〔Abstract〕 Objective To investigate the expression levels of suppression of tumorigenicity 2 (ST2) and phosphatidylinositol 3-kinase (PI3K) in patients with persistent atrial fibrillation and their relationship with the degree of left atrial fibrosis. Methods A total of 100 patients with persistent atrial fibrillation from June 2019 to June 2023 at the Xinxiang First People's Hospital were selected and divided into two groups without left atrial fibrosis (endocardial voltage amplitude > 0.5mV, 53 cases) and left atrial fibrosis (endocardial voltage amplitude < 0.5mV, 47 cases) according to left atrial voltage matrix mapping. The differences in clinical characteristic indicators between two groups were compared, and the correlation between serum ST2, PI3K and clinical characteristic indicators was analyzed. The independent risk factors for left atrial fibrosis and the predictive power of serum ST2 and PI3K levels for left ventricular fibrosis were analyzed. Results There were significant differences in age, sex, body mass index (BMI), left atrial anterior and posterior diameter (LAD), serum type I collagen carboxy-terminal propeptide (PICP), type III collagen propeptide (PⅢNP), ST2 and PI3K between the group without left atrial fibrosis and the group with left atrial fibrosis (P < 0.05). Correlation analysis showed no significant correlation between serum ST2 and PI3K (P > 0.05). ST2 was positively correlated with LAD and PICP (r = 0.681, r = 0.572, P < 0.05). PI3K was not correlated with LAD, LVEDD and other indicators (P > 0.05). Logistic multiple regression analysis showed that age, LAD, PICP, ST2, and PI3K were independent predictive factors for left atrial fibrosis. The receiver operating characteristic (ROC) curve analysis showed that the area under curve (AUC) of serum ST2 for predicting left atrial fibrosis was 0.709, with a sensitivity of 76.3% and specificity of 62.9%. The AUC of serum PI3K prediction for left atrial fibrosis was 0.633, with a sensitivity of 67.4% and a specificity of 49.6%. Conclusion The levels of serum ST2 and PI3K are related to the occurrence of left atrial fibrosis in patients with persistent atrial fibrillation, and there is no synergy between the two. The serum ST2 has more development value in predicting left atrial fibrosis.