DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids

초록

Background & Aims: Metabolic dysfunction and alcohol-associated liver disease (MetALD) results in the development of liver steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). De novo lipogenesis and cholesterol synthesis play an important role in the pathogenesis of MetALD. DHCR7 (7-dehydrocholesterol reductase) regulates the last stages of cholesterol production. Methods: We investigated whether targeting DHCR7 can ameliorate the development of MetALD and HCC using experimental models and 3D human liver spheroids. Results: Here, we demonstrate that partial genetic ablation of the Dhcr7 gene and pharmacological blockade of DHCR7 activity with the AY9944 inhibitor suppresses hepatic steatosis (. lipid area, n = 15; p <0.001), inflammation (. F4/80, n = 6; p <0.01), fibrosis (. Sirius red, n = 6; p <0.01), and HCC (.AFP/YAP, n = 6; p <0.01) in diethylnitrosamine (DEN)-challenged high-fat diet (HFD) + ethanol (EtOH)-fed mice treated with AY9944 compared with control mice. To translate our findings, the effect of DHCR7 was tested using 3D human liver spheroids, which mimicked MetALD and MetALD-HCC. MetALD liver spheroids were composed of primary human hepatocytes, non-parenchymal cells, and hepatic stellate cells. In contrast, in MetALD-HCC spheroids, the HCC cell line HepG2 was used instead of hepatocytes. Therapeutic administration of AY9944 inhibited inflammation (. TNF, p <0.05) and fibrosis in MetALD spheroids (. ACTA2, p <0.001; COL1A1, p <0.05; TIMP1, p <0.01; SERPINE1, p <0.05). In turn, dsiRNAbased knockdown of DHCR7 reduced HepG2 proliferation (.PCNA, p <0.05; CCNE, p <0.05) and expression of MetALD-HCC markers (. AFP, p <0.05; GPC3, p <0.05; YAP, p <0.01). Conclusions: Our data demonstrate that targeting DHCR7 can become a strategy for the treatment of MetALD and HCC. (c) 2025 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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