FBXL18 ubiquitinates and degrades MDFI to suppress Wnt/β-catenin signaling and reverse cisplatin resistance in lung cancer

Cisplatin resistance remains a major obstacle in lung cancer treatment, leading to therapeutic failure and disease progression. Dysregulated signaling pathways contribute to chemoresistance, but the specific molecular mechanisms driving this process are incompletely understood. This study aimed to identify key genes involved in cisplatin resistance, elucidate their functional mechanisms, and explore potential strategies to overcome this resistance. Integrated bioinformatic analysis of public datasets and clinical specimens was performed to identify candidate genes. Functional validation was conducted through in vitro and in vivo experiments, including proliferation, migration, invasion, and apoptosis assays. Molecular mechanisms were investigated using western blotting, co-immunoprecipitation, ubiquitination assays, and molecular dynamics simulations. MDFI was identified as a critical driver of cisplatin resistance. MDFI promoted malignant phenotypes and chemoresistance by activating Wnt/β-catenin signaling and epithelial-mesenchymal transition. FBXL18 was identified as an E3 ubiquitin ligase that targets MDFI for K48-linked ubiquitination and proteasomal degradation. The histone deacetylase inhibitor valproic acid (VPA) upregulates FBXL18 and promotes TIP60-mediated acetylation of FBXL18 at K365, enhancing its ability to degrade MDFI. In a preliminary preclinical xenograft study, VPA combined with cisplatin showed a trend toward suppressed tumor growth and reduced resistance. These findings suggest the FBXL18-MDFI axis as a previously unrecognized upstream regulator of β-catenin signaling in cisplatin-resistant lung cancer. The discovery that VPA enhances this pathway to restore chemosensitivity in preclinical models provides mechanistic insights that warrant further investigation as a potential approach for overcoming treatment resistance.