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. This evidence concerns the gene WFS1 and obesity due to melanocortin 4 receptor deficiency.