Molecules and Cells Short Report Oxidative stress drives liver failure during in vivo partial reprogramming

초록

In vivo reprogramming using the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC; OSKM) enables tissue regeneration but raises major safety concerns when factor expression is sustained. Here, using a doxycycline-inducible OSKM mouse model, we show that prolonged systemic OSKM induction causes early lethality associated with hepatocyte dedifferentiation and oxidative stress in the absence of tumor formation. Single-nucleus RNA sequencing revealed activation of reactive oxygen species (ROS), oxidative stress, and NRF2 signaling pathways in hepatocytes. Increased ROS production in hepatocytes, together with the higher resistance of female mice and sex-dependent differences in antioxidant response programs, implicates oxidative stress as a primary driver of mortality during sustained OSKM expression. Importantly, antioxidant treatment with N-acetylcysteine (NAC) alleviated oxidative stress and significantly improved survival without impairing reprogramming-associated cellular plasticity. These findings establish oxidative stress as a key driver of liver failure during sustained in vivo reprogramming and provide a mechanistic rationale for cyclic induction strategies. (c) 2026 The Author(s). Published by Elsevier Inc. on behalf of Korean Society for Molecular and Cellular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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