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.
