Cyclophilin D knockout significantly prevents HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH

• DOI: 10.1371/journal.pone.0301711
• Publication Date: 2024-04-04T17:28:47Z
• Authors: Winston T. Stauffer; Michael Bobardt; Daren R. Ure; Robert T. Foster; Philippe Gallay
• Keywords: Steatohepatitis; Cyclophilin; Knockout mouse; Cypa

A family of Peptidyl-prolyl isomerases (PPIases), called Cyclophilins, localize to numerous intracellular and extracellular locations where they contribute a variety essential functions. We previously reported that non-immunosuppressive pan-cyclophilin inhibitor drugs like reconfilstat (CRV431) or NV556 decreased multiple aspects non-alcoholic fatty liver disease (NAFLD) in mice under two different steatohepatitis (NASH) mouse models. Both CRV431 inhibit several cyclophilin isoforms, among which D (CypD) has not been investigated this context. It is unknown whether it necessary simultaneously members achieve therapeutic benefits if loss-of-function one sufficient. Furthermore, narrowing down the isoform most responsible for particular aspect NAFLD/NASH, such as hepatocellular carcinoma (HCC), would allow more precise future therapies. Features human diabetes-linked NAFLD/NASH can be reliably replicated by administering single high dose streptozotocin disrupt pancreatic beta cells, conjunction with sugar, fat, cholesterol western diet over course 30 weeks. Here we show while both wild-type (WT) Ppif-/- CypD KO develop multipe severe NASH features model, formation HCC nodules was significantly blunted only mice. differentially expressed transcripts qPCR panel select HCC-related genes, nearly all were downregulated background. Cyclophilin inhibition promising novel avenue treatment diet-induced NAFLD/NASH. This study highlights impact on development HCC, outcomes.