谷氨酰胺成瘾代表癌细胞的代谢脆弱性；然而，针对相关途径的有效治疗目标仍有待实现。在这里，我们揭示了干扰素相关发育调节因子 1 (IFRD1) 在谷氨酰胺饥饿期间肝细胞癌细胞 (HCC) 适应性生存中的关键作用。 IFRD1 在谷氨酰胺饥饿下被诱导，通过以 TRIM21 依赖性方式促进关键自噬调节因子 ATG14 的蛋白酶体降解来抑制自噬。相反，在谷氨酰胺剥夺状态下靶向 IFRD1 会增加自噬通量，引发癌细胞彻底死亡。这种效应主要是由于组蛋白 H1.0 的亲核降解以及随后与全局增强的染色质可及性相关的核糖体和蛋白质生物合成不受控制的增加造成的。有趣的是，临床前 HCC 模型中的 IFRD1 耗竭与谷氨酰胺酶 1 选择性抑制剂 CB-839 的治疗具有协同作用，可增强限制谷氨酰胺的效果。总之，我们的研究结果揭示了 IFRD1 如何支持癌细胞在谷氨酰胺饥饿下的适应性生存，进一步凸显了 IFRD1 作为抗癌应用中的治疗靶点的潜力。© 2024。作者。

Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.© 2024. The Author(s).