promotes liver sinusoidal endothelial cell dysfunction and induces macrophage M1 polarization in non-alcoholic fatty liver disease.

Background: The progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and liver fibrosis remains poorly understood, though liver sinusoidal endothelial cells (LSECs) are thought to play a central role in disease pathogenesis.

Aim: To investigate the role of in NAFLD fibrosis through its regulation of LSEC dysfunction and macrophage polarization.

Methods: We analysed single-cell transcriptomic data (GSE129516) from NASH and normal mouse models and identified as a key regulator in LSECs. and experiments were conducted to validate the functional role of . Human LSECs were cultured and transfected to overexpress , and evaluated using flow cytometry, enzyme-linked immunosorbent assay, and quantitative polymerase chain reaction. NAFLD mice were used to assess expression and its effects on LSEC dysfunction, endothelial-mesenchymal transition (EndMT), and microvascularization.

Results: Single-cell analysis revealed that mediates intercellular communication between LSECs and macrophages the tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (FN14) signalling pathway, promoting M1 macrophage polarization and exacerbating liver fibrosis. studies revealed that overexpression in LSECs exacerbated endothelial dysfunction and M1 polarization, whereas TWEAK inhibition attenuated these effects. Mechanistically, drives LSEC microvascularization and EndMT through the TWEAK/FN14 pathway, leading to increased secretion of pro-inflammatory cytokines and M1 macrophage polarization. , experiments demonstrated that inhibition adeno-associated virus serotype 8-short hairpin RNA reduced NAFLD progression and liver fibrosis.

Conclusion: Our findings indicate a pivotal role of in NAFLD fibrosis, demonstrating its dual function in regulating LSEC dysfunction and inflammatory responses. may be a promising target for the treatment and the prevention and management of NAFLD progression to fibrosis.