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2026

Cell Stem Cell 2026 Jun 4;33(6):1031-1046.e8. doi: 10.1016/j.stem.2026.04.017.

Ferroptosis susceptibility in hippocampal neural precursor cells influences neurogenesis and memory across aging

Zhenyu Zhang, Alison K Carlisle, Hamish P Carter, Joshua R Lowe, Menekse Mutlu-Smith, Wendy Lee, Odette Leiter, Shilong Zhang, Annie Harding, Muhammed Syed, David Brici, Rupert W Overall, Nicole Rund, Christina Steinhauer, Daniel G Blackmore, Scott Ayton, Ashley I Bush, Ming Chen, Gerd Kempermann, Sheng-Tao Hou, Tara L Walker

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Brain Research Centre, Department of Biology, School of Life Science, Southern University of Science and Technology, Shenzhen 518055, China. Department of Bioinformatics, College of Life Sciences, Zhejiang University, Hangzhou 310058, China. CRTD - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany; German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden 01307, Germany. Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Melbourne, VIC 3052, Australia.

Service type: Stock strains

Abstract

Adult hippocampal neurogenesis declines with age, but the stress pathways that shape neural precursor cell (NPC) survival and lineage progression remain incompletely understood. Here, we tested whether ferroptosis-related vulnerability contributes to the regulation of hippocampal NPCs and their progeny. Using in vitro assays, transcriptomic analyses, and in vivo genetic and pharmacologic perturbations, we find that NPCs show features consistent with elevated susceptibility to ferroptotic stress relative to more differentiated hippocampal populations. Reducing glutathione peroxidase 4 (GPX4) or increasing ferroptotic stress impairs neurogenesis-associated cellular and behavioral phenotypes, whereas pathway modulation improves selected outcomes in aged animals. These effects were context dependent, with distinct consequences across age and behavioral paradigms. Together, the findings support a model in which ferroptosis-related susceptibility contributes to the regulation of adult hippocampal neurogenesis and cognition.