Lipotoxicity in MAFLD/MASH: cellular mechanisms and targetable nodes

Metabolic dysfunction-associated fatty liver disease (MAFLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis (MASH), are now considered to be systemic metabolic disorders driven by dysregulated lipid signaling, not simply by neutral lipid accumulation, which has traditionally been regarded as the principal mechanism underlying MAFLD/MASH. Recent research evidence indicates that bioactive lipid species function within an organized system of space and time in which their subcellular origin, trafficking, and intercellular transfer determine cellular fate. Despite this, the present models of lipotoxicity that have shaped the understanding of MAFLD/MASH are still largely pathway-centric and do not fully reflect the importance of the intracellular organization of lipids and the dynamic communication between organelles. Here we review emerging insights into the spatial and time-dependent architecture of lipid signaling, with an emphasis on how organelle crosstalk and membrane contact sites coordinate lipid metabolism and cellular stress responses. Then we discuss the role of lipid-mediated intercellular communication in inflammation and fibrotic remodeling through extracellular vesicles and systemic metabolic interactions. Finally, we address therapeutic approaches targeting lipid signaling pathways and organelle-specific processes. By reframing MAFLD/MASH as a disorder of disrupted intra- and intercellular lipid communication, this review provides a conceptual framework for understanding disease progression and developing more precise, mechanism-based therapies.