Abstract
Gastric cancer (GC) is characterized by pronounced molecular and clinical heterogeneity, creating major challenges for therapeutic decision-making. Limitations in current molecular classification hinder the development of personalized therapies, underscoring the need for improved diagnostic and prognostic frameworks. we conducted an integrated multi-omics analysis of bulk, single-cell, and spatial transcriptomic data to systematically characterize three key programmed cell death pathways-pyroptosis, apoptosis, and necroptosis (collectively abbreviated as PAN). A scoring-based clustering framework integrating multiple machine learning algorithms was developed to define high-resolution molecular subtypes and construct a deep learning signature. A hybrid CNN+BiLSTM model with cross-fusion attention was applied for transcriptomic feature extraction and subtype classification, achieving superior performance compared with existing approaches. Validation in the TCGA cohort confirmed the robustness and biological relevance of our model. Among the identified subtypes, Subtype 2 showed the most favorable prognosis. We further established a nine-gene prognostic signature with strong predictive value. High-risk patients exhibited poor survival, enhanced immune infiltration, and potential sensitivity to AKT inhibitors, with several drugs, including gefitinib and paclitaxel, identified as promising candidates. Experimental validation was conducted using the Human Protein Atlas (HPA) and RT-qPCR in clinical samples. CFLAR and TNFSF13B were upregulated and PDK4 downregulated in GC, while UACA showed no significant change. Additional prognostic genes (DFFB, PSMB6, GLP1R, HDAC9, BACH2) displayed expression patterns largely consistent across HPA, TCGA, and RT-qPCR, with minor discrepancies likely due to sample size. This study integrates multi-omics and deep learning with experimental validation, providing insights into programmed cell death regulation and offering robust biomarkers and therapeutic targets for GC.