铁死亡是一种由铁依赖性脂质过氧化驱动的细胞死亡形式，正在成为癌症治疗中一个有前途的靶点。它受到调节脂质代谢、铁稳态和氧化还原平衡以及相关过程的分子和途径网络的调节。然而，仍有许多与铁死亡密切相关的调节分子有待鉴定。在这里，我们指出，抑制高尔基体蛋白酰基辅酶 A 结合域 A 3 (ACBD3) 会增加 Henrieta Lacks 和 PANC1 细胞对铁死亡的敏感性。 ACBD3 敲低通过促进铁蛋白自噬来增加不稳定铁水平。游离铁的增加，加上 ACBD3 敲低导致的谷胱甘肽过氧化物酶 4 水平降低，导致活性氧和脂质过氧化物的积累。此外，ACBD3 敲低还通过仍有待阐明的机制导致含多不饱和脂肪酸的甘油磷脂水平升高。此外，通过敲低核受体共激活剂 4 或 Bafilomycin A1 治疗来抑制 ACBD3 中的铁蛋白吞噬，从而下调细胞的铁死亡。总的来说，我们的研究结果强调了 ACBD3 在控制细胞对铁死亡的抵抗中的关键作用，并表明对 ACBD3 水平进行药理学操作是一种有前景的癌症治疗策略。© 2024 国际细胞生物学联合会。

Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, is emerging as a promising target in cancer therapy. It is regulated by a network of molecules and pathways that modulate lipid metabolism, iron homeostasis and redox balance, and related processes. However, there are still numerous regulatory molecules intricately involved in ferroptosis that remain to be identified. Here, we indicated that suppression of Golgi protein acyl-coenzyme A binding domain A containing 3 (ACBD3) increased the sensitivity of Henrieta Lacks and PANC1 cells to ferroptosis. ACBD3 knockdown increases labile iron levels by promoting ferritinophagy. This increase in free iron, coupled with reduced levels of glutathione peroxidase 4 due to ACBD3 knockdown, leads to the accumulation of reactive oxygen species and lipid peroxides. Moreover, ACBD3 knockdown also results in elevated levels of polyunsaturated fatty acid-containing glycerophospholipids through mechanisms that remain to be elucidated. Furthermore, inhibition of ferrtinophagy in ACBD3 downregulated cells by knocking down the nuclear receptor co-activator 4 or Bafilomycin A1 treatment impeded ferroptosis. Collectively, our findings highlight the pivotal role of ACBD3 in governing cellular resistance to ferroptosis and suggest that pharmacological manipulation of ACBD3 levels is a promising strategy for cancer therapy.© 2024 International Federation of Cell Biology.