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Previous literature has indicated that cyclin‐dependent kinase inhibitor 2 A (CDKN2A) is upregulated, while the Protein Inhibitor of Activated STAT1 (PIAS1) is downregulated in the liver tissues of obese mice. The current study aimed to investigate the relationship between CDKN2A and PIAS1 in the lipogenesis of fatty liver disease. In the C57BL/6J db/db mouse model and hepatocyte model of fatty liver, the expression pattern of CDKN2A, PIAS1, Protein arginine methyltransferase 1 (PRMT1) and CASP8 and FADD‐like apoptosis regulator (CFLAR) was characterized by RNA quantitative and Western blot analysis. The lipogenesis‐related genes (Srebp1c and Fas) in the liver tissues and cells were employed in the assessment of lipogenesis in response to gain‐ or loss‐of‐function of CDKN2A, PIAS1, PRMT1, and CFLAR, while triglyceride and fat content were evaluated in relation to fat accumulation. Western blot analysis was conducted to determine c‐Jun amino‐terminal kinase (JNK) phosphorylation, while the ubiquitination of CFLAR and SUMOylation of PIAS1 was examined by immunoprecipitation. PIAS1 and CFLAR were downregulated, while CDKN2A, PRMT1, and phosphorylation of JNK was elevated in the tissues and cells of the fatty liver models. Our results suggested that CDKN2A enhanced the SUMOylation of PIAS1 to reduce the expression of PIAS1. PRMT1 downregulated CFLAR by triggering its ubiquitination, while CFLAR repressed phosphorylation of JNK. The in vitro and in vivo results indicated that CDKN2A silencing prevented lipogenesis and fat accumulation by impairing the PRMT1‐dependent ubiquitination of CFLAR and blocking the phosphorylation of JNK. Taken together, the central observations of our study demonstrate that targeting CDKN2A contributes to the suppression of lipogenesis and fat accumulation in fatty liver disease. The findings of our study highlight the potential of CDKN2A as a promising target against fatty liver. [ABSTRACT FROM AUTHOR]