Tid1 Deficiency Disrupting Mitochondria To Drive Nash-Dependent Hepatocellular Carcinoma Progression.

Abstract Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor to drive hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation, meanwhile; sequentially developed fatty liver, NASH, and cirrhosis/HCC in a Diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 mRNA expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that plays a key mechanism involved in the NASH-dependent HCC development. Overall, we established a new mouse model developing NASH-dependent HCC and provided a promising approach for improving the treatment. Citation Format: Ching-Wen Chang, Yu-Syuan Chen, Jeng-Fan Lo, Xin Wei Wang. Tid1 deficiency disrupting mitochondria to drive NASH-dependent hepatocellular carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2402.