Cholesterol-rich diet exacerbates steatohepatitis in the STAM mouse model

Suitable animal models are crucial for therapeutic development, yet many fail to reproduce progression to fibrosing MASH. Here, we employed the STAM model in male C57BL/6J mice to simulate MASLD and investigated whether a high-fat, high-cholesterol (HFHC) diet would intensify disease progression compared with the standard high-fat (HF) diet.

HFHC feeding in the STAM model accelerated hepatic lipid accumulation, crown-like structure formation, inflammation, and fibrosis, as demonstrated by histological analyses. Transcriptomic profiling and pathway enrichment confirmed activation of lipid and cholesterol metabolism, regulation of TNF production, and inflammatory signaling. Reactome analysis further indicated alterations in extracellular matrix formation and immune system pathways, consistent with advanced fibrotic progression.