乳腺癌（BC）是全球癌症相关死亡的主要原因。 2,4-二烯酰辅酶 A 还原酶 (DECR1) 是 β-氧化的辅助成分，因其在前列腺癌中增强脂质过氧化和诱导铁死亡的作用而得到认可。然而，它与乳腺癌的关系在很大程度上仍未被探索。我们的研究揭示了乳腺癌组织中 DECR1 的表达显着升高，这与恶性特征的增加相关。重要的是，DECR1 的过表达显着增强了 MDA-MB-231 细胞的增殖和迁移能力。通过全面的高内涵筛选方法，我们确定蟾蜍灵及其衍生物是 DECR1 表达的有效抑制剂。值得注意的是，蟾蜍灵在分子对接研究中表现出最高的结合能，并被发现可通过自噬和泛素化促进 DECR1 的降解。此外，蟾蜍灵通过调节丙二醛（MDA）、甘油三酯（TG）、活性氧（ROS）和Fe2+的水平，同时下调激素敏感性脂肪酶（HSL）、铁蛋白重链的表达，诱导MDA-MB-231细胞铁死亡。蛋白 1 (FPN)、溶质载体家族 7 成员 11 (SLC7A11) 和谷胱甘肽过氧化物酶 4 (GPX4)。这些影响被 DECR1 过度表达所抵消。体内实验表明，蟾蜍灵可抑制肿瘤生长，同时降低 HSL、FPN、SLC7A11 和 GPX4 的表达水平，同时增加 4-羟基壬烯醛 (4-HNE) 的水平。至关重要的是，DECR1 过表达也可逆转蟾蜍灵在体内诱导的铁死亡效应。随后，我们发现SLC7A11与DECR1相互作用，抑制SLC7A11导致DECR1表达水平降低，同时MDA和Fe2积累，这种效应同样可以通过DECR1过表达而逆转。总的来说，我们的研究结果表明，针对 DECR1 的靶向治疗结合进一步抑制其涉及 SLC7A11/GPX4 的下游通路可能是治疗乳腺癌的一种有前途的策略。版权所有 © 2024。由 Elsevier GmbH 出版。

Breast cancer (BC) is a leading cause of cancer-related mortality worldwide. 2,4-dienoyl-CoA reductase (DECR1), an auxiliary component of beta-oxidation, has been recognized for its role in enhancing lipid peroxidation and inducing ferroptosis in prostate cancer. However, its involvement in breast cancer remains largely unexplored. Our study revealed a notably elevated expression of DECR1 in breast cancer tissues, which correlated with increased malignant characteristics. Importantly, the overexpression of DECR1 significantly enhanced proliferation and migration capabilities in MDA-MB-231 cells. Through a comprehensive high-content screening approach, we identified bufalin and its derivative as potent inhibitors of DECR1 expression. Notably, bufalin demonstrated the highest binding energy during molecular docking studies and was found to promote the degradation of DECR1 via autophagy and ubiquitination. Furthermore, bufalin induced ferroptosis in MDA-MB-231 cells by modulating levels of malondialdehyde (MDA), triglycerides (TG), reactive oxygen species (ROS) and Fe2+ while downregulating the expression of hormone-sensitive lipase (HSL), ferritin heavy chain protein 1 (FPN), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). These effects were counteracted by DECR1 overexpression. In vivo experiments demonstrated that bufalin inhibited the tumor growth, while decreasing the expression levels of HSL, FPN, SLC7A11, and GPX4, alongside increasing levels of 4-hydroxynonenal (4-HNE). Crucially, the ferroptosis effects induced by bufalin in vivo were also reversed by DECR1 overexpression. Subsequently, we discovered that SLC7A11 interacts with DECR1, inhibition of SLC7A11 led to decreased expression levels of DECR1 along with an accumulation of MDA and Fe2+, effects that were similarly reversed by DECR1 overexpression. Collectively, our findings suggest that targeted therapy against DECR1 combined with further inhibition of its downstream pathway involving SLC7A11/GPX4 may represent a promising strategy for treating breast cancer.Copyright © 2024. Published by Elsevier GmbH.