Pan‐Modification Proteoformics: A Framework for Decoding Proteomic Complexity in Health and Disease

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ABSTRACT Proteoformics by pan‐modifications offers a critical framework for understanding the proteomic diversity through nongenetic factor‐induced structural and functional variations. This paradigm expands the view beyond traditional proteomics to encompass a broader spectrum of protein variations from post‐translational modifications (PTMs) to nongenetic factors such as nonstandard amino acid incorporation, RNA editing, metabolism, and environmentally induced alterations. Deciphering the pan‐modification landscape requires advanced technologies, particularly bottom–up proteomics workflows integrated with sophisticated open‐search algorithms and biological validation. This review provides a comprehensive overview of how this approach delivers functional and structural insights into critical biological processes and their dysregulation in human diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. We highlight the key technological advances that enables proteoform identification and functional annotation, and discuss their translational potential for discovering diagnostic biomarkers and therapeutic targets. Collectively, proteoformics by pan‐modifications underscores the pivotal role of nongenetic protein diversity in physiology and disease, paving the way for next‐generation diagnostics and therapeutics.

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