A Critical Commentary on "Elucidating pathway-selective biased CCKBR agonism for Alzheimer's disease treatment" by Wang et al., Cell 2025; doi:10.1016/j.cell.2025.10.034

This repository contains the complete critique of the article “Elucidating pathway-selective biased CCKBR agonism for Alzheimer’s disease treatment” by Wang et al. (Cell, 2025). The submitted manuscript evaluates the validity of the core claims that a newly identified small-molecule ligand (“CCK-X”) exhibits strong pathway-selective biased agonism toward the cholecystokinin B receptor (CCKBR), and that such signaling bias contributes to neuroprotective and cognitive benefits in Alzheimer’s disease (AD) models.

Our analysis identifies several methodological and interpretive issues that materially affect the conclusions of the original study. These include: (1) incomplete quantification of signaling bias due to the absence of operational model parameters and mismatched assay conditions; (2) cryo-EM structures with insufficient resolution to support the claimed “biased conformation”; (3) underpowered neuronal and behavioral experiments lacking blinding and randomization; (4) inconsistencies in Extended Data Figures involving ELISA standards, Western blot loading controls, and behavioral swim-path traces; and (5) transcriptomic and proteomic analyses influenced by batch effects and limited proteome coverage. Together, these issues reduce confidence in the mechanistic and therapeutic interpretations put forward by the original authors.

The uploaded files include the full Matters Arising manuscript, cover letter, and supporting documentation. This Zenodo record aims to enhance transparency and accessibility in post-publication peer review, enabling researchers to critically assess evidence related to GPCR biased signaling and Alzheimer’s disease therapeutics. All content is provided for scholarly discussion and methodological clarification and does not present new experimental data.