Analysis of zebrafish homologs within the human genome provides valuable insights into exploring pan-cancer alternative splicing events as prognostic markers and therapeutic targets

• Identification of Prognostic Alternative Splicing Events: We uncovered 13 alternative splicing events significantly linked to pan-cancer patient prognosis, shedding light on potential therapeutic targets. • Validation of Prognostic Risk Model: Our established risk scoring model effectively distinguishes high and low-risk groups, aiding in the identification of poor-prognosis pan-cancer patients. • Gene Expression Correlations: Elevated expression of C1QC, DENND5A, HP, IRF5, and LRP1 correlated with lower overall survival and increased immune cell infiltration, suggesting potential targets for therapeutic intervention. • Impact on Tumor Microenvironment: High-risk groups exhibited increased immune cell infiltration and elevated immune functional marker scores, suggesting a potential link between alternative splicing events and tumor immune response. • Immune Cell Correlations: Positive correlations were observed between specific immune cell types (CD8+ T cells, NK cells) and expressions of certain genes (C1QC, IRF5), indicating potential interactions within the tumor microenvironment. • Association with Immune Checkpoint Markers: Positive correlations between C1QC and IRF5 expression with immune checkpoint markers CD274 and CTLA-4, indicating potential immunotherapeutic implications. • Confirmation through Mendelian Randomization: Mendelian randomization and Bayesian Weighted Mendelian Randomization confirmed the protective role of the C1QC gene in overall cancer, validating our findings and suggesting causal relationships, strengthening the robustness of the findings. • Insights from Zebrafish Homologs: Leveraging zebrafish homologs provided unique insights into alternative splicing mechanisms across species, enriching our understanding of cancer biology and potential therapeutic targets. Alternative splicing (AS) is pivotal in gene expression regulation and protein diversity generation. Suppression of aberrant AS holds promise in cancer management. Utilizing zebrafish-human homologous genes, we investigated AS events across 33 tumor types from TCGA, employing Cox regression analyses to identify prognostic AS events. A risk-scoring model distinguished high and low-risk groups, revealing differences in survival, tumor microenvironment, and immune cell infiltration. Notably, C1QC, DENND5A, HP, IRF5, and LRP1 were associated with poor prognosis and immune infiltration. Mendelian randomization confirmed the protective role of C1QC across cancers, further supported by Bayesian Weighted Mendelian Randomization. Leveraging zebrafish homologs enhances our understanding of AS mechanisms and potential therapeutic targets in cancer biology.