Fucoxanthin Suppresses Lipid Accumulation and Inflammatory Responses in FFA-Induced Hepatocyte Models via the EGR2-CD36 Axis

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited treatment options. Here, we demonstrate that fucoxanthin (FUCO), a natural marine carotenoid, attenuates free fatty acid (FFA)-induced hepatocellular steatosis and inflammatory responses in vitro by targeting the EGR2-CD36 axis (EGR2, early growth response protein 2; CD36, cluster of differentiation 36). In FFA-induced hepatocyte models (HepG2, Hep3B, and AML12), FUCO significantly reduced lipid accumulation and inflammatory markers without cytotoxicity. Mechanistic studies revealed that FUCO specifically inhibited fatty acid uptake and transport by downregulating CD36, while triglyceride (TG) degradation remained unaffected. RNA sequencing identified EGR2 as a master regulator induced by FFA and suppressed by FUCO. Functional validation showed that EGR2 overexpression completely blocked FUCO’s lipid-lowering effects and restored CD36 expression, confirming that FUCO acts through EGR2-dependent CD36 inhibition. Bioinformatic analysis further supported EGR2-mediated regulation of CD36 via tumor necrosis factor (TNF) and sterol regulatory element-binding factor (SREBF) pathways. Collectively, our findings establish EGR2 as a critical molecular target for FUCO and provide mechanistic insights that may support its further evaluation in preclinical models for MASH therapy.