Fatostatin (125B11) is a specific inhibitor of sterol regulatory element-binding proteins (SREBP) activation, inhibiting the activation of both SREBP-1 and SREBP-2[1]. Fatostatin blocks the occurrence of SCAP (SREBP cleavage-activating protein), preventing the transport of SREBP to the Golgi for activation, thereby reducing the transcription of genes involved in lipid and cholesterol biosynthesis[2]. Fatostatin can inhibit the AKT/mTORC1/GPX4 signaling pathway, inducing ferroptosis[3].
In vitro, Fatostatin (5μM) treatment of U87, T98G, MDA-MB-453, and Jurkat T cells for 24 or 48 hours induced spindle damage and mitotic arrest, causing all cells to be inhibited in the G2/M phase[4]. Fatostatin (0-20 μM) treatment of CHO cells dose-dependently inhibited the expression of HMG-CoA synthase (HMGCS 1), blocking intracellular SREBP processing[5].
In vivo, Fatostatin (15 mg/kg) administered via intraperitoneal injection for 42 days significantly inhibited tumor growth in mice with subcutaneous C4-2B tumor implants, reducing the proliferation index (Ki67 status), serum prostate-specific antigen (PSA) levels, and mRNA and protein levels of SREBP downstream genes in tumor cells[6]. Fatostatin (30 mg/kg) administered via intraperitoneal injection for 28 days in obese ob/ob mice blocked the increase in body weight, blood glucose, and liver fat accumulation[7].
References:
[1] Ma X, Zhao T, Yan H, et al. Fatostatin reverses progesterone resistance by inhibiting the SREBP1-NF-κB pathway in endometrial carcinoma[J]. Cell Death & Disease, 2021, 12(6): 544.
[2] Lee S H, Lee J H, Im S S. The cellular function of SCAP in metabolic signaling[J]. Experimental & molecular medicine, 2020, 52(5): 724-729.
[3] Cai J, Ye Z, Hu Y, et al. Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma[J]. Cell Death & Disease, 2023, 14(3): 211.
[4] Gholkar A A, Cheung K, Williams K J, et al. Fatostatin inhibits cancer cell proliferation by affecting mitotic microtubule spindle assembly and cell division[J]. Journal of Biological Chemistry, 2016, 291(33): 17001-17008.
[5] Shao W, Machamer C E, Espenshade P J. Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner[J]. Journal of lipid research, 2016, 57(8): 1564-1573.
[6] Li X, Chen Y T, Hu P, et al. Fatostatin displays high antitumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling[J]. Molecular cancer therapeutics, 2014, 13(4): 855-866.
[7] Kamisuki S, Mao Q, Abu-Elheiga L, et al. A small molecule that blocks fat synthesis by inhibiting the activation of SREBP[J]. Chemistry & biology, 2009, 16(8): 882-892.
Fatostatin (125B11) 是固醇调节元件结合蛋白（SREBP）激活的特异性抑制剂，可抑制SREBP-1和SREBP-2的活化[1]。Fatostatin通过阻断SCAP（SREBP裂解激活蛋白）发生，阻止SREBP转运到高尔基被激活，使参与脂质和胆固醇生物合成的基因的转录减少[2]。Fatostatin可抑制AKT/mTORC1/GPX4信号通路，诱导铁死亡[3]
在体外，Fatostatin（5μM）处理U87、T98G、MDA-MB-453、和Jurkat T细胞24h或48h，诱导了纺锤体损伤和有丝分裂阻滞，将所有细胞均抑制在G2/M期[4]。Fatostatin（0-20μM）处理CHO细胞，剂量依赖性地抑制了HMG-CoA合酶（HMGCS 1）的表达，阻断了胞内SREBP加工[5]。
在体内，Fatostatin（15mg/kg）通过腹腔注射治疗皮下接种C4-2B肿瘤的小鼠42天，显著抑制了肿瘤生长，降低了增殖指数（Ki67状态），并降低血清前列腺特异性抗原（PSA）水平，抑制了肿瘤细胞中SREBP下游基因的mRNA和蛋白水平[6]。Fatostatin（30mg/kg）通过腹腔注射治疗肥胖的ob / ob小鼠28天，阻断了小鼠的体重，血糖和肝脏脂肪堆积的增加[7]。