Ubiquitin-dependent degradation of MBD3 by TRIM59 promotes lung adenocarcinoma

• TRIM59 is identified as the E3 ubiquitin ligase that targets MBD3 for proteasomal degradation, with key ubiquitination sites at K41, K90, and K92. • The TRIM59-MBD3 axis derepresses HSF1 and HSF2, promoting malignant proliferation and tumor progression in lung adenocarcinoma. • TRIM59 and MBD3 show inverse expression patterns in LUAD tissues, with TRIM59 upregulated and MBD3 downregulated, supporting oncogenesis. • The TRIM59-MBD3 ubiquitination cascade represents a potential therapeutic vulnerability in lung adenocarcinoma.