YAP/TAZ and ATF4 collaboratively drive resistance to Sorafenib therapy in hepatocellular carcinoma by preventing ferroptosis

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA-mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib-induced ferroptosis. Mechanistically, in a TEAD-dependent manner YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovered a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ-based rewiring strategies as potential approaches to overcome HCC therapy resistance. RNA-Seq of siCtrl, siYAP/TAZ, siATF4 with DMSO or Sorafneib treatment in HLE cell line

解析癌症逃逸耐药的潜在机制，是提升当前肿瘤治疗疗效所亟待满足的临床未竟需求。本研究通过联合短发夹RNA（shRNA）介导的合成致死筛选与转录组分析，发现转录因子YAP/TAZ通过抑制索拉非尼诱导的铁死亡，成为肝细胞癌（HCC）中索拉非尼耐药的关键驱动因素。从机制层面来看，YAP/TAZ以TEAD依赖的方式诱导SLC7A11的表达——SLC7A11是维持细胞内谷胱甘肽稳态的关键转运蛋白，可使肝癌细胞规避索拉非尼诱导的铁死亡。与此同时，YAP/TAZ能够维持ATF4的蛋白质稳定性、核定位与转录活性，进而协同诱导SLC7A11的表达。本研究揭示了YAP/TAZ在抑制铁死亡及肝细胞癌索拉非尼耐药形成中的关键作用，凸显了基于YAP/TAZ的重编程策略可作为克服肝癌治疗耐药的潜在手段。本研究配套的测序数据集为：HLE细胞系经二甲基亚砜（DMSO）或索拉非尼处理，并分别转染siCtrl、siYAP/TAZ、siATF4后的RNA测序（RNA-Seq）数据。