Fatostatin A hydrobromide is a compound that specifically inhibits the activity of sterol regulatory element-binding proteins (SREBPs), effectively suppressing the activation of SREBP-1 and SREBP-2[1]. By binding to the SREBP cleavage-activating protein (SCAP), Fatostatin A hydrobromide inhibits the transport of SREBPs from the endoplasmic reticulum to the Golgi apparatus, ultimately reducing the transcriptional level of intracellular lipogenesis-related genes[2]. Fatostatin A hydrobromide also regulates glucose and lipid metabolism and suppresses cancer progression[3-4].
In vitro, treatment of cancer cells (such as HeLa, U87, and SH-SY5Y) with Fatostatin A hydrobromide (2.11–5μM) for 24–48 hours inhibits SREBP maturation and induces G₂/M phase arrest. Concurrently, Fatostatin A hydrobromide disrupts mitotic spindle assembly by inhibiting tubulin polymerization, activates the spindle assembly checkpoint, and ultimately leads to multipolar division and caspase 3/7-dependent cell death[5]. Pretreatment of pancreatic cancer cells (BxPC-3, MIAPaCa-2) with Fatostatin A hydrobromide (10–30μM) for 24–72 hours significantly suppresses cell proliferation and clonogenic ability while reducing intracellular lipid synthesis. Furthermore, Fatostatin A hydrobromide induces iron accumulation, increases reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and downregulates GPX4 expression, triggering ferroptosis[6].
In vivo, Fatostatin A hydrobromide (25mg/kg) administered via tail vein injection in a 6-week-old BALB/c nude mouse model of intracranial glioblastoma (three times per week for 4 weeks) significantly inhibits tumor growth and prolongs survival[7]. Fatostatin A hydrobromide (25mg/kg; injected three times a week for 4 weeks) was administered intraperitoneally to 4-week-old BALB/c nude mice to establish a xenograft model of endometrial cancer. Fatostatin A hydrobromide significantly inhibited tumor growth and enhanced sensitivity to progesterone therapy[8].
References:
[1] Xue L, Qi H, Zhang H, et al. Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy. Front Oncol. 2020 Aug 21;10:1510.
[2] Soyal SM, Nofziger C, Dossena S, et al. Targeting SREBPs for treatment of the metabolic syndrome. Trends Pharmacol Sci. 2015 Jun;36(6):406-16.
[3] Li M, Lu Q, Zhu Y, et al. Fatostatin inhibits SREBP2-mediated cholesterol uptake via LDLR against selective estrogen receptor α modulator-induced hepatic lipid accumulation. Chem Biol Interact. 2022 Sep 25;365:110091.
[4] Yao L, Chen S, Li W. Fatostatin inhibits the development of endometrial carcinoma in endometrial carcinoma cells and a xenograft model by targeting lipid metabolism. Arch Biochem Biophys. 2020 May 15;684:108327.
[5] Gholkar AA, Cheung K, Williams KJ, et al. Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division. J Biol Chem. 2016 Aug 12;291(33):17001-8.
[6] Cao R, Feng Z, Mo J, et al. Pharmacological inhibition of SREBP1 suppresses pancreatic cancer growth via inducing GPX4-mediated ferroptosis. Cell Signal. 2024 Dec;124:111381.
[7] Cai J, Ye Z, Hu Y, et al. Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. Cell Death Dis. 2023 Mar 25;14(3):211.
[8] Ma X, Zhao T, Yan H, et al. Fatostatin reverses progesterone resistance by inhibiting the SREBP1-NF-κB pathway in endometrial carcinoma. Cell Death Dis. 2021 May 26;12(6):544.
Fatostatin A hydrobromide是一种能够特异性抑制甾醇调节元件结合蛋白（SREBP）活性的化合物，可有效抑制SREBP-1和SREBP-2的激活过程[1]。Fatostatin A hydrobromide 通过结合SREBP裂解激活蛋白（SCAP），进而抑制SREBPs从内质网到高尔基体的转运，最终降低细胞内脂肪生成相关基因的转录水平[2]。Fatostatin A hydrobromide可调节糖脂代谢和抑制癌症发展[3-4]。
在体外，Fatostatin A hydrobromide（2.11–5μM）处理癌细胞（HeLa、U87、SH-SY5Y等）24–48小时，Fatostatin A hydrobromide可抑制SREBP成熟并诱导G₂/M期阻滞，同时通过抑制微管蛋白聚合破坏有丝分裂纺锤体组装，激活纺锤体组装检查点，最终导致多极分裂和caspase 3/7依赖的细胞死亡[5]。Fatostatin A hydrobromide（10–30μM）预处理胰腺癌细胞（BxPC-3、MIAPaCa-2）24–72小时，显著抑制细胞增殖和克隆形成能力，同时降低细胞内脂质合成；进一步通过诱导铁积累、活性氧（ROS）及丙二醛（MDA）水平升高，并下调GPX4表达，触发铁死亡[6]。
在体内，Fatostatin A hydrobromide（25mg/kg）通过尾静脉注射，用于处理6周龄BALB/c裸鼠建立的颅内胶质母细胞瘤模型（每周3次，持续4周）。Fatostatin A hydrobromide显著抑制了肿瘤生长并延长了小鼠生存期[7]。Fatostatin A hydrobromide（25mg/kg；每周注射3次，持续4周）腹腔注射处理4周龄BALB/c裸鼠建立的子宫内膜癌异种移植模型。Fatostatin A hydrobromide显著抑制了肿瘤生长并增强了孕激素治疗的敏感性[8]。