FBXW4 suppresses the proliferation and migration of lung adenocarcinoma cells by inhibiting PKNOX2 promoter methylation.

This study aimed to elucidate the molecular mechanism by which FBXW4 suppresses the progression of lung adenocarcinoma (LUAD). Functional experiments demonstrated that FBXW4 significantly inhibited LUAD cell proliferation, migration, and invasion, while promoting apoptosis. Furthermore, rescue experiments indicated that PKNOX2 silencing partially reversed the tumor-suppressive effects of FBXW4. Mechanistically, FBXW4 facilitated the ubiquitination and degradation of DNMT1, leading to a decrease of methylation of the PKNOX2 promoter. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays confirmed that PKNOX2 transcriptionally activated FHL1 by directly binding to its promoter. In addition, FHL1 was identified as a functional downstream effector responsible for mediating the inhibitory role of PKNOX2 in LUAD malignancy. These findings reveal a previously uncharacterized FBXW4/DNMT1/PKNOX2/FHL1 regulatory axis, providing mechanistic insight into LUAD suppression and potential therapeutic strategies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04646-2.