Modulation of Endoplasmic Reticulum Stress via CEBPB: a Novel Therapeutic Target in Opioid Use Disorder

Opioid use disorder is a national crisis in the United States, with 3 US FDA-approved pharmacotherapies available and rapidly rising overdose deaths driven by synthetic opioids, i.e. fentanyl. Recent population-level evidence suggests that GLP-1 receptor agonists (GLP-1RA) may reduce the risk of opioid overdose, yet underlying mechanisms remain unclear. This study investigated molecular mechanisms of fentanyl and GLP-1RA. We performed RNA-seq in human iPSC-derived forebrain organoids treated with fentanyl, liraglutide, or exenatide. We then extended this analysis to iPSC-derived forebrain neurons exposed to additional therapeutic candidates: anticonvulsants (topiramate, gabapentin) and a metabolic modulator (β-hydroxybutyrate). We performed RNA-seq and functional genomic assays using iPSC-derived cell models. All drugs were tested at clinically relevant concentrations. Our results showed modulation of endoplastic reticulum (ER) stress signaling as a shared molecular mechanism across fentanyl, GLP-1RA, and other drug classes with therapeutic potential for substance use disorders (SUDs). Fentanyl, liraglutide, and exenatide consistently down-regulated ER stress–related genes, with TRIB3 emerging as the most strongly suppressed target in brain organoids. Additional stress-response genes, including DDIT3, ATF4, and PPP1R15A, were similarly reduced, indicating broad attenuation of ER stress pathways. We further identified CEBPB as a key upstream driver of these transcriptional changes. Finally, we confirmed that diverse compounds, including anticonvulsants and metabolic modulators, suppressed ER stress genes and reduced CEBPB DNA-binding activity in neurons. In summary, these findings reveal ER stress modulation, mediated in part through CEBPB, as a convergent mechanism across multiple drug classes and highlight potential relevance to therapeutic action in SUD.