Yamada Naoya, Karasawa Tadayoshi, Ito Junya, Yamamuro Daisuke, Morimoto Kazushi, Nakamura Toshitaka, Komada Takanori, Baatarjav Chintogtokh, Saimoto Yuma, Jinnouchi Yuka, Watanabe Kazuhisa, Miura Kouichi, Yahagi Naoya, Nakagawa Kiyotaka, Matsumura Takayoshi, Yamada Ken-Ichi, Ishibashi Shun, Sata Naohiro, Conrad Marcus, Takahashi Masafumi
Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Division of Gastroenterological, General and Transplant Surgery, Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Nat Commun. 2024 Mar 12;15(1):2195. doi: 10.1038/s41467-024-46386-6.
Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.
近期证据表明，铁死亡与多种肝脏疾病的病理生理学有关；然而，其器官特异性调节机制尚不清楚。在此，我们证明胆固醇生物合成的末端酶7-脱氢胆固醇还原酶（DHCR7）是肝细胞铁死亡的调节因子。对DHCR7进行基因和药理学抑制（使用AY9944）可抑制人肝癌Huh-7细胞中的铁死亡。抑制DHCR7会增加其底物7-脱氢胆固醇（7-DHC）。此外，使用羟丙基β-环糊精补充外源性7-DHC可抑制铁死亡。在DHCR7缺陷细胞中，铁死亡诱导剂RSL-3会增加一种7-DHC衍生的氧化甾醇代谢物3β,5α-二羟基胆甾-7-烯-6-酮（DHCEO），这表明抑制DHCR7对铁死亡的抑制作用与7-DHC的氧化有关。电子自旋共振分析表明，7-DHC作为一种自由基捕获剂发挥作用，从而保护细胞免受铁死亡。我们进一步表明，AY9944可抑制肝脏缺血再灌注损伤，并且Dhcr7基因敲除可预防小鼠对乙酰氨基酚诱导的急性肝衰竭。这些发现为肝脏铁死亡的调节机制提供了新见解，并为铁死亡相关肝脏疾病提出了一种潜在的治疗选择。
