Key result
CELF4 knockout reduces cardiac fibrosis ~26% and preserves heart function in pressure-overloaded mice.
Why the study?
Cardiac fibrosis drives heart failure without specific, effective therapeutic strategies, and the role of CUGBP Elav-like family member 4 (CELF4) in heart failure remains elusive.
Absolute Event Rate: 6.2% vs 8.43%
p-value: p=<0.01
CELF4 promotes cardiac remodeling and fibrosis through inhibition of FMO2 and Smad2/3 signaling, identifying it as a potential therapeutic target for heart failure.
May reduce fibrosis in pressure-overload animal models; leaves open clinical translation for heart failure.
BACKGROUND: Cardiac fibrosis exerts a lasting influence on the development of heart failure (HF), whereas there is no specific and effective therapeutic strategy to combat cardiac fibrosis. OBJECTIVES: CUGBP Elav-like family member 4 (CELF4), an RNA-binding protein, influences tumor progression through post-transcription regulation, while the role of CELF4 in HF remains elusive. METHODS: ) mice were used as control. Primary mouse cardiac fibroblasts (CFs) were isolated and used to determine the cellular and molecular mechanisms of CELF4. RESULTS: The mRNA expression of CELF4 was significantly upregulated in mouse failing heart after TAC. In vitro experiments showed that CELF4 was specifically induced by TGF-β1 in CFs, but no change was observed in cardiomyocytes. CELF4 deficiency attenuated cardiac fibrosis and preserved the functions of pressure overload-induced hearts. We observed that depletion of CELF4 markedly reduced CF proliferation and migration induced by TGF-β1. Furthermore, depletion of CELF4 alleviated Collagen I and α-SMA expression in CFs as determined by western blots. Using RNA pull-down and Luciferase assay, we found an intrinsic binding of CELF4 with 3'UTR of flavin containing monooxygenase 2 (FMO2), which blunted the phosphorylation of Smad2/3 in CFs after TGF-β1 stimulation. CONCLUSION: Our study delineates that decreased CELF4 retards cardiac fibrosis and HF via interaction with FMO2 and suppression of Smad2/3 signaling. Inhibition of CELF4 may become a potential therapy target for cardiac fibrosis and HF.
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Zhang et al. (2025) studied Cardiac remodeling and heart failure. Global CELF4 knockout vs. Wild-type (CELF4+/+) mice was evaluated on Cardiac fibrotic area after 4 weeks of transverse aortic constriction (p=<0.01). Global knockout of CELF4 significantly reduced cardiac fibrosis (6.20% vs 8.43%, p<0.01) and preserved cardiac function in mice subjected to pressure overload.
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