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Ferroptosis modulation enhances astrocyte-to-neuron conversion induced by a novel chemical cocktail in the hemorrhagic brain.

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Τίτλος: Ferroptosis modulation enhances astrocyte-to-neuron conversion induced by a novel chemical cocktail in the hemorrhagic brain.
Συγγραφείς: Wang J; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Chen S; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Li J; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Liu X; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Department of Neurology, Jingzhou Hospital, Yangtze University, Jingzhou, China., Wang J; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Department of Neurology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China., Huang L; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Nie L; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Wu X; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Li Y; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Division of Child Healthcare, Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Feng Y; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Division of Child Healthcare, Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Liu N; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Tang Y; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Zhu L; Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Qin C; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Li G; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. lgghuster@163.com., Tang Z; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ddjtzp@163.com.; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China. ddjtzp@163.com.; National Center for Major Public Health Events, Wuhan, China. ddjtzp@163.com.; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China. ddjtzp@163.com.
Πηγή: Signal transduction and targeted therapy [Signal Transduct Target Ther] 2026 Jul 29; Vol. 11 (1). Date of Electronic Publication: 2026 Jul 29.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101676423 Publication Model: Electronic Cited Medium: Internet ISSN: 2059-3635 (Electronic) Linking ISSN: 20593635 NLM ISO Abbreviation: Signal Transduct Target Ther Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Publishing Group, [2016]-
Ιατρικοί όροι (MeSH): Astrocytes*/metabolism , Astrocytes*/pathology , Astrocytes*/drug effects , Neurons*/metabolism , Neurons*/pathology , Neurons*/drug effects , Ferroptosis*/drug effects , Ferroptosis*/genetics , Cerebral Hemorrhage*/pathology , Cerebral Hemorrhage*/genetics , Cerebral Hemorrhage*/drug therapy , Cerebral Hemorrhage*/metabolism , Cellular Reprogramming*/drug effects , Cellular Reprogramming*/genetics, Brain/pathology ; Brain/metabolism ; Brain/drug effects ; Animals ; Mice ; Humans
Περίληψη: Intracerebral hemorrhage (ICH) leads to significant neuronal loss and glial scar formation, but the regenerative capacity of the adult brain remains limited. Although small-molecule-induced astrocyte-to-neuron (AtN) conversion has shown promise in vitro, in vivo applications-particularly under pathological conditions-are still scarce. We aimed to develop and validate a small-molecule cocktail for inducing astrocyte-to-neuron reprogramming in vivo following ICH. We identified a seven-compound cocktail (DFGKLRV) capable of converting astrocytes into neurons under both physiological and ICH conditions. Using immunostaining, RT‒qPCR, electrophysiology, RNA sequencing, neural circuit tracing, and behavioral assessment, we assessed the identity and functionality of induced neurons. In vivo reprogramming was achieved via continuous intracerebral infusion of the cocktail using osmotic pumps. Lineage tracing with aldehyde dehydrogenase 1 family member L1 (Aldh1l1)-CreERT2/Rosa-CAG-tdTomato mice confirmed the astrocytic origin of the reprogrammed neurons. Additionally, we monitored ferroptosis dynamics during reprogramming and evaluated the effect of ferroptosis inhibition on conversion efficiency. DFGKLRV successfully reprogrammed astrocytes into functional, electrophysiologically active neurons. This reprogramming was effective both in vitro and in vivo, including in the hemorrhagic brain environment. Pharmacological inhibition of ferroptosis significantly improved reprogramming efficiency. Mechanistically, ferroptosis inhibition promoted astrocyte-to-neuron conversion at least in part through suppression of the TGF-β/SMAD3/SOX9 axis, whereas exogenous TGF-β1 treatment or Sox9 overexpression reversed this pro-reprogramming effect. Our findings demonstrate that the DFGKLRV cocktail enables efficient in vivo astrocyte-to-neuron reprogramming following ICH. Moreover, ferroptosis represents a key regulatory mechanism and potential therapeutic target for enhancing chemical reprogramming strategies.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
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Grant Information: 82071330 National Natural Science Foundation of China (National Science Foundation of China); 92148206 National Natural Science Foundation of China (National Science Foundation of China); 82203835 National Natural Science Foundation of China (National Science Foundation of China); 82201474 National Natural Science Foundation of China (National Science Foundation of China); 2023JCYJ033 Huazhong University of Science and Technology (HUST)
Entry Date(s): Date Created: 20260729 Date Completed: 20260729 Latest Revision: 20260801
Update Code: 20260801
PubMed Central ID: PMC13421695
DOI: 10.1038/s41392-026-02915-x
PMID: 42527413
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2059-3635
DOI:10.1038/s41392-026-02915-x