Hypoxia-preconditioned bone marrow mesenchymal stem cells alleviate acute liver failure by regulating the VEGF/c-MET pathway

Background Acute liver failure (ALF) carries a high mortality with few treatments. Although bone marrow-derived mesenchymal stem cells (BMSCs) hold therapeutic promise, their efficacy is limited by the hostile liver milieu. Hypoxia preconditioning (HP) enhances BMSC adaptability. This study investigated HP-BMSCs for ALF, focusing on the VEGF/c-MET pathway and B-cell immunity. Methods Mouse BMSCs were cultured under normoxia (21% O ₂ ) or HP (1% O ₂ ) for 4 hours (h). Western blot and Q-PCR were used to detect the expression levels of HIF-1α, VEGF and c-Met. ALF model was induced in C57BL/6J mice using D-galactosamine/LPS. Animals were randomized into Control, ALF, ALF + normoxic - BMSC, or ALF + HP-BMSC groups (n = 6). Cells were transplanted via tail vein 4h post-modeling; samples were collected 4h later. Assessments included liver function, cytokines, histology, and molecular/immunological analyses. Results HP upregulated HIF-1α, VEGF, c-MET, and PCNA in BMSCs ( P  < 0.01). In ALF mice, HP-BMSCs outperformed normoxic BMSCs, reducing liver injury, restoring function (ALT, AST, TBIL), and attenuating inflammation ( P  < 0.01). HP-BMSCs activated the hepatic VEGF/c-MET axis (upregulated VEGF, HGF-α, c-Met) and enhanced regeneration ( P  < 0.01). Notably, they modulated intrahepatic B-cells, reducing CD45R+ infiltration while increasing regulatory CD24 + CD38+ subsets. Conclusions Our research indicates that HP potentiates BMSCs for ALF primarily via VEGF/c-MET activation, enhancing their proliferative and paracrine capacities. The therapy synergistically promotes regeneration, suppresses inflammation, and reprograms intrahepatic immunity via B-cell modulation.