Integrated bioinformatics analysis and experimental validation reveal circFoxO1 as a regulator of pathological cardiac hypertrophy

Pathological Cardiac Hypertrophy (CHT) is a maladaptive response that can lead to heart failure and increase the risk of severe cardiovascular events. However, the molecular mechanisms underlying CHT remain incompletely understood, and effective targeted therapies are still limited in clinical practice. Circular RNAs (circRNAs) emerge as important epigenetic regulators in cardiovascular biology, yet their roles in CHT remain insufficiently characterized. In this study, we combined transcriptomic analysis with in vitro and in vivo experimental models to identify functional circRNAs associated with CHT. Differential expression analysis of the GSE148602 dataset, coupled with machine-learning–assisted prioritization, highlighted circFoxO1 as a potential regulator. Angiotensin II (AngII)-induced hypertrophy models were established in HL-1 cardiomyocytes and C57BL/6 mice, revealing significant downregulation of circFoxO1 under hypertrophic conditions. Gain-of-function experiments demonstrated that circFoxO1 overexpression reduced the expression of classical hypertrophic markers, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC), and alleviated AngII-induced cardiomyocyte enlargement. Mechanistic analyses further suggested that circFoxO1 may influence hypertrophic responses through the canonical Wnt/β-catenin signaling pathway, as circFoxO1 overexpression restored Wnt3a and β-catenin expression levels, whereas pharmacological inhibition with FH535 attenuated its antihypertrophic effect. Collectively, these findings indicate that circFoxO1 may modulate AngII-induced CHT and provide additional insight into circRNA-mediated regulatory mechanisms during pathological cardiac remodeling.