Shikonin Induces Ferroptosis through ROS/JNK Pathway to Intervene in the Malignant Behavior of Pancreatic Cancer
10.12259/j.issn.2095-610X.S20251005
- VernacularTitle:SKI通过ROS/JNK通路诱导铁死亡干预胰腺癌恶性行为
- Author:
Ruifeng QIN
1
;
Jiadong XUE
;
Jia ZHANG
;
Fan LIU
;
Shaohui ZHANG
;
Liyang YIN
;
Zengjiang YUAN
Author Information
1. 邯郸市中心医院普外三科,河北 邯郸 056001
- Keywords:
Shikonin;
Ferroptosis;
Pancreatic cancer;
Reactive oxygen species;
JNK
- From:
Journal of Kunming Medical University
2025;46(10):44-52
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate if Shikonin(SKI)can induce ferroptosis via the ROS/JNK pathway to inhibit the malignant behavior of pancreatic cancer.Methods Human pancreatic cancer PANC-1 or BxPC-3 cells were selected.Drug efficacy experiments were established with a blank control group(Con group)and low,medium,and high dose SKI groups(2,4,8 μmol/L).JNK-related mechanism experiments were categorized into a blank control group(Con group),SKI group,and SKI+JNK inhibitor group(SKI+SP600125 group).ROS-related mechanism experiments were divided into a blank control group(Con group),SKI group,and SKI+ROS scavenger group(SKI+NAC group).Cell viability was assessed using the CCK-8 method to calculate IC50;Transwell experiments evaluated cell migration and invasion capabilities;the C11 BODIPY 581/591 probe was utilized for flow cytometry to detect lipid peroxidation levels,while the FerroOrange fluorescent probe measured ferrous ion levels;ROS levels were determined using a ROS detection kit;the Western blot method identified ferroptosis-related key proteins(SLC7A11,GPX4),apoptosis-related proteins(Caspase3,PARP),and JNK pathway proteins(JNK,p-JNK);an in vivo xenograft tumor model was employed to assess tumor proliferation.Results SKI treatment significantly and dose-dependently inhibited PANC-1 cell viability(IC50:6.04 μmol/L,P<0.0001)and BxPC-3 cell viability(IC50:12.27 μmol/L,P<0.0001),and significantly reduced migrating and invasive cell numbers(P<0.0001),with migration cell numbers dropping to about 30%of the control group at 8 μmol/L SKI treatment(P<0.0001).Mechanistically,SKI induced increased intracellular lipid peroxidation,Fe2+accumulation,and significant ROS production(P<0.0001),significantly downregulated SLC7A11 and GPX4 protein expression(GPX4 protein expression reduced to 40%of that in the control group,P<0.0001),and activated JNK phosphorylation(p-JNK/JNK ratio increased to 2.8-fold,P<0.0001).Pretreatment with the JNK-specific inhibitor SP600125 or ROS scavenger NAC effectively reversed SKI's inhibition of cell viability and downregulation of SLC7A11/GPX4 protein(all P<0.01).SKI also inhibited pancreatic cancer tumor cell proliferation in vivo(P<0.0001).Conclusion SKI induces ferroptosis by activating the ROS/JNK pathway,thereby inhibiting pancreatic cancer proliferation,migration,and invasion.
