Targeting MYC in T-Cell lymphoma via epigenetic modulation with a small-molecule inhibitor

T-cell lymphoma (TCL) represents a heterogeneous group of highly aggressive malignancies with poor clinical outcomes because of limited therapeutic options. Hence, targeted therapeutic strategies for TCL are urgently needed. Up-regulation of MYC is observed in more than 90% of all patients with TCL and correlates with tumor progression. Thus, targeting MYC may be an attractive therapeutic strategy for TCL. Here, we identified Lanatoside C (LATC) as a potent anti-TCL agent through unbiased high-throughput screening using an FDA-approved drug library. LATC inhibited cell proliferation and invasiveness of TCL in both the tumor-bearing mice and preclinical PDX models. Mechanistically, LATC disturbed the interaction between m5C reader YBX1 and m5C-modified MYC mRNA to reduce MYC mRNA stability through binding and blocking the RNA recognition domain of YBX1. Meanwhile, LATC directly targeted oncogenic p300 to enhance its proteasomal degradation through repressing UCHL3-mediated p300 deubiquitylation, which consequently down-regulated H4K16 lactylation in the MYC promoter to inhibit its transcription. Taken together, we identified LATC as an epigenetic agent by dually targeting post-transcriptional YBX1/MYC mRNA stability and transcriptional p300/H4K16 lactylation to inhibit MYC-driven T-cell lymphoma progression, providing a novel targeted therapeutic strategy for patients with MYC overexpression. Supplementary Information: The online version contains supplementary material available at 10.1186/s12943-026-02640-7.