Background: The objectives of this study are to investigate whether cajanonic acid A (CAA) can reduce insulin resistance in HepG2 cells and to gain a preliminary understanding of the mechanisms underlying this effect. Methods: Following induction of insulin resistance in HepG2 cells, we tested the regulatory effect of CAA on glucose consumption and evaluated hepatocyte production of IL-6, TGF-β, and key molecules in the insulin transduction pathway. A transwell co-culturing system was used to assess the effect of CAA on insulin resistance in HepG2 cells during the differentiation of CD4+ T cells by calculating the ratio of Th17/Treg. We evaluated the effect of CAA on the expression of IL-17RC cells and HepG2 cell apoptosis by immunofluorescence and flow cytometry assay. Results: CAA improved dexamethasone-induced reduction of glucose consumption in HepG2 cells, inhibited hepatocyte production of IL-6 and TGF-β, increased the expression of IL-17RC cell, and increased cellular apoptosis in insulin-resistant HepG2 cells. When co-cultured with CD4+ T cells, insulin-resistant HepG2 cells induced a decreased in the ratio of Th17/Treg, but CAA dampened the effect. Application of IL-6 and TGF-β, together with CAA, reversed the effect of CAA on insulin-resistant HepG2 cells. Overexpression of IL17R, however, counteracted the effect of IL-6 neutralizing antibody within the culture system. Conclusion: CAA can regulate the ratio of Th17/Treg by mediating the expression of IL-6 and TGF-β in insulin-resistant HepG2 cells.

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