Fucoidan from Fucus vesiculosus alleviates MetALD via promoting HIF-1α ubiquitination to suppress peripheral monocyte infiltration

Li Lei^1*Jialiang Luo²Di Wang³Yuan Chang⁴Chaohui Duan¹Daming Zuo²

• ¹Sun Yat-sen Memorial Hospital, Guangzhou, China
• ²Southern Medical University, Guangzhou, Guangdong, China
• ³Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China
• ⁴Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China

Metabolic and alcohol-related liver disease (MetALD), characterized by excessive alcohol intake in individuals with metabolic dysfunction, is a growing health burden worldwide. Hepatic macrophages play a pivotal role in MetALD pathogenesis, with pro-inflammatory infiltrating monocytes/macrophages contributing to liver injury.Fucoidan, a sulfated polysaccharide derived from brown algae, is known for its antiinflammatory properties, yet its intracellular targets remain poorly defined. Here, we identify prolyl hydroxylase domain-containing protein 2 (PHD2) as a novel intracellular binding partner of fucoidan. Using a high-fat diet plus ethanol-induced MetALD mouse model, we demonstrate that fucoidan significantly attenuates hepatocyte injury, steatosis, and peripheral monocyte infiltration in a dose-dependent manner. In vitro, fucoidan markedly suppressed ethanol-and LPS-induced THP-1 monocyte migration. Mechanistically, we show that fucoidan binds directly to PHD2, enhancing proteasome-mediated ubiquitination and degradation of HIF-1α, a key transcription factor driving monocyte recruitment and inflammation. Our findings reveal a previously unrecognized mechanism by which fucoidan exerts its antiinflammatory effects via targeting the PHD2-HIF-1α axis, offering a promising therapeutic strategy for MetALD.