Dark proteome and emerging technologies for functional characterization and drug discovery

Despite major advances in genomics and proteomics, a substantial portion of the human proteome remains poorly characterized and is commonly known as the 'dark proteome'. These understudied proteins often lack detailed structural, functional, and biochemical information, limiting our understanding of their biological roles and therapeutic potential. Recent developments in artificial intelligence (AI)-based structure prediction, cryo-electron microscopy (cryo-EM), functional genomics, and multi-omics technologies have provided new opportunities to explore this hidden region of the proteome. Characterizing the dark proteome could reveal novel therapeutic targets for cancer, neurodegenerative, metabolic, and rare genetic diseases. In this review, we summarize current knowledge of the dark proteome, highlight emerging experimental and computational approaches, discuss key challenges, and outline prospects for translating dark proteome discoveries into therapeutic applications.