Calcium imbalance drives organelle network collapse and immune remodeling: novel pathogenic mechanisms in MASLD...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is initiated by ectopic lipid accumulation, but the precise mechanochemical transducers driving its progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis remain incompletely understood. This review comprehensively elucidates the central pathogenic role of intracellular calcium signaling dysregulation in MASLD. We detail how the metabolically toxic microenvironment induces pathological biophysical remodeling of lipid rafts and key calcium transporters across the plasma membrane (PM), endoplasmic reticulum (ER), and mitochondria. This pervasive transmembrane and inter-organellar calcium imbalance precipitates severe organelle network collapse, characterized by calcium depletion-driven ER stress, mitochondrial dysfunction, and the structural derangement of mitochondria-associated ER membranes (MAMs). Aberrant calcium fluxes function as critical secondary messengers that dictate hepatic immune microenvironment remodeling, at the cellular level driving Kupffer cell pro-inflammatory polarization, NLRP3 inflammasome assembly, and the amplification of damage-associated molecular patterns (DAMPs). These calcium-dependent immune-metabolic feedback loops synergistically trigger hepatic stellate cell (HSC) transdifferentiation and fibrogenesis. Finally, we highlight the latent calcium-regulatory mechanisms of current metabolic therapeutics and prospect the translational potential of targeted calcium modulators coupled with advanced nanodelivery systems, advocating for multi-targeted pharmacological strategies to arrest irreversible liver injury.