Inhibiting CXCR6 promotes senescence of activated hepatic stellate cells with limited proinflammatory SASP to attenuate hepatic fibrosis

TL;DR

Blocking CXCR6 causes liver cells to age and reduces harmful inflammation, offering a new way to treat liver scarring.

Contribution

This study reveals CXCR6 as a novel therapeutic target for hepatic fibrosis by inducing senescence and limiting SASP.

Findings

CXCR6 is significantly upregulated in fibrotic liver samples and murine models.

CXCR6 inhibition promotes aHSC senescence and reduces pro-inflammatory SASP.

The mechanism involves modulation of the IL-1α/NF-κB feedback loop.

Abstract

This study investigates the previously unexplored role of CXC chemokine receptor 6 (CXCR6) in hepatic fibrosis, where excessive extracellular matrix deposition by activated hepatic stellate cells (aHSCs) drives disease progression. Through analysis of gene expression omnibus datasets and human fibrotic liver samples, we identified significant CXCR6 upregulation, subsequently validated in murine fibrosis models. Using quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry, we demonstrated that CXCR6 silencing in vitro promoted aHSC senescence – as confirmed by senescence-associated β-galactosidase staining and Cell Counting Kit-8 assays – while simultaneously restricting the pro-inflammatory senescence-associated secretory phenotype (SASP). Mechanistically, the enzyme-linked immunosorbent assay revealed this process involves modulation of the interleukin-1 alpha/nuclear factor-kappa beta feedback loop. Our findings position CXCR6 inhibition as a promising therapeutic strategy that uniquely targets both fibrogenesis (through hepatic stellate cell senescence induction) and inflammation (via SASP regulation) in hepatic fibrosis.

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