Yan Li ^1,2 Zhuo Wang ³ Min Kong ³ Yuanyuan Yong ⁴ Xin Yang ³ Chongdong Liu ^5*

• ¹ Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
• ² General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Region, China
• ³ School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Region, China
• ⁴ Department o Gynecology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
• ⁵ Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

Objective: This study aims to investigate how changes in peripheral blood metabolites in Alzheimer's Disease (AD) patients affect the development of Pelvic Organ Prolapse (POP) using a multi-omics approach. We specifically explore the interactions of signaling pathways, gene expression, and protein-metabolite interactions, with a focus on GZMA and cysteine in age-related diseases. Methods: This study utilized multi-omics analysis, including metabolomics and transcriptomics, to evaluate the perturbations in peripheral blood metabolites and their effect on POP in AD patients. Additionally, a comprehensive pan-cancer and immune infiltration analysis was performed on the core targets of AD combined with POP, exploring their potential roles in tumor progression and elucidating their pharmacological relevance to solid tumors. Results: We identified 47 differential metabolites linked to 9 significant signaling pathways, such as unsaturated fatty acid biosynthesis and amino acid metabolism. A thorough gene expression analysis revealed numerous differentially expressed genes (DEGs), with Gene Set Enrichment Analysis (GSEA) showing significant changes in gene profiles of AD and POP. Network topology analysis highlighted central nodes in the AD-POP co-expressed genes network. Functional analyses indicated involvement in critical biological processes and pathways. Molecular docking studies showed strong interactions between cysteine and proteins PTGS2 and GZMA, and molecular dynamics simulations confirmed the stability of these complexes. In vitro validation demonstrated that cysteine reduced ROS levels and protected cell viability. GZMA was widely expressed in various cancers, associated with immune cells, and correlated with patient survival prognosis. Conclusions: Multi-omics analysis revealed the role of peripheral blood metabolites in the molecular dynamics of AD and their interactions with POP. This study identified potential biomarkers and therapeutic targets, emphasizing the effectiveness of integrative approaches in treating AD and POP concurrently. The findings highlight the need for in-depth research on novel targets and biomarkers to advance therapeutic strategies.