Fumarate hydratase-IN-1 is a cell-permeable inhibitor of fumarate hydratase, exhibiting anti-proliferative activity against multiple cancer cell lines with an average IC₅₀ of 2.2μM[1-2]. Fumarate hydratase-IN-1 interferes with the tricarboxylic acid cycle by inhibiting the activity of the key mitochondrial enzyme fumarate hydratase, thereby affecting the energy metabolism and proliferation of tumor cells[3-4].
In vitro, treatment of RCC10 and RCC4 cells with Fumarate hydratase-IN-1 (0-20μM) for 24 hours, Fumarate hydratase-IN-1 significantly upregulated the protein and mRNA expression levels of PD-L1, promoted nuclear translocation of PD-L1, and enhanced PD-L1 interaction with the nuclear transport protein importin α3[5]. Treatment of ovarian cancer CAOV4 cells with Fumarate hydratase-IN-1 (50μM) for 24 hours, Fumarate hydratase-IN-1 significantly enhanced cell migration ability[6].
In vivo, intraperitoneal administration of Fumarate hydratase-IN-1 (50mg/kg) to LPS-induced acute lung injury C57BL/6 mice (LPS 10mg/kg was administered 1 hour later), Fumarate hydratase-IN-1 significantly exacerbated the release of pulmonary inflammatory factors, oxidative stress levels, and pathological lung tissue damage, and aggravated pulmonary edema by promoting mtDNA leakage and activating the cGAS-STING pathway[7]. Intraperitoneal administration of Fumarate hydratase-IN-1 (25mg/kg) to tumor-bearing mice (B16-OVA melanoma cells) once daily for 4 consecutive days, Fumarate hydratase-IN-1 promoted tumor growth by accumulating fumarate in the tumor interstitial fluid, which inhibited phosphorylation of ZAP70 in CD8⁺ T cells and suppressed activation of the TCR signaling pathway, thereby impairing the anti-tumor function of CD8⁺ T cells[8].
References:
[1] Takeuchi T, Schumacker PT, Kozmin SA. Identification of fumarate hydratase inhibitors with nutrient-dependent cytotoxicity. J Am Chem Soc. 2015 Jan 21;137(2):564-7.
[2] Chen YJ, Shi RC, Xiang YC, et al. Malate initiates a proton-sensing pathway essential for pH regulation of inflammation. Signal Transduct Target Ther. 2024 Dec 30;9(1):367.
[3] Ham SJ, Bang S, Woo D, et al. Mitochondrial fumarate inhibits Parkin-mediated mitophagy. Mol Cell. 2025 Jun 19;85(12):2287-2302.e9.
[4] Cheng J, Liu Y, Yan J, et al. Fumarate suppresses B-cell activation and function through direct inactivation of LYN. Nat Chem Biol. 2022 Sep;18(9):954-962.
[5] Gao Y, Fan S, Sun X, et al. Oncometabolite fumarate facilitates PD-L1 expression and immune evasion in clear cell renal cell carcinoma. Cell Death Dis. 2025 Jun 3;16(1):432.
[6] Chen S, Wu Y, Gao Y, et al. Allosterically inhibited PFKL via prostaglandin E2 withholds glucose metabolism and ovarian cancer invasiveness. Cell Rep. 2023 Oct 31;42(10):113246.
[7] Jiang Z, He R, Zhong Y, et al. Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways. J Inflamm Res. 2025 Apr 21;18:5399-5413.
[8] Cheng J, Yan J, Liu Y, et al. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment. Cell Metab. 2023 Jun 6;35(6):961-978.e10.
Fumarate hydratase-IN-1是一种细胞可渗透性的Fumarate hydratase抑制剂，对多种癌细胞系具有抗增殖活性，平均IC₅₀为2.2μM[1-2]。Fumarate hydratase-IN-1可通过抑制线粒体代谢关键酶富马酸水合酶的活性，干扰三羧酸循环，进而影响肿瘤细胞的能量代谢和增殖[3-4]。
在体外，Fumarate hydratase-IN-1（0-20μM）处理RCC10和RCC4细胞24小时，Fumarate hydratase-IN-1显著上调PD-L1的蛋白和mRNA表达水平，并促进PD-L1的核转位，并促进与核转运蛋白importin α3的相互作用[5]。Fumarate hydratase-IN-1（50μM）处理卵巢癌CAOV4细胞24小时，Fumarate hydratase-IN-1显著增强细胞迁移能力[6]。
在体内，Fumarate hydratase-IN-1（50mg/kg）腹腔注射处理LPS诱导的急性肺损伤C57BL/6小鼠（注射1小时后给予10mg/kg LPS），Fumarate hydratase-IN-1显著加剧肺部炎症因子释放、氧化应激水平和肺组织病理损伤，并通过促进mtDNA泄漏激活cGAS-STING通路加重肺水肿[7]。Fumarate hydratase-IN-1（25mg/kg）腹腔注射处理荷瘤（B16-OVA黑色素瘤细胞）小鼠（每日一次，连续4天），Fumarate hydratase-IN-1通过积累肿瘤间质液中的富马酸，抑制CD8+ T细胞中ZAP70的磷酸化及其TCR信号通路激活，从而削弱CD8+ T细胞的抗肿瘤功能并促进肿瘤生长[8]。