Cai, S.-Y. | bioRxiv Science

bioRxiv2025

Liver Lymphatic Dysfunction as a Driver of Fibrosis and Cirrhosis Progression

The liver lymphatic system plays a critical role in maintaining interstitial fluid balance and immune regulation. Efficient lymphatic drainage is essential for liver homeostasis, but its role in liver disease progression remains poorly understood. In cirrhosis, lymphangiogenesis initially compensates for increased lymph production, but impaired lymphatic drainage in advanced stages may lead to complications such as ascites and portal hypertension. This study aimed to evaluate how liver lymphatic dysfunction affects disease progression and to assess therapeutic strategies. Using a surgical model to block liver lymphatic outflow, we found that impaired drainage accelerates liver injury, fibrosis, and immune cell infiltration, even in healthy livers. Mechanistically, enhanced TGF-{beta} signaling in liver lymphatic endothelial cells (LyECs) contributed to reduced lymphatic vessel (LV) density and function in late-stage decompensated cirrhosis. This dysfunction was linked to the progression from compensated to decompensated cirrhosis, particularly in patients with primary sclerosing cholangitis (PSC). Conversely, liver-specific overexpression of VEGF-C via AAV8 improved lymphatic drainage, restored LV density, reduced fibrosis, mitigated liver injury, and alleviated portal hypertension in cirrhotic rats. These findings establish impaired liver lymphatic function as a pivotal driver of cirrhosis progression and identify VEGF-C as a promising therapeutic target to prevent decompensation.

pathology↗

bioRxiv2020

Hepatic NFAT signaling regulates the expression of inflammatory cytokines in cholestasis

The inflammatory response plays an important role in cholestatic liver injury where bile acid (BA) induction of proinflammatory cytokines in hepatocytes is an initial pathophysiologic event. However, the signaling pathways involving BA stimulation of cytokine production remain to be elucidated. In this report, we examined the functional role of the Nuclear Factor of Activated T-cells (NFAT) in BA-induction of inflammatory genes in hepatic cells and cholestatic livers. We found that NFAT isoform c1 and c3 were expressed in human and mouse hepatocytes. When treated with cholestatic levels of BA, both human and mouse hepatocytes but not cholangiocytes increased NFATc3 nuclear translocation, associated with elevated mRNA levels of IL-8, Cxcl2, and Cxcl10 in these cells. Blocking NFAT activation with pathway-specific inhibitors (i.e. cyclosporine A, FK-506, KN-62 and Inca-6) or knocking down Nfatc3, significantly repressed BA-induction of these cytokines in mouse hepatocytes, including Ccl2, Cxcl2, Cxcl10, Icam1 and Egr1. Nuclear expression of NFATc3/Nfatc3 protein was also increased in cholestatic livers after bile duct ligation or in Abcb4-/- mice and in patients with primary biliary cholangitis and primary sclerosing cholangitis in association with tissue elevations of Cxcl2 and IL-8. Gene reporter assays and ChIP-PCR demonstrated that the NFAT response element in its promoter played a key role in BA-induced human IL-8 expression. Together our findings indicate that NFAT plays an important role in BA stimulation of hepatic cytokines in cholestasis and is a mechanism that may provide novel targets to reduce cholestatic liver injury.

molecular biology↗