PPARG as a central regulator of ferroptosis in Alzheimer's disease: integrated transcriptomic, single-cell, and experimental evidence

<h4>Background</h4>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, β-amyloid (Aβ) plaque accumulation, neurofibrillary tangle formation, and chronic neuroinflammation. Increasing evidence suggests that ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, contributes to AD pathogenesis; however, its upstream regulatory mechanisms remain incompletely understood.<h4>Methods</h4>Transcriptomic datasets from the Gene Expression Omnibus (GSE1297, GSE5281, and GSE157827) were analyzed to identify AD-associated differentially expressed genes (DEGs). Ferroptosis-related genes were obtained from curated databases and intersected with AD-associated DEGs. Protein-protein interaction (PPI) networks were constructed using the STRING database and analyzed via Cytoscape to identify key regulatory genes. Immune cell infiltration was quantified using CIBERSORT. Molecular docking was performed to evaluate ligand-PPARG binding. Functional validation was conducted using <i>in vitro</i> neuronal ferroptosis models and an <i>in vivo</i> AD mouse model.<h4>Results</h4>A total of 50 reproducible differentially expressed genes (DEGs) were identified across two independent transcriptomic datasets, of which 24 genes were associated with ferroptosis. Network analysis consistently identified peroxisome proliferator-activated receptor gamma (PPARG) as a central hub gene within the ferroptosis regulatory network. Immune infiltration analysis revealed increased M2 macrophage abundance in AD tissues, suggesting an association between ferroptosis-related gene expression and immune-related transcriptional signatures. Molecular docking demonstrated stable ligand binding to PPARG with a binding affinity of -5.6 kcal/mol, supported by hydrogen-bond and hydrophobic interactions. Experimental validation confirmed that PPARG modulation significantly influenced ferroptosis-associated neuronal injury both <i>in vitro</i> and <i>in vivo</i>.<h4>Conclusion</h4>These findings identify PPARG as a key regulator linking ferroptosis and neuroinflammation in Alzheimer's disease. Targeting PPARG-mediated ferroptotic pathways may therefore represent a promising therapeutic strategy for mitigating neurodegeneration in AD.