SBFI26, an inhibitor of FABP5, has been shown to suppress the proliferation and metastasis of tumour cells. However, the underlying mechanism by which SBFI26 induces ferroptosis in breast cancer cells remains largely unknown. Three breast cancer cell lines were treated with SBFI26 and CCK‐8 assessed cytotoxicity. Transcriptome was performed on the Illumina platform and verified by qPCR. Western blot evaluated protein levels. Malondialdehyde (MDA), total superoxide dismutase (T‐SOD), Fe, glutathione (GSH) and oxidized glutathione (GSSG) were measured. SBFI26 induced cell death time‐ and dose‐dependent, with a more significant inhibitory effect on MDA‐MB‐231 cells. Fer‐1, GSH and Vitamin C attenuated the effects but not erastin. RNA‐Seq analysis revealed that SBFI26 treatment significantly enriched differentially expressed genes related to ferroptosis. Furthermore, SBFI26 increased intracellular MDA, iron ion, and GSSG levels while decreasing T‐SOD, total glutathione (T‐GSH), and GSH levels.SBFI26 dose‐dependently up‐regulates the expression of HMOX1 and ALOX12 at both gene and protein levels, promoting ferroptosis. Similarly, it significantly increases the expression of SAT1, ALOX5, ALOX15, ALOXE3 and CHAC1 that, promoting ferroptosis while downregulating the NFE2L2 gene and protein that inhibit ferroptosis. SBFI26 leads to cellular accumulation of fatty acids, which triggers excess ferrous ions and subsequent lipid peroxidation for inducing ferroptosis.

中文翻译：

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SBFI26通过脂质过氧化诱导三阴性乳腺癌细胞铁死亡

SBFI26 是 FABP5 的抑制剂，已被证明可以抑制肿瘤细胞的增殖和转移。然而，SBFI26 诱导乳腺癌细胞铁死亡的潜在机制仍然很大程度上未知。三种乳腺癌细胞系用 SBFI26 处理，CCK-8 评估细胞毒性。转录组在 Illumina 平台上进行，并通过 qPCR 进行验证。蛋白质印迹评估蛋白质水平。测量了丙二醛（MDA）、总超氧化物歧化酶（T-SOD）、Fe、谷胱甘肽（GSH）和氧化型谷胱甘肽（GSSG）。 SBFI26诱导细胞死亡具有时间和剂量依赖性，对MDA-MB-231细胞有更显着的抑制作用。 Fer-1、GSH 和维生素 C 减弱了这种作用，但erastin 没有。 RNA-Seq 分析显示，SBFI26 处理显着富集了与铁死亡相关的差异表达基因。此外，SBFI26 增加细胞内 MDA、铁离子和 GSSG 水平，同时降低 T-SOD、总谷胱甘肽 (T-GSH) 和 GSH 水平。SBFI26 在基因和蛋白质水平上剂量依赖性上调 HMOX1 和 ALOX12 的表达，促进铁死亡。同样，它显着增加 SAT1、ALOX5、ALOX15、ALOXE3 和 CHAC1 的表达，促进铁死亡，同时下调抑制铁死亡的 NFE2L2 基因和蛋白质。 SBFI26 导致细胞内脂肪酸的积累，从而引发过量的亚铁离子和随后的脂质过氧化，从而诱导铁死亡。