萝卜硫素，一种 NRF2 激动剂，通过调节 HDAC6 活性缓解急性肝衰竭中的铁死亡。
Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity.
机构信息
Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
出版信息
J Integr Med. 2023 Sep;21(5):464-473. doi: 10.1016/j.joim.2023.08.002. Epub 2023 Aug 9.
OBJECTIVE
Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action.
METHODS
Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence.
RESULTS
Our results show that NRF2 was activated by SFN. LDH, Fe, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity.
CONCLUSION
SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6. Please cite this article as: Zhang YQ, Shi CX, Zhang DM, Zhang LY, Wang LW, Gong ZJ. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 2023; 21(5): 464-473.
目的
急性肝衰竭（ALF）的特点是严重的肝功能障碍、快速进展和高死亡率，且难以治疗。研究发现，萝卜硫素（SFN）作为核因子 E2 相关因子 2（NRF2）激动剂，具有抗炎、抗氧化和抗癌作用，对神经退行性疾病、癌症和肝纤维化有一定的保护作用。本文旨在探讨 SFN 在 ALF 中的保护作用及其可能的作用机制。
方法
采用脂多糖和 D-半乳糖胺在体外和体内诱导肝损伤。使用 NRF2 激动剂 SFN 和组蛋白去乙酰化酶 6（HDAC6）抑制剂 ACY1215 分别观察 SFN 在 ALF 中的保护作用及其可能的作用机制。检测细胞活力、乳酸脱氢酶（LDH）、铁、谷胱甘肽（GSH）和丙二醛（MDA）。通过 Western blot 和免疫荧光检测 HDAC6、NRF2、谷胱甘肽过氧化物酶 4（GPX4）、长链酰基辅酶 A 合成酶家族成员 4（ACSL4）和溶质载体家族 7 成员 11（SLC7A11）的表达。
结果
结果表明，SFN 激活了 NRF2。SFN 在体外和体内均下调了 LDH、Fe、MDA 和 ACSL4，而上调了 GSH、GPX4 和 SLC7A11，表明 SFN 抑制了铁死亡。此外，SFN 组 HDAC6 表达降低，表明 SFN 可下调 ALF 中 HDAC6 的表达。使用 HDAC6 抑制剂 ACY1215 后，SFN 进一步降低了 HDAC6 的表达并抑制了铁死亡，表明 SFN 可能通过调节 HDAC6 活性抑制铁死亡。
结论
SFN 对 ALF 具有保护作用，其机制可能包括通过调节 HDAC6 减少铁死亡。请引用本文：张运强，史纯霞，张冬梅，张丽媛，王立伟，宫照杰。NRF2 激动剂萝卜硫素通过调节 HDAC6 活性减轻急性肝衰竭中的铁死亡。中国整合医学杂志。2023；21（5）：464-473.
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