Smoking-associated cadmium activates MAPK9/JNK2 to drive neuronal mitochondrial dysfunction and APP protein accumulation in Alzheimer’s disease

Cadmium (Cd) exposure has been linked to cognitive decline and Alzheimer’s disease (AD) risk, but the public sources of this toxin, as well as its pathogenic mechanisms and preventive measures, have not yet been fully elucidated. We integrated survey-weighted NHANES data with transcriptomic and single-nucleus analyses to identify the sources of cadmium in the human body and potential pathogenic mechanisms for AD. Tissue and cell experiments validated expression changes and AD-related pathology, while docking and molecular dynamics assessed target-ligand binding. Ever smoking was associated with higher whole-blood Cd concentrations in the survey-weighted population analysis. Integrative analyses highlighted c-Jun N-terminal kinase 2 (JNK2)/Mitogen-Activated Protein Kinase 9 (MAPK9) as the candidate gene, enriched in excitatory neurons with heightened communication and Aβ-linked mitochondrial complex I dysfunction. In human brain, JNK2 phosphorylation increased in AD. In neurons, CdCl2 elevated JNK2 phosphorylation and APP protein abundance and impaired mitochondria. Molecular docking supported sanguinarine stable binding MAPK9 and mitigating mitochondrial dysfunction. Our findings nominate the profound impact of the smoking-cadmium-MAPK9 axis on neuronal mitochondrial dysfunction and APP protein accumulation. Sanguinarine may represent a candidate compound for targeting this pathway.