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. 2024 Apr 4;19(4):e0301711.
doi: 10.1371/journal.pone.0301711. eCollection 2024.

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

Winston T Stauffer  1 , Michael Bobardt  1 , Daren R Ure  2 , Robert T Foster  2 , Philippe Gallay  1
Affiliations

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

Winston T Stauffer et al. PLoS One. .

Abstract

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

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Conflict of interest statement

Daren R. Ure and Robert T. Foster are employees of Hepion Pharmaceuticals, the developers of Reconfilstat/CRV431.

Figures

Fig 1
Fig 1. CypD KO mice have similar liver morphology to WT mice except for the appearance of HCC tumors in the STZ-WD model.
Fig 2
Fig 2. CypD KO mice develop liver fibrosis similar to WT after administration of a CCl4 model or a STZ-WD model.
Fig 3
Fig 3. CypD KO mice develop significantly less HCC tumor burden in the STZ-WD model.
Fig 4
Fig 4. CypD KO mice develop features of NAFLD/NASH similar to WT after administration of the STZ-WD model.
Fig 5
Fig 5. CypD KO mice downregulate HCC-related genes relative to WT mice undergoing a NAFLD/NASH model.
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Grants and funding

PG 5R01AI143931-04 Funding for this study was supplied by a grant from the National Institutes of Health/National Institute of Allergy and Infectious Diseases NIH/NIAID https://www.niaid.nih.gov/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.