Cognitive dysfunction is a major and disabling complication of neuropsychiatric systemic lupus erythematosus (NPSLE), and impaired adult hippocampal neurogenesis is considered a key pathological mechanism. We investigated whether dysfunction of cannabinoid receptor 1 (CB1R) contributes to abnormalities in neural progenitor cell (NPC) proliferation and differentiation, and whether selective CB1R activation exerts neuroprotective effects. This project integrated multi-omics analyses, virtual screening, and in vivo/in vitro models to elucidate this mechanism and evaluate the therapeutic potential of novel CB1R agonists.

A pristane-induced lupus (PIL) mouse model was established, and Ascl1-CreERT2;Ai14 lineage-tracing mice and Ascl1-CreERT2;Ai14;Cnr1-/- mice were used. Single-cell transcriptomic data from human brain tissue and PIL mice were analyzed. CB1R-targeted high-throughput virtual screening and molecular docking were performed using Boltz-2 and AutoDock Vina. The effects of candidate agonists in NE-4C cells were evaluated by BrdU incorporation and western blotting. Changes in cognitive function and adult hippocampal neurogenesis were assessed using behavioral and morphological analyses, and in vivo target specificity of CB1R-directed pharmacological effects was further validated.

Multi-omics analyses revealed dysregulation of the endocannabinoid system, significant downregulation of CB1R expression in NPSLE, and severe blockade of the NPC-to-neuron differentiation trajectory. Virtual screening identified a novel high-affinity CB1R agonist. In vitro validation showed that this agonist effectively attenuated cytotoxicity induced by the NPSLE microenvironment and significantly restored the suppressed proliferative and differentiative potential of NPCs. In vivo lineage-tracing and behavioral experiments showed a marked reduction in newborn hippocampal neurons in model mice, accompanied by significant spatial cognitive decline, whereas targeted CB1R agonist treatment partially restored adult hippocampal neurogenesis and improved learning and memory deficits.

This study highlights the critical role of impaired adult neurogenesis in NPSLE-associated cognitive dysfunction and identifies CB1R as a central regulatory node. Both in vitro and in vivo findings indicate that targeted CB1R activation can alleviate microenvironment-mediated suppression of NPCs. These results provide mechanistic insight into NPSLE pathogenesis and yield promising lead candidates for the development of targeted therapies for cognitive impairment.