iFSP1 is a potent glutathione-independent ferroptosis suppressor protein 1 (FSP1) inhibitor , which has an EC50 value of 103nM[1]. iFSP1 inhibits ferroptosis by catalyzing the production of antioxidant CoQH2 [2].
iFSP1 ( 6μM , 24h ) will restore cancer cell sensitivity to ferroptosis[3] . iFSP1 ( 3μM , 3h ) only exerts its function on hFSP1 but not mFSP1[4]. iFSP1 ( 3μM , 24h ) combined with CD36 overexpression induces the increasing synthesis of ferroptosis marker ACSL4 in Transformed C3H Mouse Kidney-1 (TCMK-1) cells upon the treatment of cisplatin[5].
iFSP1 ( 10mg/kg/day ; 4 weeks ; intraperitoneal injection ) potently induced ferroptosis, which promoted innate and adaptive antitumor immune responses and effectively suppressed Hepatocellular carcinoma ( HCC ) tumor growth[6]. iFSP1 (2mg/kg/day ; 2 weeks ; intraperitoneal injection ) and olaparib combined treatment strongly inhibited tumour proliferation in breast cancer susceptibility gene ( BRCA )-proficient ovarian cancer cell lines , patient-derived organoids ( PDOs ) and xenograft mouse models[7].
References:
[1] DOLL S, FREITAS F P, SHAH R, et al. FSP1 is a glutathione-independent ferroptosis suppressor [J]. Nature, 2019, 575(7784): 693-8.
[2] TAO H, DAR H Y, TIAN C, et al. Differences in hepatocellular iron metabolism underlie sexual dimorphism in hepatocyte ferroptosis [J]. Redox Biol, 2023, 67(102892.
[3] PANCZYSZYN E, SAVERIO V, MONZANI R, et al. FSP1 is a predictive biomarker of osteosarcoma cells' susceptibility to ferroptotic cell death and a potential therapeutic target [J]. Cell Death Discov, 2024, 10(1): 87.
[4] XAVIER DA SILVA T N, SCHULTE C, ALVES A N, et al. Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules [J]. Cell Death Dis, 2023, 14(4): 281.
[5] MA Y, HUANG L, ZHANG Z, et al. CD36 promotes tubular ferroptosis by regulating the ubiquitination of FSP1 in acute kidney injury [J]. Genes Dis, 2024, 11(1): 449-63.
[6] CHEU J W, LEE D, LI Q, et al. Ferroptosis Suppressor Protein 1 Inhibition Promotes Tumor Ferroptosis and Anti-tumor Immune Responses in Liver Cancer [J]. Cell Mol Gastroenterol Hepatol, 2023, 16(1): 133-59.
[7] MIAO H, MENG H, ZHANG Y, et al. FSP1 inhibition enhances olaparib sensitivity in BRCA-proficient ovarian cancer patients via a nonferroptosis mechanism [J]. Cell Death Differ, 2024, 31(4): 497-510.
iFSP1是一种有效的不依赖谷胱甘肽的铁死亡抑制蛋白1（FSP1）抑制剂，其EC50值为103nM[1]。iFSP1通过催化抗氧化剂CoQH2的产生抑制铁死亡[2]。
iFSP1（6μM，24h）可恢复癌细胞对铁死亡的敏感性[3]。iFSP1 （3μM，3h）只对hFSP1起作用，对mFSP1不起作用[4]。iFSP1 （3μM，24h）联合CD36过表达诱导转化的小鼠肾小管上皮细胞系（TCMK-1）细胞中铁死亡标志物ACSL4的合成增加[5]。
iFSP1(10毫克/公斤/天；4周；腹腔注射)能诱导铁死亡，促进先天和适应性抗肿瘤免疫反应，有效抑制肝细胞（HCC）肿瘤生长[6]。iFSP1 (2毫克/公斤/天；2周；腹腔注射)和奥拉帕利（olaparib）联合治疗在具有乳腺癌易感基因（BRCA）功能的卵巢癌细胞系、患者来源的类器官（PDOs）和异种移植小鼠模型中显著抑制了肿瘤的增殖[7]。