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 uncovers 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.

中文翻译：

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YAP/TAZ 和 ATF4 通过预防铁死亡来驱动肝细​​胞癌对索拉非尼的耐药性


了解癌症逃避抵抗的机制是提高现有疗法疗效的未满足的医学需求。在这项研究中，shRNA介导的合成致死率筛选和转录组分析相结合，揭示了转录因子 YAP/TAZ 通过抑制索拉非尼诱导的铁死亡而成为肝细胞癌 (HCC) 索拉非尼耐药的关键驱动因素。从机制上讲，YAP/TAZ 以 TEAD 依赖性方式诱导 SLC7A11（维持细胞内谷胱甘肽稳态的关键转运蛋白）的表达，从而使 HCC 细胞能够克服索拉非尼诱导的铁死亡。同时，YAP/TAZ 维持 ATF4 的蛋白质稳定性、核定位和转录活性，进而协同诱导 SLC7A11 表达。我们的研究揭示了 YAP/TAZ 在抑制铁死亡以及 HCC 索拉非尼耐药建立中的关键作用，强调基于 YAP/TAZ 的重连策略是克服 HCC 治疗耐药的潜在方法。