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While glucagon\u2010like peptide\u20101 receptor (GLP\u20101R) agonists show neuroprotective potential, their capacity to directly mitigate cholesterol\u2010induced metabolic stress in human neural cells remains to be established.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Here, we modeled metabolic stress using human induced pluripotent stem cell\u2013derived forebrain organoids exposed to cholesterol overload. The protective effects of the GLP\u20101R agonist semaglutide were characterized by integrating bulk\/single\u2010cell transcriptomics, calcium imaging, and biochemical assays. Furthermore, clinical translatability was supported by mapping organoid expression signatures against human\n                      <jats:italic>post mortem<\/jats:italic>\n                      neurodegenerative brain datasets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Cholesterol overload induced cellular stress and transcriptomic alterations that partially overlapped with AD\u2010associated signatures. Semaglutide protected neural cells from lipotoxic injury. Intracellularly, GLP\u20101R activation engaged the cyclic adenosine 3',5'\u2010monophosphate\u2013protein kinase A and phosphoinositide 3 kinase\u2013protein kinase B\u2013mechanistic target of rapamycin signaling pathways, consistent with reduced lipid droplet accumulation and oxidative stress. Intercellularly, single\u2010cell analysis indicated partial preservation of disrupted cellular communication, including the neurotrophic midkine signaling network. Functionally, semaglutide stabilized cellular calcium activity patterns under metabolic stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings highlight the role of cholesterol homeostasis in maintaining neuronal integrity and position GLP\u20101R signaling as a candidate protective axis under metabolic stress, offering insights into therapeutic strategies for AD and broader neurodegenerative disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71888","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:57:44Z","timestamp":1790650664000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GLP\u20101R agonist semaglutide protects human forebrain organoids from cholesterol\u2010induced neurotoxicity"],"prefix":"10.1002","volume":"22","author":[{"given":"Feifei","family":"Yu","sequence":"first","affiliation":[{"name":"Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School (SIGS) Tsinghua University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School (SIGS) Tsinghua University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibo","family":"Hou","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School (SIGS) Tsinghua University  Shenzhen 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