Liver Lymphatic Dysfunction as a Driver of Fibrosis and Cirrhosis Progression

Abstract 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-β 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. Competing Interest Statement The authors have declared no competing interest. Footnotes Conflict of interest statement The authors declare no competing interests. Financial supports: This work was funded by NIH grants (R01DK121511, 1R01DK117597, 1R21AA031400 and R01 DK135303) to YI; (K08AA029182) to MJM. We would like to thank the Yale Liver Center for the resources (5P30DK034989-37).