Objective: To investigate whether the RNA?binding protein CELF2 promotes cardiac fibroblast transdifferentiation by regulating COX?2 mRNA stability. METHODS: Bioinformatics analysis was used to screen core genes associated with myocardial fibrosis. A fibrosis model was established by treating human cardiac fibroblasts with angiotensin II (Ang II), and cell phenotype as well as CELF2 expression were examined using immunofluorescence, Western blot, qPCR and CCK?8 assays. CELF2 knockdown and overexpression cell models were constructed to evaluate their effects on fibrosis markers (α?SMA, Collagen I/III) and cell proliferation. Candidate downstream targets of CELF2 were screened by qPCR, and RNA immunoprecipitation (RIP) together with mRNA half?life assays were performed to verify the binding of CELF2 to COX?2 mRNA and its effect on mRNA stability. RESULTS: Ang II induced concentration?dependent transdifferentiation of fibroblasts, upregulated CELF2 expression, and increased the expression of fibrosis markers as well as cell proliferation (all P < 0.01). Overexpression of CELF2 aggravated these fibrotic phenotypes, whereas knockdown of CELF2 produced the opposite effect (all P < 0.01). CELF2 exhibited the most pronounced regulatory effect on COX?2, and knockdown of COX?2 partially reversed the fibrotic changes induced by CELF2 overexpression (P < 0.01). RIP assays confirmed direct binding of CELF2 to COX?2 mRNA, and stability assays showed that CELF2 prolonged the half?life of COX?2 mRNA. CONCLUSION: CELF2 promotes cardiac fibroblast transdifferentiation by binding to and enhancing the stability of COX?2 mRNA, suggesting that the CELF2–COX?2 axis may play a regulatory role in myocardial fibrosis.