AAV-mediated inducible expression of OSK and OSKM ameliorates acute ischemic and chronic steatotic liver disease

Short-term expression of the Yamanaka factors Oct4, Sox2, Klf4 and c-Myc (OSKM) has been shown to promote liver regeneration, whereas sustained in vivo expression has been linked to tumorigenesis. Here, we evaluated doxycycline-inducible AAV-mediated expression of OSKM or OSK in male Wistar rats subjected to warm hepatic ischemia, metabolic dysfunction-associated steatohepatitis (MASH), or MASH with cirrhosis. A single AAV dose was administered, with transgene expression activated intermittently by doxycycline once a week. Short-term OSKM expression in healthy rats did not induce liver tumors up to 12 weeks after administration. In warm hepatic ischemia, both OSKM and OSK reduced liver damage. In contrast, only OSK improved chronic liver disease, attenuating tissue injury and fibrosis in MASH and MASH-cirrhosis and increasing survival. OSKM provided no therapeutic benefit in either chronic model and, in MASH without cirrhosis, exacerbated liver injury and fibrosis, induced tumors, and reduced survival. These findings support transient OSK expression as a potential therapeutic strategy for hepatic ischemia and MASH-associated liver damage.

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Publication Details

Journal
Communications Biology
Published
2026-10-05
DOI
https://doi.org/10.1038/s42003-026-11116-9
Primary Topic
Liver physiology and pathology
Type
article
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article

AAV-mediated inducible expression of OSK and OSKM ameliorates acute ischemic and chronic steatotic liver disease

Marc Micó-Carnero, Cristina Maroto-Serrat, Jordi Gracia‐Sancho, Josep Maria Campistol et al.
Communications Biology
Liver physiology and pathology
article

AAV-mediated inducible expression of OSK and OSKM ameliorates acute ischemic and chronic steatotic liver disease

Marc Micó-Carnero, Cristina Maroto-Serrat, Jordi Gracia‐Sancho, Josep Maria Campistol, Yosu Luque, Enrique Montagud‐Marrahí, Albert Caballeria-Casals, Rubén Rabadán-Ros, Carmen Peralta, Carlos Rojano-Alfonso, Francisco Sanus, Isabel Lopez-Sanchez
article en

Abstract

Short-term expression of the Yamanaka factors Oct4, Sox2, Klf4 and c-Myc (OSKM) has been shown to promote liver regeneration, whereas sustained in vivo expression has been linked to tumorigenesis. Here, we evaluated doxycycline-inducible AAV-mediated expression of OSKM or OSK in male Wistar rats subjected to warm hepatic ischemia, metabolic dysfunction-associated steatohepatitis (MASH), or MASH with cirrhosis. A single AAV dose was administered, with transgene expression activated intermittently by doxycycline once a week. Short-term OSKM expression in healthy rats did not induce liver tumors up to 12 weeks after administration. In warm hepatic ischemia, both OSKM and OSK reduced liver damage. In contrast, only OSK improved chronic liver disease, attenuating tissue injury and fibrosis in MASH and MASH-cirrhosis and increasing survival. OSKM provided no therapeutic benefit in either chronic model and, in MASH without cirrhosis, exacerbated liver injury and fibrosis, induced tumors, and reduced survival. These findings support transient OSK expression as a potential therapeutic strategy for hepatic ischemia and MASH-associated liver damage.

Communications Biology
Inserm (FR), University Hospital of Bern (CH), Instituto de Salud Carlos III (ES), Sorbonne Université (FR), Hospital de Nens de Barcelona (ES), Assistance Publique – Hôpitaux de Paris (FR), Hospital Clínic de Barcelona (ES), Fundació ACE (ES), Fundació Clínic per a la Recerca Biomèdica (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Maladies rénales fréquentes et rares : des mécanismes moléculaires à la médecine personnalisée, Universidad Católica de Murcia (ES), Universitat de Barcelona (ES)
Openalex Percentile: Top 13%
Liver physiology and pathology
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