<i>Lycium barbaru</i>m glycopeptide ameliorates aberrant neuronal activity via ER stress modulation in ventral forebrain organoids derived from depressive patients

Major depressive disorder (MDD) is a debilitating psychiatric condition associated with substantial personal, societal, and economic costs. Despite considerable advances in research, most conventional antidepressant therapies fail to achieve adequate response in a significant proportion of patients, underscoring the need for novel, mechanism-based interventions. <i>Lycium barbarum</i> glycopeptide (LbGp), a bioactive compound with emerging neuroprotective properties, has been proposed as a candidate for antidepressant development; however, its therapeutic efficacy and underlying mechanisms remain largely uncharacterized. In this study, ventral forebrain organoids were generated from patients with MDD to investigate disease-related neurophysiological abnormalities. These organoids exhibited disrupted neuronal morphology, diminished calcium signaling, and impaired electrophysiological activity. Administration of LbGp effectively restored structural and functional deficits in MDD-derived organoids. Transcriptomic profiling revealed that LbGp ameliorated endoplasmic reticulum (ER) stress responses. To investigate the causative role of ER stress, control organoids were treated with the ER stress agonist CCT020312, which elicited neural activity impairments resembling those observed in MDD organoids. Notably, LbGp reversed the phenotypic consequences of CCT020312 exposure in control organoids. In conclusion, ventral forebrain organoids derived from individuals with MDD demonstrated that LbGp ameliorates disease-associated phenotypes by modulating ER stress.