Year: 2026
Type: article
Abstract: RNA 5-methylcytosine (m 5 C) methylation has emerged as an important epitranscriptomic regulator of gene expression, yet its role in stem cell maintenance remains not well understood. Here we identify a previously unrecognized function of the m 5 C methyltransferase NSUN2 in protecting stem cells from ferroptosis and promoting tissue regeneration. NSUN2 deletion reduced GPX4 expression, decreased intracellular GSH levels, increased Fe 2+ accumulation, and enhanced lipid peroxidation in stem cells, leading to ferroptotic cell death, loss of tissue stem cells and impaired tissue regeneration across multiple organs. Mechanistically, NSUN2 catalyzed m 5 C methylation of Klf4 mRNA, thereby increasing KLF4 expression and transcriptionally promoting GPX4 to suppress ferroptosis in stem cells. Importantly, KLF4 restoration in vivo rescued NSUN2 deficiency-induced stem cell defects and impaired tissue regeneration. Furthermore, NSUN2 gene therapy significantly bolstered tissue stem cells with superior tissue regeneration and repair in multiple tissues. These findings highlight the NSUN2/KLF4/GPX4 axis in safeguarding stem cells against ferroptosis for tissue repair and a promising therapeutic value of NSUN2 in regenerative medicine.
Source: Redox Biology
Institutions: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Stanford Medicine, Stanford University, Zhongnan Hospital of Wuhan University, Changsha Medical University, Brigham and Women's Hospital, Harvard University, Peking University Third Hospital, Beijing Tsinghua Chang Gung Hospital, Tsinghua University, Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Gastrointestinal Disease Research Center, Sun Yat-sen University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,310
OpenAlex ID: W7171823786