfusion injury (IRI) poses a significant threat to clinical outcomes and graft survival during hemorrhagic shock, hepatic resection, and liver transplantation. Current pharmacological interventions for hepatic IRI are inadequate. In this study, we identified ginsenoside...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | MedComm |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mco2.70047 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594187477843968 |
|---|---|
| author | Hong Shen Jiajun Fu Jiayue Liu Toujun Zou Kun Wang Xiao‐Jing Zhang Jian‐Bo Wan |
| author_facet | Hong Shen Jiajun Fu Jiayue Liu Toujun Zou Kun Wang Xiao‐Jing Zhang Jian‐Bo Wan |
| author_sort | Hong Shen |
| collection | DOAJ |
| description | Abstract Hepatic ischemia–reperfusion injury (IRI) poses a significant threat to clinical outcomes and graft survival during hemorrhagic shock, hepatic resection, and liver transplantation. Current pharmacological interventions for hepatic IRI are inadequate. In this study, we identified ginsenoside Rk2 (Rk2), a rare dehydroprotopanaxadiol saponin, as a promising agent against hepatic IRI through high‐throughput screening. The pharmacological effects and molecular mechanisms of Rk2 on hepatic IRI were further evaluated and elucidated in vitro and in vivo. Rk2 significantly reduced inflammation and apoptosis caused by oxygen‐glucose deprivation and reperfusion in hepatocytes and dose dependently protected against hepatic I/R‐induced liver injury in mice. Integrated approaches, including network pharmacology, molecular docking, transcriptome analysis, and isothermal titration calorimetry, along with experimental validation, indicated that Rk2 protects against hepatic IRI by targeting and activating the AKT (RAC serine/threonine protein kinase) signaling pathway. Pharmacological inhibition of AKT pathway or knockdown of AKT1 effectively diminished protective effects of Rk2. Rk2 directly binds to AKT1, facilitating its translocation from the cytoplasm to plasma membrane. This process markedly enhanced AKT interaction with PDPK1, promoting the activation of AKT1 and its downstream signaling. Our findings demonstrate that Rk2 protects against hepatic IRI by activating AKT signaling through direct binding to AKT1 and facilitating its membrane translocation. |
| format | Article |
| id | doaj-art-045d5053d361433baeb5684974421ab8 |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-045d5053d361433baeb5684974421ab82025-01-20T01:45:44ZengWileyMedComm2688-26632025-01-0161n/an/a10.1002/mco2.70047Ginsenoside Rk2 alleviates hepatic ischemia/reperfusion injury by enhancing AKT membrane translocation and activationHong Shen0Jiajun Fu1Jiayue Liu2Toujun Zou3Kun Wang4Xiao‐Jing Zhang5Jian‐Bo Wan6State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macao SAR ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases Gannan Innovation and Translational Medicine Research Institute Gannan Medical University Ganzhou ChinaState Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macao SAR ChinaDepartment of Cardiology Renmin Hospital of Wuhan University Wuhan ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases Gannan Innovation and Translational Medicine Research Institute Gannan Medical University Ganzhou ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases Gannan Innovation and Translational Medicine Research Institute Gannan Medical University Ganzhou ChinaState Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macao SAR ChinaAbstract Hepatic ischemia–reperfusion injury (IRI) poses a significant threat to clinical outcomes and graft survival during hemorrhagic shock, hepatic resection, and liver transplantation. Current pharmacological interventions for hepatic IRI are inadequate. In this study, we identified ginsenoside Rk2 (Rk2), a rare dehydroprotopanaxadiol saponin, as a promising agent against hepatic IRI through high‐throughput screening. The pharmacological effects and molecular mechanisms of Rk2 on hepatic IRI were further evaluated and elucidated in vitro and in vivo. Rk2 significantly reduced inflammation and apoptosis caused by oxygen‐glucose deprivation and reperfusion in hepatocytes and dose dependently protected against hepatic I/R‐induced liver injury in mice. Integrated approaches, including network pharmacology, molecular docking, transcriptome analysis, and isothermal titration calorimetry, along with experimental validation, indicated that Rk2 protects against hepatic IRI by targeting and activating the AKT (RAC serine/threonine protein kinase) signaling pathway. Pharmacological inhibition of AKT pathway or knockdown of AKT1 effectively diminished protective effects of Rk2. Rk2 directly binds to AKT1, facilitating its translocation from the cytoplasm to plasma membrane. This process markedly enhanced AKT interaction with PDPK1, promoting the activation of AKT1 and its downstream signaling. Our findings demonstrate that Rk2 protects against hepatic IRI by activating AKT signaling through direct binding to AKT1 and facilitating its membrane translocation.https://doi.org/10.1002/mco2.70047AKT signalingapoptosisginsenoside Rk2inflammationischemia–reperfusionmembrane translocation |
| spellingShingle | Hong Shen Jiajun Fu Jiayue Liu Toujun Zou Kun Wang Xiao‐Jing Zhang Jian‐Bo Wan Ginsenoside Rk2 alleviates hepatic ischemia/reperfusion injury by enhancing AKT membrane translocation and activation MedComm AKT signaling apoptosis ginsenoside Rk2 inflammation ischemia–reperfusion membrane translocation |
| title | Ginsenoside Rk2 alleviates hepatic ischemia/reperfusion injury by enhancing AKT membrane translocation and activation |
| title_full | Ginsenoside Rk2 alleviates hepatic ischemia/reperfusion injury by enhancing AKT membrane translocation and activation |
| title_fullStr | Ginsenoside Rk2 alleviates hepatic ischemia/reperfusion injury by enhancing AKT membrane translocation and activation |
| title_full_unstemmed | Ginsenoside Rk2 alleviates hepatic ischemia/reperfusion injury by enhancing AKT membrane translocation and activation |
| title_short | Ginsenoside Rk2 alleviates hepatic ischemia/reperfusion injury by enhancing AKT membrane translocation and activation |
| title_sort | ginsenoside rk2 alleviates hepatic ischemia reperfusion injury by enhancing akt membrane translocation and activation |
| topic | AKT signaling apoptosis ginsenoside Rk2 inflammation ischemia–reperfusion membrane translocation |
| url | https://doi.org/10.1002/mco2.70047 |
| work_keys_str_mv | AT hongshen ginsenosiderk2alleviateshepaticischemiareperfusioninjurybyenhancingaktmembranetranslocationandactivation AT jiajunfu ginsenosiderk2alleviateshepaticischemiareperfusioninjurybyenhancingaktmembranetranslocationandactivation AT jiayueliu ginsenosiderk2alleviateshepaticischemiareperfusioninjurybyenhancingaktmembranetranslocationandactivation AT toujunzou ginsenosiderk2alleviateshepaticischemiareperfusioninjurybyenhancingaktmembranetranslocationandactivation AT kunwang ginsenosiderk2alleviateshepaticischemiareperfusioninjurybyenhancingaktmembranetranslocationandactivation AT xiaojingzhang ginsenosiderk2alleviateshepaticischemiareperfusioninjurybyenhancingaktmembranetranslocationandactivation AT jianbowan ginsenosiderk2alleviateshepaticischemiareperfusioninjurybyenhancingaktmembranetranslocationandactivation |