MSR1 Drives MASLD Progression Via Disrupting FoxO3a-SOD3 Mediated Redox Balance in Liver Macrophages

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are globally prevalent conditions with limited therapeutic options. While macrophage scavenger receptor 1 (MSR1) is implicated in lipid uptake and inflammation, its role in MASLD pathogenesis remains poorly defined.

MSR1 expression was analyzed using public databases and diet-induced animal models. Myeloid-specific Msr1 knockout (Msr1^ΔMφ) mice were generated to investigate the specific function of MSR1. In vitro, oxidized low-density lipoprotein (ox-LDL)-stimulated primary mouse hepatic macrophages and bone marrow-derived macrophages were analyzed to explore potential mechanisms. Finally, an MSR1 inhibitor was employed to demonstrate therapeutic potential.

MSR1 was upregulated in liver tissues and hepatic macrophages of MASLD/MASH patients and mice. Msr1^ΔMφ mice exhibited significant attenuation of steatosis, inflammation, and fibrosis in comparison to wild-type littermates. In vitro, ox-LDL induced MSR1 expression, triggering lipid accumulation and pro-inflammatory cytokine release. Mechanistically, Msr1 deficiency upregulated the antioxidant enzyme superoxide dismutase 3 (SOD3) by inhibiting the PI3K/AKT/FoxO3a pathway, and these protective effects were blunted by Sod3 knockdown. Conversely, Sod3 overexpression ameliorated metabolic inflammation. Notably, pharmacological inhibition of MSR1 by fucoidan markedly attenuated the progression of diet-induced MASLD in mice.

MSR1 promotes MASLD progression by mediating ox-LDL uptake in hepatic macrophages, which in turn exacerbates hepatic inflammation and fibrosis via PI3K/AKT/FoxO3a-dependent suppression of SOD3. Targeting MSR1 or its downstream pathway represents a promising novel therapeutic strategy for treating MASLD and MASH.