Atypical hemolytic uremic syndrome (aHUS) is a rare disease associated with high morbidity and mortality. Existing evidence suggests that the central pathogenesis to aHUS might be endothelial cell damage. Nevertheless, the role of endothelial cell alterations in aHUS has not been well characterized and the underlying mechanisms remain unclear. Utilizing an induced pluripotent stem cell-derived endothelial cell (iPSC-EC) model, we showed that anti-complement factor H autoantibody-associated aHUS patient-specific iPSC-ECs exhibited an intrinsic defect in endothelial functions. Stimulation using aHUS serums exacerbated endothelial dysfunctions, leading to cell apoptosis in iPSC-ECs. Importantly, we identified p38 as a novel signaling pathway contributing to endothelial dysfunctions in aHUS. These results illustrate that iPSC-ECs can be a reliable model to recapitulate EC pathological features, thus providing a unique platform for gaining mechanistic insights into EC injury in aHUS. Our findings highlight that the p38 MAPK signaling pathway can be a therapeutic target for treatment of aHUS.

非典型溶血性尿毒症综合征 (aHUS) 是一种与高发病率和死亡率相关的罕见疾病。现有证据表明，aHUS 的中心发病机制可能是内皮细胞损伤。然而，内皮细胞改变在 aHUS 中的作用尚未得到很好的表征，其潜在机制仍不清楚。利用诱导多能干细胞衍生的内皮细胞 (iPSC-EC) 模型，我们发现抗补体因子 H 自身抗体相关的 aHUS 患者特异性 iPSC-EC 表现出内皮功能的内在缺陷。使用 aHUS 血清刺激会加剧内皮功能障碍，导致 iPSC-EC 中的细胞凋亡。重要的是，我们将 p38 确定为导致 aHUS 内皮功能障碍的新信号通路。这些结果表明，iPSC-EC 可以成为概括 EC 病理特征的可靠模型，从而为获得 aHUS 中 EC 损伤的机制见解提供了一个独特的平台。我们的研究结果强调 p38 MAPK 信号通路可以成为治疗 aHUS 的治疗靶点。