Lentinan inhibits melanoma development by regulating the AKT/Nur77/Bcl-2 signaling axis

<b>Background:</b> Melanoma is a highly malignant and difficult-to-treat skin cancer. Many researchers are exploring natural products for its treatment. Lentinan (LNT), extracted from <i>Lentinus edodes</i>, exerts strong anti-tumor effects. In this study, we aimed to establish a new approach for melanoma treatment by analyzing the pharmacological properties of LNT. <b>Methods:</b> A tumor-bearing mouse model was established to assess tumor growth. Cell survival was analyzed using the cell counting kit-8 assay. Molecular localization and expression were assessed via western blotting, histological staining, and cell staining. <b>Results:</b> LNT significantly inhibited the growth and proliferation of melanoma cells. <i>In vitro</i>, LNT inhibited the proliferation of B16F10 cells. It also decreased the expression levels of the proliferation-related molecules, poly (ADP ribose) polymerase 1 and proliferating cell nuclear antigen, in B16F10 murine melanoma cells. Moreover, LNT decreased the expression of the orphan nuclear receptor, Nur77, but increased that of the apoptosis-related protein, Bcl-2. LNT promoted the interaction between nuclear receptor Nur77 and mitochondrial apoptosis-associated protein Bcl-2, thereby inducing apoptosis in melanoma cells. Small-interfering RNA-mediated <i>Nur77</i> knockdown revealed that LNT promoted melanoma cell apoptosis via the Nur77/Bcl-2 pathway. Furthermore, AKT played key roles in the cell apoptosis-inducing and anti-tumor effects of LNT via the Nur77/Bcl-2 pathway. <b>Conclusion:</b> Overall, LNT inhibited tumor growth and promoted apoptosis by regulating the AKT/Nur77/Bcl-2 pathway in melanoma cells. Our findings highlight the potential of LNT for drug development and clinical treatment of melanoma.