Abstract / Summary
Liver fibrosis is a common consequence of chronic liver injury and is driven not only by extracellular matrix accumulation but also by disruption of the hepatic sinusoidal microenvironment. Liver sinusoidal endothelial cells (LSECs) are specialized endothelial cells that maintain sinusoidal homeostasis, and their dysfunction is increasingly recognized as an important contributor to fibrotic progression. In this study, we investigated whether LSECs undergo senescence-associated phenotypic remodeling during CCl₄-induced liver fibrosis and explored potential regulatory mechanisms involved in this process. Using mouse models of CCl₄-induced liver fibrosis and natural aging, we found that fibrotic LSECs exhibited loss of fenestrae, impaired scavenging function, enhanced capillarization, altered paracrine profiles, and increased expression of senescence markers. These changes partially overlapped with abnormalities observed in LSECs from naturally aged mice, suggesting that fibrotic stress is associated with an aging-like endothelial phenotype. Transcriptomic analysis of fibrotic LSECs further revealed that dysregulation of the AMPK–SIRT1/p53 axis may contribute to these phenotypic alterations. In vivo, systemic pharmacological activation of AMPK with AICAR was associated with partial restoration of AMPK–SIRT1/p53 signaling in LSECs, attenuation of sinusoidal capillarization, and improvement of liver fibrosis, supporting LSEC senescence-related pathways as potential therapeutic targets for liver fibrosis.