Inositol hexaphosphate and inositol prevent WD/CCl₄-induced metabolic dysfunction-associated steatohepatitis in mice

Given the significant clinical and economic burden of metabolic dysfunction-associated steatohepatitis (MASH), there is an urgent imperative to develop effective preventive and therapeutic agents. In this study, we evaluated the preventive effects and potential mechanisms of plant-derived compounds inositols (INS) and inositol hexakisphosphate (IP6) against MASH, utilizing a mouse model induced by western diet combined with low doses of CCl₄ (WD/CCl₄). The results showed that pretreatment with IP6 or INS significantly reduced obesity, fibrosis and lipid accumulation, alleviated insulin resistance, and prevented hyperglycemia in MASH mice. Both IP6 and INS also alleviated free fatty acid (FFA)- induced lipid accumulation in HepG2 cells. Transcriptomics analysis of the liver revealed that IP6 and INS reversed MASH-related transcriptomic changes, suppressing the expression of pro-fibrotic, pro-inflammatory, and lipid-metabolic genes. Integrated metabolomics and lipidomics revealed that the preventive effect of IP6 and INS against MASH was mediated through the rectification of disordered glycerophospholipid metabolism. Notably, knockdown of PEMT expression abolished the inhibitory effects of IP6 and INS on lipid accumulation, as well as α-SMA and COL-1 expression, in in vitro assays. These findings provide evidence that both IP6 and INS can prevent the development of MASH by improving disorders in glycerophospholipid metabolism, at least partially through the upregulation of PEMT.