Sinusoidal endothelial cells control liver inflammation and fibrosis
Yingfen Chen, Yong He
Yingfen Chen, Yong He
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Commentary

Sinusoidal endothelial cells control liver inflammation and fibrosis

Abstract

Liver fibrosis is a common pathological outcome of chronic liver disease and is driven by inflammatory responses. However, the early signals that initiate the inflammatory cascade remain poorly understood. Emerging evidence suggests that liver sinusoidal endothelial cells (LSECs) are not merely passive bystanders, but active regulators during liver fibrosis. In this issue of the JCI, Gan et al. demonstrated in multiple preclinical models that BRD4/PML-mediated super-enhancer activation in LSECs drives proinflammatory angiocrine signaling, thereby initiating liver fibrosis. Thus, targeting this endothelial axis may offer a promising therapeutic strategy for the treatment of liver fibrosis.

Authors

Yingfen Chen, Yong He

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Figure 1

Roles of LSECs in liver fibrosis.

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Roles of LSECs in liver fibrosis. (A) LSECs line the hepatic sinusoids a...
(A) LSECs line the hepatic sinusoids and maintain liver homeostasis by facilitating substance exchange, preserving Kupffer cell identity, and supporting immune tolerance. Endothelial regulators, including GATA4, ZEB2, RUNX3, POFUT1, and RAP1A, help preserve LSEC homeostasis and restrain liver fibrosis, whereas ROCK2-selective inhibition with TDI01 represents a potential antifibrotic strategy. (B) Upon liver injury, loss of fenestrae and development of a basement membrane drive sinusoidal capillarization, and capillarized LSECs can further undergo partial endothelial-to-mesenchymal transition, resulting in enhanced profibrotic angiocrine signaling and excessive extracellular matrix deposition. Injured LSECs can also adopt a proinflammatory phenotype, with increased expression of CXCL1, CCL2, and VCAM-1, thereby contributing to inflammatory cell recruitment and fibrogenesis. (C) Notably, as Gan et al. (18) reported in this issue of the JCI, BRD4/PML-driven epigenetic rewiring in TIMP1+ LSECs promotes super-enhancer–dependent inflammatory gene activation, recruits CD63+ monocyte-derived macrophages, and amplifies inflammation, finally aggravating liver fibrosis.