Background: Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, characterized by cardiac hypertrophy, fibrosis, and impaired function. Despite advances in therapeutic strategies, novel molecular targets are urgently needed to improve clinical outcomes. Trefoil factor 3 (Tff3) is reported to be upregulated in patients with heart failure. However, its functional role and underlying mechanisms in disease progression remain unclear. This study aimed to investigate the role of Tff3 in heart failure progression in vivo and to elucidate its molecular mechanisms.

Methods: A mouse model of heart failure was established via thoracic aortic coarctation (TAC). Tff3 expression in cardiac tissue was evaluated using immunoblotting and immunohistochemistry. Cardiac hypertrophy and fibrosis were assessed by immunoblotting, Masson's trichrome staining, and wheat germ agglutinin (WGA) staining. Autophagy levels were determined through immunoblotting and immunostaining. The involvement of the C-X-C Chemokine Receptor Type 4 (CXCR4)/Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway was examined by immunoblot analysis.

Results: Tff3 expression was significantly upregulated in heart failure models (p < 0.05). Knockdown of Tff3 alleviated TAC-induced cardiac hypertrophy and fibrosis (p < 0.05). Furthermore, Tff3 depletion enhanced autophagy in heart failure models (p < 0.05). Mechanistically, Tff3 knockdown suppressed activation of the CXCR4/JAK/STAT signaling axis in heart failure mice (p < 0.05). These findings suggest that Tff3 depletion mitigates heart failure progression through the CXCR4/JAK/STAT axis (p < 0.05).

Conclusion: Tff3 knockdown promotes autophagy and attenuates cardiac hypertrophy and fibrosis by regulating the CXCR4/JAK/STAT signaling pathway. Tff3 may serve as a promising therapeutic target for heart failure.