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.