Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet-induced steatotic liver disease

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Abstract

Obesity-linked steatosis is a significant risk factor for hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying the transition from metabolic dysfunction–associated steatotic liver disease (MASLD) to HCC remain unclear. Here, we explored the role of the ER-associated protein NgBR, an essential component of the cis-prenyltransferase (cis-PTase) enzyme, in chronic liver disease. Hepatocyte-specific NgBR deletion in mice (N-LKO) intensified triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and fibrosis, ultimately resulting in HCC development with 100% penetrance after 4 months on a high-fat diet. Similarly, liver-specific knockout of DHDDS, NgBR’s cis-PTase partner, and a knockin model carrying a human NgBR mutation that impairs cis-PTase activity developed HCC under high-fat diet conditions, although with lower penetrance. A single-cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Mechanistically, NgBR deficiency promoted excessive hepatic TAG accumulation by enhancing lipid uptake and impairing VLDL secretion. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in TAG synthesis, abrogated diet-induced liver damage and HCC burden in N-LKO mice. Overall, our findings establish cis-PTase as a critical suppressor of MASLD-HCC conversion and suggest DGAT2 inhibition may serve as a promising therapeutic approach to delay HCC formation in advanced metabolic dysfunction–associated steatohepatitis.

Authors

Abhishek K. Singh, Balkrishna Chaube, Kathryn M. Citrin, Joseph W.M. Fowler, Sungwoon Lee, Jonatas Catarino, James Knight, Sarah C. Lowery, Sonal Shree, Keira E. Mahoney, Nabil E. Boutagy, Inmaculada Ruz-Maldonado, Kathy Harry, Marya Shanabrough, Trenton T. Ross, Stacy A. Malaker, Yajaira Suárez, Carlos Fernández-Hernando, Kariona A. Grabińska, William C. Sessa