anscriptome and proteome sequencing analyses of lenvatinib-resistant cell lines and patient tissues to identify critical genes and proteins associated with lenvatinib resistance. Subcutaneous mouse models were established, the half maximal inhibitory concentration (IC50) was determined, and colony formation assays were employed to investigate the biological role of microtubule-associated serine/threonine kinase-like (MASTL) in tumor progression and therapeutic resistance. Molecular and biochemical methodologies, including RNA sequencing, chromatin immunoprecipitation sequencing, and mass spectrometry, were employed to explore the underlying mechanisms by which MASTL contributes to poor responses to lenvatinib in HCC. Results: MASTL was frequently upregulated in lenvatinib-resistant HCC cells and tissues. Increased expression of MASTL drove lenvatinib resistance through reactivation of mitogen-activated protein kinase (MAPK) signaling pathways, which is typically inhibited by lenvatinib

illance. While thermal ablation has been established to cause immediate cell death in the center of the thermal ablation zone, its metabolic impact in the peri-ablational region remains unclear. We aimed to elucidate the metabolic mechanism by which Galectin-1 (Gal-1) promotes thermal-ablation-induced hyperthermia resistance in HCC and demonstrate the therapeutic potential of inhibiting Gal-1 in combination with thermal ablation in vivo. Approach and Results: Proteomic analysis was performed using an untargeted approach on pre-ablation formalin-fixed paraffin-embedded (FFPE) biopsy specimens of thermal ablation responders (n=32) and nonresponders (n=23). Gal-1 was found to be overexpressed in thermal ablation nonresponders compared to responders. Moreover, HCC with Gal-1 overexpression demonstrated reduced sensitivity to hyperthermia in vitro and increased utilization of glycolysis and downstream TCA cycle under hyperthermia-induced stress. Gal-1-overexpressing HCC enhanced its metabol