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Abstract：
BACKGROUND: Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study.
METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines\'s interaction with key genes.
RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines.
CONCLUSIONS: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.
METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines\'s interaction with key genes.
RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines.
CONCLUSIONS: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.
摘要：
背景：抗肿瘤药物，包括阿霉素,伊达比星,和表柔比星,已发现由于氧化应激-线粒体功能障碍-铁凋亡（ORMFs）而对心脏产生不利影响，这是对蒽环类抗生素诱导的心脏毒性的贡献。为了更好地理解这种现象，本研究分析了ORMFS基因的时间分辨测量值.
方法：使用人类3D心脏微组织细胞模型研究了三种蒽环类药物对ORMFs基因的影响。以两种剂量(治疗性和毒性)在14天内收集转录组数据。WGCNA确定了关键模块相关基因，功能富集分析研究了ssGSEA量化的生物过程，如免疫细胞浸润和血管生成。从心力衰竭患者和对照受试者收集活检。收集GSE59672和GSE2965用于验证。分子对接用于鉴定蒽环类抗生素与关键基因的相互作用。
结果:在体内或体外筛选ORMFs基因。使用WGCNA，六个共表达的基因模块被分组，MEblue成为最重要的模块。获得了8个与蓝色模块相交的关键基因与动态响应基因：CD36，CDH5，CHI3L1，HBA2，HSD11B1，OGN，RPL8和VWF。与对照样品相比，除RPL8外，所有关键基因在体外ANT处理设置中都下调，他们的表达水平随着时间的推移而变化。根据功能分析，关键模块相关基因参与血管生成和免疫系统通路.在所有ANT处理的设置中，ssGSEA显示血管生成评分和免疫细胞活性的显著下调，包括活化的CD4T细胞，未成熟B细胞,记忆B细胞，自然杀伤细胞,1型辅助T细胞,和2型T辅助细胞。分子对接显示RPL8和CHI3L1对蒽环类药物显示出显著的结合亲和力。
结论：本研究集中于人心脏微组织和ANT治疗患者心脏活检组织中ORMFs基因的动态特征。已经强调，在蒽环类抗生素诱导的心脏毒性的情况下，ORMF基因可能有助于免疫浸润和血管生成。对这些基因的透彻了解可能会导致疾病的诊断和治疗。
方法：使用人类3D心脏微组织细胞模型研究了三种蒽环类药物对ORMFs基因的影响。以两种剂量(治疗性和毒性)在14天内收集转录组数据。WGCNA确定了关键模块相关基因，功能富集分析研究了ssGSEA量化的生物过程，如免疫细胞浸润和血管生成。从心力衰竭患者和对照受试者收集活检。收集GSE59672和GSE2965用于验证。分子对接用于鉴定蒽环类抗生素与关键基因的相互作用。
结果:在体内或体外筛选ORMFs基因。使用WGCNA，六个共表达的基因模块被分组，MEblue成为最重要的模块。获得了8个与蓝色模块相交的关键基因与动态响应基因：CD36，CDH5，CHI3L1，HBA2，HSD11B1，OGN，RPL8和VWF。与对照样品相比，除RPL8外，所有关键基因在体外ANT处理设置中都下调，他们的表达水平随着时间的推移而变化。根据功能分析，关键模块相关基因参与血管生成和免疫系统通路.在所有ANT处理的设置中，ssGSEA显示血管生成评分和免疫细胞活性的显著下调，包括活化的CD4T细胞，未成熟B细胞,记忆B细胞，自然杀伤细胞,1型辅助T细胞,和2型T辅助细胞。分子对接显示RPL8和CHI3L1对蒽环类药物显示出显著的结合亲和力。
结论：本研究集中于人心脏微组织和ANT治疗患者心脏活检组织中ORMFs基因的动态特征。已经强调，在蒽环类抗生素诱导的心脏毒性的情况下，ORMF基因可能有助于免疫浸润和血管生成。对这些基因的透彻了解可能会导致疾病的诊断和治疗。
