Licochalcone A suppresses pancreatic ductal adenocarcinoma progression by targeting eEF2K-mediated pyroptosis
Pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy with increasing incidence and low survival rates, urgently requires novel therapeutic strategies to overcome the limitations posed by current treatment agents like gemcitabine. Licochalcone A (LHA), a bioactive flavonoid derived...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-06-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1595686/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850162360377933824 |
|---|---|
| author | Junjie Peng Hiutung Chan Wenqing Chen Ken Kin-Lam Yung King-Ho Cheung Zhu Zhang |
| author_facet | Junjie Peng Hiutung Chan Wenqing Chen Ken Kin-Lam Yung King-Ho Cheung Zhu Zhang |
| author_sort | Junjie Peng |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy with increasing incidence and low survival rates, urgently requires novel therapeutic strategies to overcome the limitations posed by current treatment agents like gemcitabine. Licochalcone A (LHA), a bioactive flavonoid derived from Glycyrrhiza species, exhibits anticancer properties in multiple cancers, yet its efficacy and mechanisms in PDAC remain unexplored. This study aims to investigate the anticancer potential of LHA in PDAC. In vitro assays demonstrated that LHA dose-dependently inhibited PDAC cell proliferation and induced pyroptosis, a lytic inflammatory cell death, while autophagy inhibition synergistically enhanced the cytotoxicity of LHA. Furthermore, LHA suppressed the migration of PDAC cells. Mechanistically, molecular docking and functional studies revealed that LHA directly binds to eukaryotic elongation factor 2 kinase (eEF2K), reducing its expression and downstream phosphorylation of eukaryotic elongation factor 2 (p-eEF2). Notably, eEF2K overexpression reversed LHA-induced pyroptosis in PDAC cells. In vivo, LHA significantly reduced tumor growth and altered tumor histopathology in a PDAC xenograft model, along with downregulated eEF2K and upregulated pyroptosis executors (GSDMD/GSDME). Collectively, these findings identify LHA as a dual-function agent: a natural eEF2K inhibitor and a pyroptosis inducer with potent antitumor activity against PDAC. This study provides a foundational rationale for further clinical exploration of LHA as a promising chemotherapeutic agent or adjuvant to enhance PDAC treatment outcomes. |
| format | Article |
| id | doaj-art-868dae5f4fea429fb1803ac8ba61d7d9 |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-868dae5f4fea429fb1803ac8ba61d7d92025-08-20T02:22:36ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-06-011610.3389/fphar.2025.15956861595686Licochalcone A suppresses pancreatic ductal adenocarcinoma progression by targeting eEF2K-mediated pyroptosisJunjie Peng0Hiutung Chan1Wenqing Chen2Ken Kin-Lam Yung3King-Ho Cheung4Zhu Zhang5Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, ChinaTeaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, ChinaTeaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, ChinaDepartment of Science and Environmental Studies, The Education University of Hong Kong, Tai Po, Hong Kong SAR, ChinaTeaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, ChinaTeaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, ChinaPancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy with increasing incidence and low survival rates, urgently requires novel therapeutic strategies to overcome the limitations posed by current treatment agents like gemcitabine. Licochalcone A (LHA), a bioactive flavonoid derived from Glycyrrhiza species, exhibits anticancer properties in multiple cancers, yet its efficacy and mechanisms in PDAC remain unexplored. This study aims to investigate the anticancer potential of LHA in PDAC. In vitro assays demonstrated that LHA dose-dependently inhibited PDAC cell proliferation and induced pyroptosis, a lytic inflammatory cell death, while autophagy inhibition synergistically enhanced the cytotoxicity of LHA. Furthermore, LHA suppressed the migration of PDAC cells. Mechanistically, molecular docking and functional studies revealed that LHA directly binds to eukaryotic elongation factor 2 kinase (eEF2K), reducing its expression and downstream phosphorylation of eukaryotic elongation factor 2 (p-eEF2). Notably, eEF2K overexpression reversed LHA-induced pyroptosis in PDAC cells. In vivo, LHA significantly reduced tumor growth and altered tumor histopathology in a PDAC xenograft model, along with downregulated eEF2K and upregulated pyroptosis executors (GSDMD/GSDME). Collectively, these findings identify LHA as a dual-function agent: a natural eEF2K inhibitor and a pyroptosis inducer with potent antitumor activity against PDAC. This study provides a foundational rationale for further clinical exploration of LHA as a promising chemotherapeutic agent or adjuvant to enhance PDAC treatment outcomes.https://www.frontiersin.org/articles/10.3389/fphar.2025.1595686/fullpancreatic ductal adenocarcinomalicochalcone ApyroptosisautophagyeEF2K |
| spellingShingle | Junjie Peng Hiutung Chan Wenqing Chen Ken Kin-Lam Yung King-Ho Cheung Zhu Zhang Licochalcone A suppresses pancreatic ductal adenocarcinoma progression by targeting eEF2K-mediated pyroptosis Frontiers in Pharmacology pancreatic ductal adenocarcinoma licochalcone A pyroptosis autophagy eEF2K |
| title | Licochalcone A suppresses pancreatic ductal adenocarcinoma progression by targeting eEF2K-mediated pyroptosis |
| title_full | Licochalcone A suppresses pancreatic ductal adenocarcinoma progression by targeting eEF2K-mediated pyroptosis |
| title_fullStr | Licochalcone A suppresses pancreatic ductal adenocarcinoma progression by targeting eEF2K-mediated pyroptosis |
| title_full_unstemmed | Licochalcone A suppresses pancreatic ductal adenocarcinoma progression by targeting eEF2K-mediated pyroptosis |
| title_short | Licochalcone A suppresses pancreatic ductal adenocarcinoma progression by targeting eEF2K-mediated pyroptosis |
| title_sort | licochalcone a suppresses pancreatic ductal adenocarcinoma progression by targeting eef2k mediated pyroptosis |
| topic | pancreatic ductal adenocarcinoma licochalcone A pyroptosis autophagy eEF2K |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1595686/full |
| work_keys_str_mv | AT junjiepeng licochalconeasuppressespancreaticductaladenocarcinomaprogressionbytargetingeef2kmediatedpyroptosis AT hiutungchan licochalconeasuppressespancreaticductaladenocarcinomaprogressionbytargetingeef2kmediatedpyroptosis AT wenqingchen licochalconeasuppressespancreaticductaladenocarcinomaprogressionbytargetingeef2kmediatedpyroptosis AT kenkinlamyung licochalconeasuppressespancreaticductaladenocarcinomaprogressionbytargetingeef2kmediatedpyroptosis AT kinghocheung licochalconeasuppressespancreaticductaladenocarcinomaprogressionbytargetingeef2kmediatedpyroptosis AT zhuzhang licochalconeasuppressespancreaticductaladenocarcinomaprogressionbytargetingeef2kmediatedpyroptosis |