Integrative multi-omics analysis identifies programmed cell death-related biomarkers and their environmentally relevant toxicological interactions in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular condition driven by interactions between genetic regulation and environmental influences, yet reliable biomarkers are lacking. Although individual programmed cell death (PCD) pathways have been implicated in AAA, their integrated dysregulation, particularly in environmental and toxicological contexts, remains unclear. Here, we conducted an integrative multi-omics analysis combining bulk transcriptomic datasets, single-cell RNA sequencing cohorts, and independently sequenced clinical samples to systematically characterize PCD dysregulation in AAA. Our results revealed widespread activation of cell-death and inflammatory signaling, cell type-specific enrichment of multiple PCD modalities, and two distinct PCD-related molecular subtypes with distinct immune infiltration patterns. Using machine learning approaches, we identified four core PCD genes (AGER, CX3CR1, LEP, and SATB1) and incorporated them into an artificial neural network-based AAA risk model, which demonstrated robust diagnostic performance across multiple cohorts and revealed potential therapeutic relevance. Chemical‑gene interaction analysis further prioritized three environmental compounds (triphenyl phosphate, sodium arsenite, and propylthiouracil) as high‑risk exposures linked to these PCD core genes. Notably, LEP consistently emerged as a key gene across predictive modeling and subsequent experimental validation. It exhibited marked upregulation in AAA tissues, predominant localization to inflammatory cells, and significantly elevated circulating levels in both an independent clinical cohort and the UK Biobank population. Together, this work supports PCD dysregulation as a central feature of AAA and positions LEP as a potential candidate biomarker linking molecular alterations, environmental exposures, and disease risk. Our findings provide new insights into biomarker-guided evaluation and implicate environmental toxicants in AAA progression via PCD-centric networks.