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.