Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis.

1. Acta Pharmacol Sin. 2023 May;44(5):1014-1028. doi: 10.1038/s41401-022-01010-5. Epub 2022 Nov 2. Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis. Tong J(#)(1), Lan XT(#)(1), Zhang Z(#)(1), Liu Y(1), Sun DY(2), Wang XJ(1), Ou-Yang SX(1), Zhuang CL(2), Shen FM(1), Wang P(3), Li DJ(4)(5). Author information: (1)Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. (2)School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, 200433, China. (3)School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, 200433, China. pwang@smmu.edu.cn. (4)Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. djli@tongji.edu.cn. (5)Institute of Nuclear Medicine, Tongji University School of Medicine, Shanghai, 200072, China. djli@tongji.edu.cn. (#)Contributed equally 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-1·d-1, ip) or DFP (100 mg·kg-1·d-1, 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. © 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society. DOI: 10.1038/s41401-022-01010-5 PMCID: PMC10104837 PMID: 36323829 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests.