Lonidamine ameliorates MASH by reducing SREBP1 and inhibiting the MAPK pathway
Yuhan Chen1, Feiyan Pan2, Lusheng Tang3
1Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China.
Abstract:
Metabolic dysfunction-associated steatohepatitis (MASH) has become a global epidemic, and effective therapeutic strategies are urgently needed. Lonidamine (LND) has been reported to possess anti-inflammatory effects; however, few studies have investigated whether LND exerts a therapeutic effect on MASH. Therefore, in this study, we aim to explore the effects of LND on inflammatory responses and abnormal lipid metabolism in MASH mice. A mouse MASH model is established by feeding C57BL/6 mice a high-fat, high-cholesterol (CL) diet. The results show that LND attenuates CL-induced increases in body weight, serum glucose and lipid levels, inflammatory responses, and hepatocellular steatosis. In addition, the mitogen-activated protein kinase (MAPK) signaling pathway is inhibited, and the expression level of sterol regulatory element-binding protein 1 (SREBP1) protein is significantly reduced. Meanwhile, in vitro models of cellular inflammation and lipid metabolism are simulated, and molecular docking and biolayer interferometry (BLI) analysis are used to verify that LND and SREBP1 have a direct interaction and that LND promotes the degradation of SREBP1. Furthermore, specific knockdown of Srebp1 in AML12 cells is performed to further verify the effect of LND on MASH. The results confirm that LND exerts anti-inflammatory effects in MASH by inhibiting the activity of the MAPK signaling pathway and improves abnormal lipid metabolism through its interaction with SREBP1. Overall, LND holds promise as a potential therapeutic agent for the treatment of MASH.
Insights
Lonidamine (LND) shows therapeutic potential for metabolic dysfunction-associated steatohepatitis (MASH). It reduces inflammation and improves lipid metabolism by inhibiting the MAPK pathway and interacting with SREBP1.
Area of Science:
- Hepatology
- Metabolic Disorders
- Pharmacology
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern requiring novel therapeutic interventions.
- Lonidamine (LND) exhibits anti-inflammatory properties, but its efficacy in treating MASH remains largely unexplored.
Purpose of the Study:
- To investigate the therapeutic effects of Lonidamine (LND) on inflammatory responses and lipid metabolism in a mouse model of MASH.
- To elucidate the underlying molecular mechanisms of LND action in MASH.
Main Methods:
- A MASH mouse model was induced using a high-fat, high-cholesterol diet.
- In vitro cell models were employed to simulate inflammation and lipid metabolism.
- Molecular docking and biolayer interferometry (BLI) were used to assess LND-SREBP1 interaction.
- Specific knockdown of SREBP1 was performed in AML12 cells.
Main Results:
- LND treatment attenuated MASH-related increases in body weight, serum glucose, and lipid levels.
- LND significantly reduced hepatic steatosis and inflammatory responses in MASH mice.
- LND inhibited the MAPK signaling pathway and promoted SREBP1 degradation.
- Direct interaction between LND and SREBP1 was confirmed, improving lipid metabolism.
Conclusions:
- Lonidamine (LND) demonstrates significant therapeutic potential for MASH by reducing inflammation via MAPK pathway inhibition.
- LND improves abnormal lipid metabolism through direct interaction and promotion of SREBP1 degradation.
- LND represents a promising candidate for MASH treatment, warranting further clinical investigation.
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