6-姜酚基于调控ACSL4/xCT/GPX4途径抑制铁死亡干预动脉粥样硬化形成机制研究OA

Objective:To investigate the influence and underlying mechanisms of 6-gingerol(6-G)in suppressing ferroptosis in ApoE(-/-)atherosclerotic mice by modulating the ACSL4(Acyl-CoA synthetase 4)/xCT(solute carrier 7 family member 11,SLC7A11)/GPX4(glutathione peroxidase 4)signaling pathway.Methods:A total of 6 male C57BL/6J mice were placed on a normal diet to serve as the control group(Con).A total of 18 SPF grade ApoE(-/-)mice were randomly assigned to the AS model group(Atherosclerosis Model group,Mod),the 6-G treatment group(6-Gingerol group,6-G),and the Ferrostatin-1 group(Fer-rostatin-1 group,Fer-1),with 6 mice allocated to group.The Con group continued with a normal diet,while all other groups were subjected to a high-fat diet for a duration of 10 weeks to establish the AS animal model.Upon successful modeling,the 6-G group received 20 mg/kg of 6-G via gavage,while the Fer-1 group was administered 1 mg/kg/of Fer-1 through intraperitoneal injection.Apart from the Con group,which consumed a normal diet,the other groups remained on the high-fat diet for an additional 6 weeks.Blood lipid profiles were assessed using an automatic biochemical analyzer,while atherosclerosis levels in the mice were evaluated through oil red O staining.The ultra-structural alterations of aortic mitochondria across all groups were examined using a transmission electron microscope.Fe2+levels was detected using a reagent kit,while serum levels of GSH and MDA were quanti-fied via ELISA.The protein levels of ACSL4,xCT,and GPX4 in the aortic tissues of the mice from each group were determined through Western blot analysis.Results:Compared to the Con group,the aortic tissues of Mod mice exhibited significant lipid plaque accumulation,along with elevated serum levels of TC,TG,LDL-C,Fe2+,and MDA was increased and HDL-C and GSH levels was decreased(P<0.01).The expression of ACSL4 protein in the aortic tissue was notably elevated,whereas the ex-pression of GPX4 and xCT proteins was significantly reduced(P<0.01).Additionally,mitochondrial structure and morphology were severely compromised.Compare to the Mod group,both the 6-G group and the Fer-1 group exhibited a reduction in aortic lip-id plaque accumulation following treatment.There was a notable decrease in the levels of serum TC,TG,LDL-C,Fe2+,and MDA,while levels of HDL-C and GSH were found to be elevated,with significant differences observed(P<0.05).Additional-ly,there was a down-regulation of ACSL4 protein expression,while GPX4 and xCT protein expressions were up-regulated,also showing significant differences(P<0.05),with mitochondrial structures nearing normalcy.Conclusion:6-gingerol can mitigate the level of atherosclerosis,potentially through the modulation of the ACSL4/xCT/GPX4 pathway,which mediates the suppres-sion of ferroptosis and lipid peroxidation,providing protection to the aorta.