Chronic liver disease (CLD) remains a major global health burden, driven by persistent hepatic injury that triggers inflammation, vascular dysfunction and progressive extracellular matrix (ECM) deposition. These processes disrupt the liver architecture, leading to advanced liver fibrosis or cirrhosis and increasing the risk of severe complications such as portal hypertension, hepatocarcinoma and even death. While fibrosis and cirrhosis were historically regarded as irreversible, accumulating experimental and clinical evidence now support the potential for fibrosis and even cirrhosis regression once the etiological insult is controlled. Nevertheless, fibrosis regression is not universally observed: about 25% of patients with advanced CLD and sustained hepatitis B virus suppression and over one-third of those with metabolic dysfunction-associated steatotic liver disease after bariatric surgery fail to experience fibrosis regression. Notably, fibrosis regression is often partial and slower in advanced CLD or cirrhosis, especially in decompensated stages, highlighting the need for a better understanding of the cellular and molecular mechanisms that either facilitate or restrict hepatic tissue repair. This review summarizes current knowledge on the dynamics of liver fibrosis regression, with a particular emphasis on the liver sinusoidal endothelial cell (LSEC) as a central regulator of the microenvironment. We discuss how LSEC phenotype determines interactions with hepatic stellate cells (HSCs), immune cells, and hepatocytes, thereby shaping the balance between fibrogenesis and resolution. Mechanisms such as endothelial capillarization, macrophage-driven inflammation, HSC activation and hepatocyte regeneration are examined in the context of both disease progression and regression. Special attention is given to vascular alterations, which represent a major limiting factor for recovery in advanced CLD. We also highlight recent experimental advances, including insights from extracellular vesicle-mediated communication, microenvironmental stiffness, transcriptomic studies of LSEC plasticity during regression, and novel biomarkers of fibrosis regression. Understanding the spatiotemporal orchestration of these processes may inform novel therapeutic strategies aimed at restoring vascular and parenchymal homeostasis, ultimately enabling fibrosis reversal, portal pressure reduction, and improved clinical outcomes in patients with advanced CLD.
Mendoza et al. (Fri,) studied this question.