American journal of translational research · 2026
MCT4 alleviates lipid accumulation, inflammation and PANoptosis in non-alcoholic fatty liver disease by inhibiting JAK-STAT signaling transduction.
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Wu Bing, Xu Hao, Zeng Yuqiao, Shen Ao, Zhang Cheng, Wu Pengfei, Zhang Xinyue, Zhang Han, He Yiyu, Wang Likun
Аннотация
OBJECTIVES: To investigate the role of monocarboxylate transporter 4 (MCT4) in non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms.
METHODS: Palmitic acid (PA) was used to stimulate L-02 cells, establishing an in vitro lipid accumulation model, and the effects of MCT4 overexpression on cell lipid accumulation, inflammatory response, and PANoptosis were analyzed. Mechanistically, the role of JAK1-STAT3 in NAFLD was explored by introducing the JAK1 activator Oncostatin. In addition, a NAFLD mouse model was established through a high-fat diet to validate the effects of MCT4 on liver lipid metabolism and inflammatory injury in vivo.
RESULTS: After PA treatment, the levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in cells increased, while the level of high-density lipoprotein cholesterol (HDL-C) decreased. The expression of lipid synthesis-related genes was upregulated, while the expression of lipid breakdown-related genes was downregulated. Similarly, PA induced cellular inflammatory infiltration and PANoptosis. However, overexpression of MCT4 reversed PA induced lipid accumulation and inflammatory response. Mechanistic studies demonstrated that MCT4 alleviated PA-induced lipid accumulation and inflammatory response by reducing the phosphorylation levels of JAK1 and STAT3. Compared with the model group, mice overexpressing MCT4 showed reduced liver tissue damage.
CONCLUSIONS: MCT4 provides new reference for the treatment of NAFLD by inhibiting the JAK-STAT pathway, slowing down lipid accumulation and inflammatory response in NAFLD.
METHODS: Palmitic acid (PA) was used to stimulate L-02 cells, establishing an in vitro lipid accumulation model, and the effects of MCT4 overexpression on cell lipid accumulation, inflammatory response, and PANoptosis were analyzed. Mechanistically, the role of JAK1-STAT3 in NAFLD was explored by introducing the JAK1 activator Oncostatin. In addition, a NAFLD mouse model was established through a high-fat diet to validate the effects of MCT4 on liver lipid metabolism and inflammatory injury in vivo.
RESULTS: After PA treatment, the levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in cells increased, while the level of high-density lipoprotein cholesterol (HDL-C) decreased. The expression of lipid synthesis-related genes was upregulated, while the expression of lipid breakdown-related genes was downregulated. Similarly, PA induced cellular inflammatory infiltration and PANoptosis. However, overexpression of MCT4 reversed PA induced lipid accumulation and inflammatory response. Mechanistic studies demonstrated that MCT4 alleviated PA-induced lipid accumulation and inflammatory response by reducing the phosphorylation levels of JAK1 and STAT3. Compared with the model group, mice overexpressing MCT4 showed reduced liver tissue damage.
CONCLUSIONS: MCT4 provides new reference for the treatment of NAFLD by inhibiting the JAK-STAT pathway, slowing down lipid accumulation and inflammatory response in NAFLD.