Fibroblast growth factor-18 (FGF18) has diverse organ development and damage repair roles. However, its role in cardiac homeostasis following hypertrophic stimulation remains unknown. Here we investigate the regulation and function of the FGF18 in pressure overload (PO)-induced pathological cardiac hypertrophy. FGF18 heterozygous (Fgf18^+/−) and inducible cardiomyocyte-specific FGF18 knockout (Fgf18-CKO) male mice exposed to transverse aortic constriction (TAC) demonstrate exacerbated pathological cardiac hypertrophy with increased oxidative stress, cardiomyocyte death, fibrosis, and dysfunction. In contrast, cardiac-specific overexpression of FGF18 alleviates hypertrophy, decreased oxidative stress, attenuates cardiomyocyte apoptosis, and ameliorates fibrosis and cardiac function. Tyrosine-protein kinase FYN (FYN), the downstream factor of FGF18, was identified by bioinformatics analysis, LC-MS/MS and experiment validation. Mechanistic studies indicate that FGF18/FGFR3 promote FYN activity and expression and negatively regulate NADPH oxidase 4 (NOX4), thereby inhibiting reactive oxygen species (ROS) generation and alleviating pathological cardiac hypertrophy. This study uncovered the previously unknown cardioprotective effect of FGF18 mediated by the maintenance of redox homeostasis through the FYN/NOX4 signaling axis in male mice, suggesting a promising therapeutic target for the treatment of cardiac hypertrophy.

成纤维细胞生长因子 18 (FGF18) 具有多种器官发育和损伤修复作用。然而，它在肥大刺激后心脏稳态中的作用仍然未知。在这里，我们研究了 FGF18 在压力超负荷 (PO) 诱导的病理性心脏肥大中的调节和功能。FGF18 杂合子 ( Fgf18 ^+/- ) 和诱导型心肌细胞特异性FGF18敲除 ( Fgf18-CKO) 暴露于横向主动脉缩窄 (TAC) 的雄性小鼠表现出加剧的病理性心脏肥大，伴有氧化应激增加、心肌细胞死亡、纤维化和功能障碍。相比之下，FGF18 的心脏特异性过表达可减轻心肌肥厚、减少氧化应激、减弱心肌细胞凋亡，并改善纤维化和心脏功能。通过生物信息学分析、LC-MS/MS 和实验验证鉴定了 FGF18 的下游因子酪氨酸蛋白激酶 FYN (FYN)。机制研究表明，FGF18/FGFR3 促进 FYN 活性和表达并负向调节 NADPH 氧化酶 4 (NOX4)，从而抑制活性氧 (ROS) 的产生并减轻病理性心肌肥大。