代谢功能障碍,脂肪性肝 z-bio 2025-03-28 397

　　Schematic diagram of SMPD3 as a lipophilic receptor disrupting the balance of cell membrane lipid metabolism and promoting the progression of MASH

　　Supported by the National Natural Science Foundation of China (Grant No.: 82222071, 22337003, 82322063), Xie Cen, a researcher from the Chinese Academy of Sciences Shanghai Institute of Materia Medica, Xie Qing, a professor from Ruijin Hospital affiliated to Shanghai Jiaotong University, Liu Hong, a researcher from the Chinese Academy of Sciences Shanghai Institute of Materia Medica, and Liu Yameng, an associate researcher, cooperated to make progress in the research of original drug targets for steatohepatitis related to metabolic dysfunction. The relevant results were published online on February 26, 2025 in the journal Cell Metabolism under the title "Liver sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism". Paper link: https://www.cell.com/cell-metabolism/fulltext/S1550-4131 (25)00016-6。

　　Metabolic dysfunction associated steatohepatitis (MASH) is the main cause of cirrhosis and liver cancer, affecting approximately 25% of adults worldwide, and there is currently a lack of effective intervention methods. MASH is characterized by fatty degeneration, hepatocyte ballooning, inflammation, and fibrosis as its main pathological features. Although inhibiting de novo lipid synthesis can effectively reduce liver lipid accumulation, its effectiveness in preventing the progression of MASH varies, and comprehensive inhibition of lipid synthesis may affect membrane system stability and exacerbate liver damage. Therefore, the core driving factor for the deterioration of MASH may not be the total lipid burden, but rather the pathological cascade reactions triggered by specific toxic lipids. Sphingolipids and their core metabolite ceramide are considered key molecules involved in lipid toxicity, but the changes in the sphingolipid metabolic network during MASH progression have not been elucidated.

　　The research team analyzed the sphingolipid profile of MASH patients and mouse models, and determined that sphingomyelin phosphodiesterase 3 (SMPD3) on the cell membrane is a key driving factor in promoting the accumulation of ceramides in MASH liver. Although SMPD3 expression is extremely low in healthy liver, lipotoxicity induced DNA damage triggers pathological upregulation of SMPD3 during MASH by inhibiting sirtuin 1 (SIRT1); SMPD3 enhances pit dependent lipid uptake and extracellular vesicle secretion in steatotic liver cells by disrupting the balance of sphingolipid metabolism in the small pit area of the cell membrane, thereby exacerbating inflammation and fibrosis and promoting disease progression. Therefore, the study proposes that SMPD3 is the central hub and potential therapeutic target connecting key pathological features of MASH; Through further small molecule compound dual target design and activity screening, dual target compounds that simultaneously activate SIRT1 and inhibit SMPD3 were discovered, demonstrating therapeutic potential superior to single target drugs in various MASH animal models (Figure).

　　This study reveals that the imbalance of hepatic cell membrane lipid metabolism is an important characteristic of MASH progression, and proposes precise intervention of hepatic SMPD3 to restore membrane lipid metabolism or help improve MASH. This research provides potential original drug targets and lead compounds for the treatment of MASH.