Artesunate Enhances the Sensitization of Hepatocellular Carcinoma Cells by Inhibiting Nrf2/HIF-1α in Hypoxia
10.14148/j.issn.1672-0482.2025.0243
- VernacularTitle:青蒿琥酯抑制Nrf2/HIF-1α促进缺氧肝癌细胞增敏作用
- Author:
Yuan CHEN
1
;
Meihui WANG
;
Wei LI
;
Xuefen XU
Author Information
1. 南京中医药大学医学院,江苏 南京 210023
- Publication Type:Journal Article
- Keywords:
artesunate;
ferroptosis;
HCC cells;
sorafenib;
ROS;
Nrf2;
HIF-1α
- From:
Journal of Nanjing University of Traditional Chinese Medicine
2025;41(2):243-250
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To investigate the mechanism of artesunate increasing the sensitivity of hepatocellular carcinoma(HCC)cells to sorafenib in hypoxic microenvironment.METHODS Firstly,hypoxia-resistant HCC cell models were established.NAC(a ROS scavenger),necrostatin-1(a necrosis inhibitor),and ferrostatin-1(a ferroptosis inhibitor)were added to examine the effects of artesunate on the inhibition rate of HCC cells and the primary modes of cell death in hypoxic microenvironment by MTT assays.Intra-cellular levels of GSH,ROS,lipid peroxidation product MDA,and iron ions were measured using corresponding kits.Mitochondrial membrane potential changes were assessed using JC-1 staining.Western blot and qPCR were performed to detect the expression of fer-roptosis-related proteins after the addition of artesunate.RESULTS The sensitivity of HCC cells to sorafenib decreased under hy-poxic microenvironment,but artesunate significantly enhanced this sensitivity.Further analysis revealed that artesunate promoted sor-afenib-induced ferroptosis by increasing ROS levels in HCC cells(P<0.05,P<0.01,P<0.001).Additionally,artesunate was found to inhibit Nrf2 mRNA and protein levels(P<0.05,P<0.01,P<0.001)and downregulate HIF-1α expression(P<0.05,P<0.01,P<0.001).CONCLUSION Artesunate increases intracellular oxidative stress by inhibiting Nrf2 and HIF-1α protein levels,subse-quently induces ferroptosis and enhances the sensitivity of HCC cells to sorafenib in hypoxic microenvironment.
