Kojic acid inhibits melanoma progression by targeting the MYC-CCNA2/KPNA2 axis.

Fungal metabolites represent a valuable but underexplored source of anticancer agents, in part due to poorly defined mechanisms of action. Kojic acid (KA) is a fungal secondary metabolite with reported anti-melanoma activity, but its mechanism of action remains unclear. Here, we show that KA inhibits melanoma progression by disrupting MYC-driven transcriptional programs. KA treatment reduced proliferation and induced apoptosis in melanoma cells in vitro, and suppressed tumor growth in xenograft models. Transcriptomic profiling revealed a dose-dependent repression of MYC target genes, with CCNA2 and KPNA2 identified as key effectors. Both genes were validated as direct MYC targets and were associated with poor prognosis in the melanoma cohort (TCGA-SKCM). KA did not alter MYC expression but impaired its promoter binding and transcriptional activation of CCNA2 and KPNA2. Single-cell analysis further localized this axis to a proliferative mitotic subpopulation, promoting melanoma progression. These findings uncover a previously unrecognized mechanism by which KA inhibits melanoma growth and suggest that targeting the MYC-CCNA2/KPNA2 pathway may provide a therapeutic strategy for melanoma.