TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease

Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in patients with alcohol-associated liver disease (ALD), but how LSEC alteration contributes to the pathogenesis of ALD remains unclear. Here, we found that the hepatic level of thioredoxin interacting protein (TXNIP) was up-regulated in ALD patients and ethanol diet-fed mice with high expression in LSECs. Notably, endothelial cell-specific Txnip deficiency in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma (HCC) development. Deletion of Txnip in LSECs led to sinusoidal capillarization, down-regulation of endothelial nitric oxide synthase (eNOS) level and nitric oxide (NO) production, and increased release of pro-inflammatory cytokines and adhesion molecules. Mechanistically, TXNIP interacted with transforming growth factor ?-activated kinase 1 (TAK1) and subsequently suppressed TAK1/c-Jun N-terminal kinase (JNK) pathway. Inhibition of TAK1 activation restored the effect of Txnip deficiency on LSECs, thereby blocking ethanol-induced liver injury and inflammation. Overall, TXNIP in LSECs protects against ALD progression through TAK1/JNK signaling and TXNIP targeting may be a potential therapeutic approach for ALD. ### Competing Interest Statement The authors have declared no competing interest.