Cruz Santos, Maria, Kidd, Ethan, Li, Zongze  ORCID: https://orcid.org/0000-0002-9923-7205, Cabezas De La Fuente, Daniel, Davies, Sara, Vinh, Ngoc-Nga, Fjodorova, Marija and Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643
2026.
Autism-relevant oxysterol signaling regulates GABAergic neurogenesis and interneuron subtype specification.
Translational Psychiatry
10.1038/s41398-026-04396-6
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Abstract
Disturbances in GABAergic neurodevelopment are thought to underlie cortical network dysfunction in neurodevelopmental disorders (NDDs) such as autism and schizophrenia. The diversity of GABAergic neurons is shaped by cortical cues during prolonged postmitotic differentiation, yet how pathological environments associated with NDDs influence this process remains poorly understood. Oxysterols, oxidized cholesterol metabolites or its precursors, modulate key developmental signaling pathways. Here, using an iPSC-based model of human forebrain GABAergic neuron differentiation combined with single-cell transcriptomics, we show that 24S,25-epoxycholesterol, an oxysterol enriched in the fetal brain and dysregulated in NDDs, enhances neurogenesis while altering the distribution of GABAergic neuronal subtypes. Pharmacological and genetic perturbations further identify the liver X receptor as a critical mediator of these effects. Together, these findings uncover a link between cholesterol metabolism and GABAergic fate specification, suggesting that aberrant oxysterol signaling contributes to the pathogenesis of NDDs.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | In Press |
| Schools: | Schools > Medicine Schools > Biosciences |
| Publisher: | Springer Nature |
| ISSN: | 2158-3188 |
| Date of First Compliant Deposit: | 13 August 2026 |
| Date of Acceptance: | 12 August 2026 |
| Last Modified: | 25 Aug 2026 10:53 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/188962 |
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