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Introduction: Obese patients are often accompanied by hyperleptinemia and prone to develop liver fibrosis. Accumulating data including those obtained from human studies suggested the promotion role of leptin in liver fibrosis. The remodeling of the DNA methylation is an epigenetic mechanism for regulating gene expression and is essential for hepatic stellate cell (HSC) activation, a key step in liver fibrogenesis. Leptin increases the expression of methionine adenosyltransferase 2A (MAT2A) which is associated with DNA methylation and HSC activation. Curcumin, an active polyphenol of the golden spice turmeric, inhibits leptin-induced HSC activation and liver fibrogenesis. Thus, the present research aimed to investigate the influence of curcumin on the roles of leptin in MAT2A expression in HSCs. Methods: The in vivo experiments were conducted by using leptin-deficient obese mice. The gene expressions were examined by Western blot, real-time PCR, promoter activity assay, and immunostaining analysis. Results: Curcumin reduced leptin-induced MAT2A expression. JNK signaling contributed to leptin-induced increase in MAT2A level, which could be interrupted by curcumin treatment. Curcumin inhibited leptin-induced MAT2A promoter activity by influencing MAT2A promoter fragments between −2,847 bp and − 2,752 bp and between −2,752 bp and +49 bp. The effect of curcumin on leptin-induced MAT2A expression paralleled the reductions in leptin-induced activated HSCs and liver fibrosis. Conclusion: These results might have implications for curcumin inhibition of the liver fibrogenesis in obese patients with hyperleptinemia. [ABSTRACT FROM AUTHOR]