Miao Yufan, Zhang Yujing, Zhang Luoya, Chen Hao, Tang Lulu, Li Wenjie, Gu Chenxi, Lang Lili, Li Xing, Song Hanlu
Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.
Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Front Immunol. 2025 Jul 17;16:1626295. doi: 10.3389/fimmu.2025.1626295. eCollection 2025.
Vitamin D (VD) deficiency is closely associated with metabolic health and cardiac function in prediabetic patients, yet its underlying mechanisms remain unclear. This study investigated the role of VD intervention in prediabetic cardiac injury through and models, with particular focus on the ErbB4/ferroptosis axis. Using a high-fat diet-induced KKAy prediabetic mouse model, we observed significant metabolic abnormalities (increased body weight, hyperglycemia, insulin resistance) and cardiac remodeling (cardiac hypertrophy and functional impairment) (<0.05). Remarkably, 16-week vitamin D (VD) supplementation substantially ameliorated these pathological changes and reduced serum cardiac injury markers (<0.05). Mechanistic studies revealed that VD downregulated myocardial NRG1 expression, inhibited ErbB4 phosphorylation (p-ErbB4) and YAP activation (p-YAP), while reversing the abnormal expression of ferroptosis-related proteins. experiments confirmed that high glucose combined with palmitic acid (HGPA) induced ferroptosis in H9c2 cardiomyocytes, which was alleviated by 1,25(OH)D intervention through suppression of ErbB4 phosphorylation. Notably, combined treatment with 1,25(OH)D and the ErbB4 phosphorylation inhibitor dacomitinib demonstrated synergistic protective effects. Our findings not only expand the understanding of the association between prediabetes and VD, but also reveal a relationship between ErbB4 and cardiac ferroptosis in prediabetic conditions.
维生素D（VD）缺乏与糖尿病前期患者的代谢健康和心脏功能密切相关，但其潜在机制仍不清楚。本研究通过[具体模型1]和[具体模型2]模型研究了VD干预在糖尿病前期心脏损伤中的作用，特别关注ErbB4/铁死亡轴。使用高脂饮食诱导的KKAy糖尿病前期小鼠模型，我们观察到显著的代谢异常（体重增加、高血糖、胰岛素抵抗）和心脏重塑（心脏肥大和功能障碍）（P<0.05）。值得注意的是，补充16周的维生素D（VD）显著改善了这些病理变化，并降低了血清心脏损伤标志物（P<0.05）。机制研究表明，VD下调心肌NRG1表达，抑制ErbB4磷酸化（p-ErbB4）和YAP激活（p-YAP），同时逆转铁死亡相关蛋白的异常表达。[细胞实验名称]实验证实，高糖联合棕榈酸（HGPA）诱导H9c2心肌细胞铁死亡，1,25(OH)D干预通过抑制ErbB4磷酸化减轻了铁死亡。值得注意的是，1,25(OH)D与ErbB4磷酸化抑制剂达可替尼联合治疗显示出协同保护作用。我们的研究结果不仅扩展了对糖尿病前期与VD之间关联的理解，还揭示了糖尿病前期状态下ErbB4与心脏铁死亡之间的关系。
