Physiological roles of phosphoinositides and inositol phosphates: Implications for metabolic dysfunction-associated steatotic liver disease.

Phosphoinositides and inositol phosphates (IPs) are integral to numerous cellular processes, including membrane trafficking, signal transduction and calcium dynamics. These lipid-derived signalling mediators orchestrate the spatial and temporal regulation of many signalling cascades, largely through interactions with specific effector proteins. Recent studies have highlighted their critical roles in metabolic homeostasis and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we examine the pathways important for phosphoinositide and IP synthesis, and the physiological functions of myo-inositol, d-chiro-inositol and phosphatidylinositol, as well as their phosphorylated inositol counterparts, including phosphoinositides (PI(3)P, PI(4)P, PI(3,4)P2, PI(3,5)P2, PI(4,5)P2, PI(3,4,5)P3) and IPs (inositol 1,4,5-trisphosphate (IP3), inositol 1,3,4,5-tetrakisphosphate (IP4), inositol pentakisphosphate (IP5), inositol hexaphosphate (IP6 or phytic acid) and inositol pyrophosphates (IP7 and IP8)), with an emphasis on their emerging significance in hepatic metabolism. We explore how perturbations in IP metabolism contribute to the development and progression of MASLD, liver inflammation, fibrosis and hepatic insulin resistance. We further highlight recent studies utilizing genetic models and pharmacological interventions that underscore the therapeutic potential of targeting inositol metabolism in MASLD. This review synthesizes current knowledge to provide a comprehensive understanding of how phosphoinositides and IPs integrate metabolic cues and contribute to hepatic pathophysiology, identifying knowledge gaps and offering novel insights for therapeutic innovation in the management of MASLD.