Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare but potentially fatal immune-related adverse event. Previously, we reported a case of ICI-associated myocarditis with elevated autoantibodies to 4E-binding protein 3 (4E-BP3). Recent studies have suggested that 4E-BP3 may play an important role in tumor development. However, its role in cardiac diseases including myocarditis is unknown. We investigated the role of 4E-BP3 in an autoimmune myocarditis mouse model. Myocarditis was induced in wild-type and 4E-BP3 knockout mice by immunization with murine α-myosin peptide. 4E-BP3 gene expression was upregulated in the heart of myocarditis mouse. We found that genetic deletion of 4E-BP3 attenuated myocardial inflammation, reduced fibrosis area, and improved cardiac function in myocarditis mice. Studies in bone marrow-chimeric mice demonstrated that immune cell-derived 4E-BP3 plays a pivotal role in the pathogenesis of myocarditis. Immune cell transfer experiments revealed that 4E-BP3 deficiency in dendritic cells and CD4⁺ T cells decreased disease severity in recipient mice. Furthermore, dendritic cells that were deficient in 4E-BP3 exhibited a diminished capacity to produce IL-6 and IL-1β. Naive CD4⁺ T cells lacking 4E-BP3 had a reduced ability to differentiate into T-helper (Th)1 and Th17 cells. These findings suggest that 4E-BP3 in dendritic cells and CD4⁺ T cells may be critically involved in the pathogenesis of α-myosin-specific T cell-mediated myocarditis. Thus, 4E-BP3 could be a possible therapeutic target for myocarditis.

免疫检查点抑制剂 （ICI） 相关心肌炎是一种罕见但可能致命的免疫相关不良事件。以前，我们报道了一例 ICI 相关心肌炎病例，伴 4E 结合蛋白 3 （4E-BP3） 自身抗体升高。最近的研究表明，4E-BP3 可能在肿瘤发展中发挥重要作用。然而，它在包括心肌炎在内的心脏病中的作用尚不清楚。我们研究了 4E-BP3 在自身免疫性心肌炎小鼠模型中的作用。通过小鼠 α-肌球蛋白肽免疫，在野生型和 4E-BP3 敲除小鼠中诱导心肌炎。4E-BP3 基因在心肌炎小鼠心脏中的表达上调。我们发现 4E-BP3 的基因缺失减轻了心肌炎小鼠的心肌炎症，减少了纤维化面积，并改善了心肌功能。骨髓嵌合小鼠研究表明，免疫细胞来源的 4E-BP3 在心肌炎的发病机制中起关键作用。免疫细胞转移实验显示，树突状细胞和 CD4⁺ T 细胞中的 4E-BP3 缺陷降低了受体小鼠的疾病严重程度。此外，缺乏 4E-BP3 的树突状细胞表现出产生 IL-6 和 IL-1β 的能力降低。缺乏 4E-BP3 的幼稚 CD4⁺ T 细胞分化为辅助性 T 细胞 （Th） 1 和 Th17 细胞的能力降低。这些发现表明，树突状细胞和 CD4⁺ T 细胞中的 4E-BP3 可能与α肌球蛋白特异性 T 细胞介导的心肌炎的发病机制密切相关。因此，4E-BP3 可能是心肌炎的可能治疗靶点。