RB1肿瘤抑制基因失活在多种治疗耐药癌症中很常见，包括转移性去势抵抗型前列腺癌，且预示临床预后差。然而，针对RB1缺失癌症的有效治疗策略仍然难以找到。本研究表明，RB1丢失/E2F激活增强了癌细胞对铁依赖性脂质过氧化引起的一种调节型细胞死亡，即铁死亡，通过上调ACSL4表达并丰富脂质中含有花生四烯酸的ACSL4依赖型磷脂，这是铁死亡执行的关键成分。ACSL4似乎是E2F的直接靶基因，对于RB1的缺失导致对铁死亡敏感性的提高至关重要。值得注意的是，通过细胞系源性异种移植和基因工程肿瘤模型，我们证明了高度选择性和稳定的GPX4抑制剂JKE-1674在体内诱导铁死亡，阻止了RB1缺失的前列腺肿瘤的生长和转移，并提高了小鼠的生存率。因此，我们的发现揭示了一个控制铁死亡的RB/E2F/ACSL4分子轴，也为治疗RB1缺失的恶性肿瘤提供了有希望的途径。

Inactivation of the RB1 tumor suppressor gene is common in several types of therapy-resistant cancers, including metastatic castration-resistant prostate cancer, and predicts poor clinical outcomes. Effective therapeutic strategies against RB1-deficient cancers, however, remain elusive. Here we showed that RB1-loss/E2F activation sensitized cancer cells to ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, by upregulating expression of ACSL4 and enriching ACSL4-dependent arachidonic acid-containing phospholipids, which are key components of ferroptosis execution. ACSL4 appeared to be a direct E2F target gene and was critical to RB1 loss-induced sensitization to ferroptosis. Importantly, using cell line-derived xenografts and genetically engineered tumor models, we demonstrated that induction of ferroptosis in vivo by JKE-1674, a highly selective and stable GPX4 inhibitor, blocked RB1-deficient prostate tumor growth and metastasis and led to improved survival of the mice. Thus, our findings uncover an RB/E2F/ACSL4 molecular axis that governs ferroptosis, and also suggest a promising approach for the treatment of RB1-deficient malignancies.