Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, 200433, China.
Acta Pharmacol Sin. 2023 May;44(5):1014-1028. doi: 10.1038/s41401-022-01010-5. Epub 2022 Nov 2.
Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in metabolic dysfunction-associated fatty liver disease (MAFLD) is not fully elucidated. In this study we compared the therapeutic effects of ferroptosis inhibitor liproxstatin-1 (LPT1) and iron chelator deferiprone (DFP) in MAFLD mouse models. This model was established in mice by feeding a high-fat diet with 30% fructose in water (HFHF) for 16 weeks. The mice then received LPT1 (10 mg·kg·d, ip) or DFP (100 mg·kg·d, ig) for another 2 weeks. We showed that both LPT1 and DFP treatment blocked the ferroptosis markers ACSL4 and ALOX15 in MAFLD mice. Furthermore, LPT1 treatment significantly reduced the liver levels of triglycerides and cholesterol, lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and ameliorated the expression of lipid synthesis/oxidation genes (Pparα, Scd1, Fasn, Hmgcr and Cpt1a), insulin resistance, mitochondrial ROS content and liver fibrosis. Importantly, LPT1 treatment potently inhibited hepatic apoptosis (Bax/Bcl-xL ratio and TUNEL cell number), pyroptosis (cleavages of Caspase-1 and GSDMD) and necroptosis (phosphorylation of MLKL). Moreover, LPT1 treatment markedly inhibited cleavages of PANoptosis-related caspase-8 and caspase-6 in MAFLD mouse liver. In an in vitro MAFLD model, treatment with LPT1 (100 nM) prevented cultured hepatocyte against cell death induced by pro-PANoptosis molecules (TNF-α, LPS and nigericin) upon lipid stress. On the contrary, DFP treatment only mildly attenuated hepatic inflammation but failed to alleviate lipid deposition, insulin resistance, apoptosis, pyroptosis and necroptosis in MAFLD mice. We conclude that ferroptosis inhibitor LPT1 protects against steatosis and steatohepatitis in MAFLD mice, which may involve regulation of PANoptosis, a coordinated cell death pathway that involves apoptosis, pyroptosis and necroptosis. These results suggest a potential link between ferroptosis and PANoptosis.
铁死亡是一种新的受调控的细胞死亡形式，其特征为铁蓄积过多和脂质过氧化不可控。铁死亡在代谢相关脂肪性肝病（MAFLD）中的作用尚未完全阐明。在本研究中，我们比较了铁死亡抑制剂 liproxstatin-1（LPT1）和铁螯合剂地拉罗司（DFP）在 MAFLD 小鼠模型中的治疗效果。通过在水中给予 30%果糖的高脂肪饮食（HFHF）喂养 16 周，建立了该模型。然后，这些小鼠接受 LPT1（10mg·kg·d，腹腔内注射）或 DFP（100mg·kg·d，灌胃）治疗 2 周。我们表明，LPT1 和 DFP 治疗均阻断了 MAFLD 小鼠的铁死亡标志物 ACSL4 和 ALOX15。此外，LPT1 治疗显著降低了 MAFLD 小鼠肝脏的甘油三酯和胆固醇水平、脂质过氧化标志物 4-羟基壬烯醛（4-HNE）和丙二醛（MDA）水平，并改善了脂质合成/氧化基因（Pparα、Scd1、Fasn、Hmgcr 和 Cpt1a）、胰岛素抵抗、线粒体 ROS 含量和肝纤维化的表达。重要的是，LPT1 治疗强烈抑制了肝凋亡（Bax/Bcl-xL 比值和 TUNEL 细胞数）、焦亡（Caspase-1 和 GSDMD 的切割）和坏死性凋亡（MLKL 的磷酸化）。此外，LPT1 治疗显著抑制了 MAFLD 小鼠肝中 PANoptosis 相关的 caspase-8 和 caspase-6 的切割。在体外 MAFLD 模型中，用 LPT1（100nM）处理可防止培养的肝细胞在脂质应激下受到促 PANoptosis 分子（TNF-α、LPS 和 Nigericin）诱导的细胞死亡。相反，DFP 治疗仅轻度减轻肝脏炎症，但未能减轻 MAFLD 小鼠的脂质沉积、胰岛素抵抗、凋亡、焦亡和坏死性凋亡。我们的结论是，铁死亡抑制剂 LPT1 可预防 MAFLD 小鼠的脂肪变性和脂肪性肝炎，这可能涉及 PANoptosis 的调节，PANoptosis 是一种涉及凋亡、焦亡和坏死性凋亡的协调性细胞死亡途径。这些结果提示铁死亡和 PANoptosis 之间可能存在联系。
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