Resident CD24+LCN2+ Liver Progenitor Cells Aggravate Fibrosis and Inflammatory Progression via Recruitment of TPPP3+COL10A1+ Macrophages in Non-Alcoholic Steatohepatitis

• • Resident CD24+LCN2+ LPCs are significantly enriched in NASH patients, with scRNA-seq data showing a >2-fold increase compared to healthy controls (p < 0.01), indicating their potential as a biomarker for NASH progression and a target for anti-fibrotic therapy. • • CellChat and NicheNet analyses predict strong interactions between LPCs and proinflammatory macrophage subtypes, with MP-2 identified as the primary recipient of LPC-derived signals, exhibiting hyperactivation of the NF-κB pathway (fold change >3, p < 0.001), which correlates with fibrosis severity. • • The macrophage subtype MP-2 markers COL10A1 and TPPP3 are validated in human NASH liver samples and mouse models (CDAHFD and HFD), with COL10A1 expression showing a 4.5-fold increase in NASH livers (p < 0.0001), providing a potential diagnostic and therapeutic target. • • NASH livers recruit PBMC-derived macrophages and polarize them into proinflammatory subtypes, with MP-2 frequency increasing from 5% to 25% of total macrophages (p < 0.01), highlighting a mechanism for macrophage-driven inflammation and fibrosis that could be targeted to halt NASH progression.