SETD5 dysfunction in human astrocytes drives IL-6-mediated neuronal impairments via the JAK/STAT signaling pathway
in human-induced pluripotent stem cell (hiPSC)-derived astrocytes affects neuronal physiology. We show that SETD5-deficient astrocytes have increased levels of extracellular reactive oxygen species (ROS), glutamate, and interleukins-6 and 8 (IL-6 and (IL-8). Elevated astrocytic IL-6 exerts a non-cell autonomous harmful effect on healthy neurons. Using SETD5-deficient astrocytes as a screening platform, we identify the JAK/STAT pathway as an upstream regulator of abnormal IL-6 accumulation associated with SETD5 dysfunction. Accordingly, pharmacological inhibition of JAK-STAT signaling restores extracellular IL-6 to basal levels and partially rescues astrocyte morphology and neuronal deficits. Collectively, these findings highlight the JAK/STAT pathway as a key regulator of SETD5-mediated astrocytic function and suggest its potential as a therapeutic target for astrocytic-driven neuronal impairments in ASD and ID.
Authors
- Marc Ferrer (ORCID: https://orcid.org/0000-0003-4569-9137)
- Kelsey L. Dang
- Alon Goren (ORCID: https://orcid.org/0000-0001-5669-9357)
- Georgia Chaldaiopoulou (ORCID: https://orcid.org/0000-0002-0142-6113)
- Eugin Destici (ORCID: https://orcid.org/0000-0002-8472-1766)
- Ivan García-Bassets (ORCID: https://orcid.org/0000-0002-6941-9585)
- Noel Southall (ORCID: https://orcid.org/0000-0003-4500-880X)
- Alysson Renato Muotri (ORCID: https://orcid.org/0000-0003-0867-2875)
- Raul R. Calvo
- Christopher Benner (ORCID: https://orcid.org/0000-0002-4618-0719)
- Juan Marugán (ORCID: https://orcid.org/0000-0002-3951-7061)
- Isabella Rodrigues Fernandes (ORCID: https://orcid.org/0000-0002-8985-4517)
- Brett M. Taylor (ORCID: https://orcid.org/0000-0002-4746-7228)
- Adriano Ferrasa (ORCID: https://orcid.org/0000-0001-6653-1849)
- Roberto H. Herai (ORCID: https://orcid.org/0000-0001-9885-2735)
- Pinar Mesci (ORCID: https://orcid.org/0000-0003-3402-5671)
- Dylan Phan
- Max Chang
- Luisa BV Coelho
- Anju Singh
- Angels Almenar-Queralt
- Livia Luz S Nascimento
- Janaina S de Souza
- Luisa F Paredes-Brito
- Xiwei Shan
- Allen Y Wang
Institutions
- Pontifícia Universidade Católica do Paraná (BR)
- San Diego State University (US)
- University of California San Diego (US)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Sanford Consortium for Regenerative Medicine (US)
- Precision for Medicine (United States) (US)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-07
- DOI
- https://doi.org/10.64898/2026.04.05.716613
- Citations
- 1
- Primary Topic
- Autism Spectrum Disorder Research
- Type
- article
- Field-Weighted Citation Impact
- 21.32