Fucoxanthin Ameliorates MASLD by Directly Targeting GRP78 to Restore ER Homeostasis and Activate AMPK Signaling

mice and palmitic acid-induced HepG2 cells, fucoxanthin treatment significantly alleviated hepatic steatosis and suppressed ER stress. Mechanistically, the fucoxanthin-GRP78 interaction was found to be indispensable for the subsequent activation of AMP-activated protein kinase (AMPK) signaling. Notably, siRNA-mediated knockdown of GRP78 or pharmacological inhibition of AMPK completely abolished the lipid-lowering and ER stress-relieving effects of fucoxanthin, confirming a causal GRP78-AMPK axis. This study elucidates a novel target-driven mechanism wherein fucoxanthin acts as a GRP78 ligand to restore ER homeostasis and reprogram lipid metabolism. These findings position the fucoxanthin-GRP78 axis as a specific therapeutic target for nutritional strategies against MASLD.