Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells

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外文摘要：Objective:Research has shown that celastrol can effectively treat a variety of diseases,yet when passing a certain dosage threshold,celastrol becomes toxic,causing complications such as liver and kidney damage and erythrocytopenia,among others.With this dichotomy in mind,it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity.Methods:In this study,insulin-resistant HepG2(IR-HepG2)cells were prepared using palmitic acid and used for in vitro experiments.IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine(NAC)or ferrostatin-1(Fer-1)for 12,24 or 48 h,at a range of doses.Cell counting kit-8 assay,Western blotting,quantitative reverse transcription-polymerase chain reaction,glucose consump-tion assessment,and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis.Results:Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis pro-teins in IR-HepG2 cells.Celastrol downregulated glutathione peroxidase 4(GPX4)mRNA.Molecular docking models predicted that solute carrier family 7 member 11(SLC7A11)and GPX4 were covalently bound by celastrol.Importantly,we found for the first time that the application of ferroptosis inhibitors(especially NAC)was able to reduce celastrol's toxicity while preserving its ability to improve insulin sen-sitivity in IR-HepG2 cells.Conclusion:One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis,which can be alleviated by treatment with ferroptosis inhibitors.These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects.

外文关键词：

CelastrolInsulin resistanceFerroptosisN-AcetylcysteinePalmitic acidMolecular docking

作者：

Jia-jia Liu、Xue Zhang、Bang-lan Cai、Man-man Qi、Yong-bin Chi、Bin Peng、Deng-hai Zhang

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作者单位：

School of Medicine,Shanghai University,Shanghai 200444,China

Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases,Shanghai Pudong Gongli Hospital,Secondary Military Medical University,Shanghai 200135,China

School of Basic Medicine,Ningxia Medical University,Yinchuan 750004,Ningxia Hui Autonomous Region,China

基金：

Shanghai Leading Talent Grants in MedicineOutstanding Leaders Training Program of Shanghai Pudong New Aera Health CommissionShanghai Pudong New Area Youth Talent Project in MedicineShanghai Traditional Chinese Medicine Content Construction Innovation ProjectKey Disciplines Group Construction Project of Shanghai Pudong New Aera Health Commission

项目编号：

2019LG26PWRd2018-12PWRq2020-61ZY3-CCCX-3-7001PWZXP2017-15

出版年：

2024

DOI：

10.1016/j.joim.2024.03.007

结合医学学报(英文版)

上海市中西医结合学会,上海长海医院

结合医学学报(英文版)

CSTPCD

影响因子：0.711

ISSN：2095-4964

年,卷(期)：2024.22(3)

参考文献量45