TARGETING LSD1 PROMOTES NEUROPROTECTION AND FUNCTIONAL RECOVERY AFTER ISCHEMIC STROKE

Background: Ischemic stroke is a leading cause of adult disability worldwide, resulting in acute neuronal death and long-lasting neurological impairment. Despite advances in acute care, current therapeutic strategies remain limited to early revascularization, and no clinically approved neuroprotective agents are available to mitigate secondary neuronal damage or promote functional recovery. Increasing evidence indicates that epigenetic mechanisms play a central role in post-stroke pathophysiology. Among these, Lysine-Specific Demethylase 1 (LSD1) regulates gene networks critical for neuronal survival, inflammation, and plasticity. Therefore, we hypothesized that targeting LSD1 could represent a promising therapeutic strategy to confer neuroprotection and improve functional outcomes after ischemic stroke.
Methods and results: We evaluated the therapeutic potential of RN-1, a selective LSD1 inhibitor, in both vivo and vitro models of ischemic injury. In a mouse photothrombotic stroke model, RN-1 treatment significantly reduced infarct volume at both acute (1 dpo) and chronic (14 dpo) time points, as well as attenuated molecular and cellular hallmarks of secondary injury phase, consistent with sustained neuroprotective effects. Importantly, these neuroprotective effects were accompanied by improved neurological function.Using a primary cortical neuron model of oxygen–glucose deprivation/reperfusion, LSD1 inhibition modulated neuroprotective, apoptotic, and inflammatory gene expression programs. Together, these findings suggest that RN-1 exerts beneficial effects by regulating key pathways involved in neuronal survival and recovery.
Conclusion: Our study supports a central role for LSD1 in the epigenetic regulation of post-ischemic pathophysiology and highlights LSD1 inhibition as a potential therapeutic approach to promote recovery after ischemic stroke.