中国药理学通报2026，Vol.42Issue(1)：39-48,10.DOI:10.12360/CPB202504052
Alox5、Alox15参与阿霉素诱导的心肌细胞铁死亡
Involvement of Alox5 and Alox15 in doxorubicin-induced ferroptosis of cardiomyocytes
摘要
Abstract
Aim To investigate the role of lipoxygen-ases in doxorubicin-induced ferroptosis in cardiomyo-cytes based on transcriptomics.Methods RNA se-quencing(RNA-seq)was performed on RNA samples from doxorubicin(DOX)-treated H9c2 cardiomyo-cytes,with untreated H9c2 cells serving as the control group.Differential gene expression analysis was con-ducted using the edgeR package,and protein-protein interaction(PPI)analysis of differentially expressed genes(DEGs)was performed using the STRING data-base.Key genes Alox5 and Alox15 were further vali-dated at both mRNA and protein levels.Cell viability was assessed using the CCK-8 assay to determine the optimal drug concentration.The experiment was di-vided into five groups:Control,DOX,DOX+Fer-1(ferroptosis inhibitor),DOX+Zileuton(Alox5 inhibi-tor),and DOX+PD146176(Alox15 inhibitor).Apoptosis was quantified by flow cytometry.Reactive oxygen species(ROS)levels were measured via fluo-rescence microscopy and FITC-channel flow cytom-etry.Intracellular Fe²⁺,malondialdehyde(MDA),glutathione(GSH),and superoxide dismutase(SOD)were analyzed using assay kits.The protein expression of Alox5,Alox15,ACSL4,Ptgs2,and GPX4 was as-sessed by Western blot,while their mRNA levels were evaluated via RT-qPCR.Secreted IL-6 and TNF-α were detected by ELISA.Results Compared with the control group,the DOX-induced injury model showed 3 603 significantly upregulated genes and 1 378 signifi-cantly downregulated genes.Alox5 and Alox15,which exhibited extensive PPI interactions,were selected as target genes.Western blot and RT-qPCR confirmed that DOX treatment significantly upregulated Alox5 and Alox15 expression in H9c2 cells,consistent with RNA-seq results.Inhibitor intervention demonstrated that both Alox5 and Alox15 inhibitors reduced DOX-induced H9c2 cell death,decreased ROS,Fe2+and MDA levels,suppressed the upregulation of ACSL4,Ptgs2,IL-6,and TNF-α,and restored GPX4,GSH,and SOD levels.Conclusions DOX-treated H9c2 cardiomyocytes exhibit overexpression of Alox5 and Alox15.Inhibitors of Alox5 and Alox15 can mitigate DOX-induced ferroptosis and inflammatory responses in cardiomyocytes.关键词
阿霉素心脏毒性/转录组学/铁死亡/脂质过氧化/脂质代谢/脂氧合酶Key words
adriamycin-induced cardiotoxicity/tran-scriptomics/ferroptosis/lipid peroxidation/lipid me-tabolism/lipoxygenase分类
医药卫生引用本文复制引用
沈明妹,张尚博,武凯鑫,赵慧,张志宏,章文,刘永超..Alox5、Alox15参与阿霉素诱导的心肌细胞铁死亡[J].中国药理学通报,2026,42(1):39-48,10.基金项目
吉林省科学技术厅科技发展计划项目(No 20220402072GH) （No 20220402072GH）
