Cerebral organoids play a crucial role in modeling human brain development and disease.[60, 61, 62] PA‐induced lipotoxicity is known to promote ER stress, autophagy, and then subsequent cell apoptosis in rat cortical cells.[63, 64] Previous reports suggested that Wfs1 deficiency exacerbates neurodegeneration via chronic ER stress in mice and rats.[29, 57] Here, we used human pluripotent stem cell‐derived NPCs and cerebral organoids harboring WFS1 deficiency with PA to mimic obesity and depression in vitro. Here, WFS1 is linked to depressive symptom measurement.