MFN2 is downregulated in livers of MASLD patients. Impaired IP3R-GRP75-VDAC/MCU-mediated PS transfer is observed in HFD-fed mouse and yellow catfish models. Upregulating Mfn2 in HFD mouse models restores MAMs and improves lipid metabolism. Imbalanced Mfn2/Grp75 expression causes lipid accumulation via different mechanisms (ER stress or mitochondrial dysfunction). This evidence concerns the gene HSPA9 and metabolic dysfunction-associated steatotic liver disease.