MSR1
Drives
MASLD
Progression Via Disrupting
FoxO3a
‐
SOD3
Mediate
Wei Sheng, Ziqi Zhang, Deji Song, Yunshu Shen, Xuming Zhang, Yingying Xiang, Lili Lu, Chunlin Li, Cheng Liu, Guang Ji, Li Zhang ABSTRACT
Background and Aims
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.
Methods
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.
Results
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.
Conclusions
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.