Tissue & cell · 2026
Calpain-1 deficiency alleviates oxidative stress and hepatic injury in ApoE-deficient mice with MASH.
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Gu Wenjiao, Wei Yujie, Li Shuangyi, Awad Mohamed Ali, Shi Youming, Jiang Ying, Zhou Xiaochun, Wang Zhimin, Liu Jixin, Tang Futian
Аннотация
BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a critical stage of metabolic dysfunction-associated fatty liver disease (MAFLD) characterized by hepatocyte ballooning, inflammatory infiltration, and fibrosis, often accompanied by oxidative stress, lipotoxicity, and apoptosis. Calpain-1 is involved in the regulation of oxidative stress and inflammation in cellular stress responses, but its role in MASH remains unclear.
METHODS: This study established MASH models in ApoE knockout (ApoE KO) and ApoE/calpain-1 double knockout (AxC DKO) mice. Serum lipids and liver function were assessed. Hepatic lipid deposition was evaluated by magnetic resonance imaging (MRI) and Oil Red O staining. Liver injury and inflammation were examined by H&E staining and inflammatory cytokine assays. Hepatic oxidative stress was assessed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. Proteomic analysis was performed to explore the underlying mechanisms.
RESULTS: Compared with C57 mice, ApoE KO mice exhibited hyperlipidemia, liver dysfunction, increased lipid deposition, elevated ROS and MDA levels, decreased SOD activity and GSH/GSSG ratio, and exacerbated hepatic inflammation. Compared with ApoE KO mice, AxC DKO mice exhibited improved liver function, reduced ROS and MDA, increased SOD activity and GSH/GSSG ratio, and reduced inflammatory markers, without altering hepatic lipid deposition. Proteomic analysis revealed that calpain-1 deficiency partially restored antioxidant protein expression, attenuated the upregulation of CYP450 metabolic enzymes, normalized mitochondrial protein abnormalities, and reduced inflammation-related protein expression.
CONCLUSIONS: Calpain-1 deficiency alleviates MASH-related liver injury by modulating redox homeostasis, reducing oxidative stress and inflammatory, independent of directly lowering hepatic lipid accumulation.
METHODS: This study established MASH models in ApoE knockout (ApoE KO) and ApoE/calpain-1 double knockout (AxC DKO) mice. Serum lipids and liver function were assessed. Hepatic lipid deposition was evaluated by magnetic resonance imaging (MRI) and Oil Red O staining. Liver injury and inflammation were examined by H&E staining and inflammatory cytokine assays. Hepatic oxidative stress was assessed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. Proteomic analysis was performed to explore the underlying mechanisms.
RESULTS: Compared with C57 mice, ApoE KO mice exhibited hyperlipidemia, liver dysfunction, increased lipid deposition, elevated ROS and MDA levels, decreased SOD activity and GSH/GSSG ratio, and exacerbated hepatic inflammation. Compared with ApoE KO mice, AxC DKO mice exhibited improved liver function, reduced ROS and MDA, increased SOD activity and GSH/GSSG ratio, and reduced inflammatory markers, without altering hepatic lipid deposition. Proteomic analysis revealed that calpain-1 deficiency partially restored antioxidant protein expression, attenuated the upregulation of CYP450 metabolic enzymes, normalized mitochondrial protein abnormalities, and reduced inflammation-related protein expression.
CONCLUSIONS: Calpain-1 deficiency alleviates MASH-related liver injury by modulating redox homeostasis, reducing oxidative stress and inflammatory, independent of directly lowering hepatic lipid accumulation.