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Life sciences · Journal article
Cureus · October 22, 2026
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Complex diseases arise from interactions among genetic susceptibility, epigenetic regulation, transcriptomic variation, protein expression, environmental exposure, and clinical phenotype. Background evidence indicates that genomic information alone may not fully explain disease progression, molecular heterogeneity, or therapeutic response, as functional disease mechanisms are frequently executed at the protein level. The objective of this review is to synthesize current knowledge on proteogenomic signatures in complex diseases and evaluate their implications for biomarker discovery, risk stratification, clinical decision-making, and targeted interventions. The methodology involved an integrative literature review of English-language studies published between 2015 and 2026, identified through PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar using terms related to proteogenomics, multi-omics, complex diseases, precision medicine, biomarkers, and targeted therapy. Eligible studies included original articles, reviews, meta-analyses, and consensus reports addressing human complex diseases with proteomic integration. The review highlights proteogenomic applications in cancer, cardiometabolic disorders, neurodegenerative diseases, autoimmune conditions, and inflammatory disorders. Integrated molecular profiling supports identification of active disease pathways, clinically relevant biomarkers, therapeutic vulnerabilities, and molecular subtypes beyond conventional diagnostic categories. In conclusion, proteogenomic signatures offer a promising route toward mechanism-guided precision medicine, although clinical translation requires standardized workflows, diverse validation cohorts, ethical governance, and cost-effective integration into healthcare systems.