In a report published in the Journal of Proteome Research last years advances and efforts within the Human Proteome Project (HPP) to define the human proteome and make proteomics an integral part of functional multiomics are presented.

The Human Proteome Organization (HUPO) has since 2010 coordinated the Human Proteome Project (HPP), which aim to identify at least one isoform of every protein-coding gene and to integrate proteomics into functional multiomics studies of health and disease.

The HPP reference proteome has transitioned from the NeXtProt list of proteins to a reference proteome based on GENCODE with the integration of data from UniProtKB, Human Protein Atlas, and PeptideAtlas. During 2025 the pipe line has been further refined and the current HPP reference proteome now contains 19,435 protein-coding genes, of which 94 % have confident detection of expression (PE1).

The progress in detecting the last 6%, the so called "missing proteins", has slowed down due to the difficulty of detecting genes with low expression or expresssion in highly specific tissues that are difficult to aquire. Targeted strategies, including ubiquitin enrichment, analysis of understudied tissues (e.g., brain, sperm, eye), and machine-learning models predicting protein detectability have been implemented to help solving these issues.

Beyond detection, the Grand Challenge Project within HPP aims to determine at least one function for each protein in the HPP reference proteome. Within this project a large drug perturbation study involving 63 drug compounds across 18 human breast cancer cell lines was completed this year and can hopefully help in the investigation of protein interactions and in obtaining the basis of protein function.

The progress of the HPP Grand ChallengeProject is evaluated with a function existence (FE) score, computed in a similar manner to the UNiProtKB PE scores. During 2025 the number of protein entries with the highest score increased by 288 resulting in a total of 5520 proteins with function score FE1 (highly specific function information from experimental evidence).

These efforts are moving HPP from cataloging proteins toward understanding their biological roles and clinical relevance.

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