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.