Inhibiting FAT1 Blocks Metabolic Bypass to Enhance Antitumor Efficacy of TCA Cycle Inhibition through Suppressing CPT1A-Dependent Fatty Acid Oxidation.

ABSTRACT: FAT atypical cadherin 1 (FAT1) is one of the most frequently mutated genes in head and neck squamous cell carcinoma (HNSCC), exhibiting the highest mutation rate across different tumor types. Although FAT1's role has attracted considerable attention, its impact on cancer metabolism and treatment resistance remains poorly understood. In this study, it is demonstrated that knockout of mutant FAT1 in HNSCC cells attenuates CPT1A-driven fatty acid oxidation (FAO) through downregulation of the transcription factor ASCL2, leading to marked suppression of tumor growth. Notably, FAT1-mutant HNSCC cells exhibit resistance to the TCA cycle inhibitor CPI-613 through activation of CPT1A-mediated FAO, whereas genetic ablation of mutant FAT1 restores sensitivity to CPI-613. To achieve in vivo depletion

SUBMITTER: Chen F 

PROVIDER: S-EPMC12376706 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature