KLF5-driven TAZ–FASN signaling reprograms fatty acid metabolism to support Treg differentiation in lung cancer

作者：Hongxiang Huang, J K Chen, Peiyuan Zhong, SuJuan Peng, Qiuxa Zhong, C Deng, Fang Wang, Zhihui Lu, Yangyang Liu, Li Chen · 发表于：Journal of Translational Medicine · 年份：2026 · DOI：10.1186/s12967-026-08557-5 · 研究领域：Kruppel-like factors research、Hippo pathway signaling and YAP/TAZ、Lipid metabolism and disorders

BACKGROUND: Metabolic reprogramming is a fundamental hallmark of cancer and provides essential biochemical support for malignant progression. In lung cancer, aberrant fatty acid metabolism not only fuels cancer cell growth but also influences regulatory T cell (Treg) differentiation through altered lipid availability. Krüppel-like factor 5 (KLF5) has been implicated in lung cancer progression; however, its role in coordinating cancer fatty acid metabolism and Treg differentiation remains insufficiently defined. METHODS: We combined clinical lung cancer specimens, genetically modified lung cancer cell models, Treg differentiation systems, and mouse tumor models to define the metabolic function of KLF5. Gain- and loss-of-function approaches were used to determine how KLF5 affects lipid storage, fatty acid synthesis, extracellular free fatty acid production, and tumor growth. Conditioned-medium transfer experiments, fatty acid uptake assays, fatty acid oxidation measurements, and flow cytometry were applied to evaluate the impact of cancer cell-derived lipid output on Treg differentiation. Mechanistically, promoter-binding assays, transcriptional reporter analysis, protein-interaction experiments, molecular docking, and TAZ depletion were used to dissect how KLF5 regulates FASN-dependent fatty acid synthesis. RESULTS: KLF5 was highly expressed in lung cancer tissues and cells and showed positive associations with lipogenic markers and Treg-related indicators. Suppression of KLF5...