Academic Journal
Oxidative stress drives liver failure during in vivo partial reprogramming.
| Title: | Oxidative stress drives liver failure during in vivo partial reprogramming. |
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| Authors: | Eom HJ; College of Pharmacy, Seoul National University, Seoul, Republic of Korea., Jo BK; College of Pharmacy, Seoul National University, Seoul, Republic of Korea., Kim J; College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea., Cha HJ; College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address: hjcha93@snu.ac.kr. |
| Source: | Molecules and cells [Mol Cells] 2026 Aug; Vol. 49 (8), pp. 100378. Date of Electronic Publication: 2026 Jun 04. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: United States NLM ID: 9610936 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 0219-1032 (Electronic) Linking ISSN: 10168478 NLM ISO Abbreviation: Mol Cells Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2024- : [New York] : Elsevier Original Publication: Seoul : Korean Society for Molecular Biology |
| MeSH Terms: | Oxidative Stress*/drug effects , Liver Failure*/metabolism , Liver Failure*/pathology , Liver Failure*/genetics , Cellular Reprogramming*, Hepatocytes/metabolism ; Hepatocytes/drug effects ; Hepatocytes/pathology ; Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology ; NF-E2-Related Factor 2/metabolism ; Antioxidants/pharmacology ; Animals ; Kruppel-Like Factor 4 ; Mice ; Female ; Male ; Signal Transduction |
| Abstract: | 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. (Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: In vivo reprogramming; Liver failure; N-acetylcysteine; Oxidative stress; Reactive oxygen species |
| Substance Nomenclature: | 0 (Kruppel-Like Factor 4) 0 (Klf4 protein, mouse) 0 (Reactive Oxygen Species) WYQ7N0BPYC (Acetylcysteine) 0 (NF-E2-Related Factor 2) 0 (Antioxidants) |
| Entry Date(s): | Date Created: 20260605 Date Completed: 20260717 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13330666 |
| DOI: | 10.1016/j.mocell.2026.100378 |
| PMID: | 42248561 |
| Database: | MEDLINE |
| ISSN: | 0219-1032 |
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| DOI: | 10.1016/j.mocell.2026.100378 |