2型糖尿病(T2D)患者的胰岛素缺乏与β细胞功能障碍有关,一种越来越被认为涉及去分化和细胞凋亡等过程的病症。此外,新出现的研究指出,在T2D的发病机制中,铁性凋亡具有潜在的作用。在这项研究中,我们的目的是研究铁凋亡在T2Dβ细胞去分化中的潜在参与。我们对六个公共数据集进行了单细胞RNA测序分析。进行差异表达和基因集富集分析以研究铁凋亡的作用。随后使用基因集变异和伪时间轨迹分析来验证铁凋亡相关的β簇。细胞根据其铁凋亡和去分化评分进行分类后,我们构建了转录和竞争性内源性RNA网络,并通过机器学习和免疫组织化学验证了hub基因。我们发现,在T2Dβ细胞中富集了铁凋亡,并且铁凋亡与去分化过程之间存在正相关。经进一步分析,我们确定了两个β簇,它们表现出与铁凋亡和去分化相关的显著特征.鉴定了几个关键转录因子和2个长链非编码RNA(MALAT1和MEG3)。最后,我们证实了高脂饮食小鼠的胰腺发生铁凋亡,并鉴定了4种蛋白质(NFE2L2,CHMP5,PTEN,和STAT3)可能参与铁凋亡对去分化的影响。这项研究有助于阐明铁死亡与β细胞健康之间的相互作用,并为开发治疗糖尿病的治疗策略开辟了新途径。
Insulin deficiency in patients with type 2 diabetes mellitus (T2D) is associated with beta-cell dysfunction, a condition increasingly recognized to involve processes such as
dedifferentiation and apoptosis. Moreover, emerging research points to a potential role for ferroptosis in the pathogenesis of T2D. In this study, we aimed to investigate the potential involvement of ferroptosis in the
dedifferentiation of beta cells in T2D. We performed single-cell RNA sequencing analysis of six public datasets. Differential expression and gene set enrichment analyses were carried out to investigate the role of ferroptosis. Gene set variation and pseudo-time trajectory analyses were subsequently used to verify ferroptosis-related beta clusters. After cells were categorized according to their ferroptosis and
dedifferentiation scores, we constructed transcriptional and competitive endogenous RNA networks, and validated the hub genes via machine learning and immunohistochemistry. We found that ferroptosis was enriched in T2D beta cells and that there was a positive correlation between ferroptosis and the process of
dedifferentiation. Upon further analysis, we identified two beta clusters that presented pronounced features associated with ferroptosis and
dedifferentiation. Several key transcription factors and 2 long noncoding RNAs (MALAT1 and MEG3) were identified. Finally, we confirmed that ferroptosis occurred in the pancreas of high-fat diet-fed mice and identified 4 proteins (NFE2L2, CHMP5, PTEN, and STAT3) that may participate in the effect of ferroptosis on dedifferentiation. This study helps to elucidate the interplay between ferroptosis and beta-cell health and opens new avenues for developing therapeutic strategies to treat diabetes.