Modulation of Endoplasmic Reticulum Stress via CEBPB : A Potential Molecular Link to Therapeutic Action in Substance Use Disorders

AIMS: Opioid use disorder remains a major public health crisis in the United States, driven largely by rising overdose deaths from synthetic opioids, such as fentanyl. Emerging population-level evidence suggests that GLP-1 receptor agonists (GLP-1RAs) may reduce overdose risk. However, their underlying molecular mechanisms are not well understood. We investigated the transcriptional effects of fentanyl and GLP-1RAs using human induced pluripotent stem cell (iPSC)-derived forebrain organoids and neurons. METHODS: Organoids were treated with fentanyl, liraglutide, or exenatide, followed by RNA sequencing. We extended these analyses to iPSC-derived neurons exposed to additional therapeutic candidates, including the anticonvulsants topiramate and gabapentin, and the metabolic modulator β-hydroxybutyrate. All compounds were tested at clinically relevant concentrations, and transcriptomic and functional genomic assays were performed. RESULTS: Across models and drug classes, we identified modulation of endoplasmic reticulum (ER) stress signaling as a shared molecular mechanism. Fentanyl and GLP-1RAs consistently downregulated ER stress-related genes, with TRIB3 as the most strongly suppressed target. We further identified CEBPB as a key upstream regulator and confirmed reduced CEBPB DNA-binding activity in ER stress-related genes. CONCLUSION: These findings highlight ER stress modulation as a convergent pathway with potential therapeutic relevance for substance use disorders.