TIPIN Couples Epigenetic Rewiring to EGFR Stabilization and Lenvatinib Resistance in Liver Cancer

AIMS: Liver cancer is an aggressive tumor marked by substantial morbidity and mortality. Timeless-interacting protein (TIPIN) is dysregulated in multiple cancers, but its epigenetic regulation, biological function, and downstream pathways in liver cancer remain poorly defined. This study sought to explore TIPIN's function in liver cancer tumorigenesis, metastasis, and lenvatinib resistance. METHODS: We analyzed TCGA data and 94 paired clinical samples. DNA methylation sequencing, whole-body TIPIN knockout mouse hydrodynamic injection models, RNA-seq, immunoprecipitation-mass spectrometry, co-immunoprecipitation, protein stability and ubiquitination assays, and patient‑derived xenograft and patient‑derived organoid models were used. RESULTS: TIPIN was upregulated by DNA hypomethylation in liver cancer and associated with poor prognosis. TIPIN promoted liver cancer initiation and progression in vivo. Mechanistically, TIPIN binds Epidermal Growth Factor Receptor (EGFR) and competes with E3 ligase c‑Cbl for the Tyr1045-containing interface, thereby repressing c‑Cbl-mediated EGFR ubiquitination and degradation and activating downstream ERK1/2 signaling to facilitate tumor proliferation and metastasis. TIPIN depletion accelerates EGFR turnover and sensitizes liver cancer cells to lenvatinib. CONCLUSIONS: TIPIN stabilizes EGFR via competitive binding to the Tyr1045 interface, restricting its ubiquitin-dependent degradation to drive liver cancer progression and lenvatinib resistance. Targeting the TIPIN-EGFR axis could be an effective therapy for liver cancer.