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

[UNLABELLED] 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 mRNA to reduce 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/ 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.