Integrating WGCNA, machine learning, and single-cell sequencing analysis to elucidate the molecular mechanism of SREBF1 in Alzheimer’s disease: evidence from Mendelian randomization and exploration of potential therapeutic agents targeting SREBF1 via molecular docking

Objective The purpose of this research is to investigate the molecular mechanisms of the senescence-related gene ( SREBF1 ) in Alzheimer's disease (AD). Methods A consensus clustering approach was applied to 8 AD datasets to discern different subtypes. Then, weighted correlation network and machine learning analysis were employed to screen for hub genes. Next, Mendelian randomization (MR) was used to separately assess the causal relationships between SREBF1 /731 immune cells and AD. Finally, Single-cell RNA sequencing (scRNA-seq) analysis was conducted to explore the mechanisms of SREBF1 in AD, and molecular docking was used to evaluate the interactions between small-molecule drugs and SREBF1 . Results Two AD subtypes were identified, with patients in cluster 1 exhibiting higher immune infiltration levels and poor progression. We developed the SRG.score, which demonstrated excellent predictive capability for AD across multiple datasets. MR analysis further revealed a potential association between SREBF1 and AD (OR: 1.143 (1.033-1.265)). CD33 on CD66b++ myeloid cells mediated 7.1% (95% CI: 5.3%-21.6%) and amyloid-beta 87.5% (95% CI: 13.2%-100.0%) of the total effect of SREBF1 on AD. Furthermore, scRNA-seq analysis revealed a close association between SREBF1 and oligodendrocyte differentiation in AD. Additionally, we identified a mature oligodendrocyte subpopulation in AD with high SREBF1 expression related to ferroptosis. Molecular docking and dynamics simulation demonstrated strong binding specificity between SREBP1 (gene name: SREBF1 ) and efavirenz. Conclusion This study suggests SREBF1 may advance AD by regulating CD33 on CD66b++ myeloid cells and promoting amyloid-beta deposition. The high binding affinity between efavirenz and SREBP1 indicates its potential for treating AD.