Chinese Researchers Unveil Highest-Resolution Human Proteome Map, Opening New Frontiers in Drug Discovery and Precision Oncology
核心洞察
A Chinese-led team analyzed over 13,000 proteins across nearly 3,000 tissue samples spanning 58 normal tissues and 25 cancer types, creating the most comprehensive spatial human proteome atlas to date.
The study, published in Nature, used a novel DIA-MS platform that increases analytical speed tenfold while enabling proteomic analysis from tissue samples as small as a sesame seed.
Researchers identified 8,940 differentially expressed proteins across cancers and linked 2,598 drugs to 402 tissue-enriched protein targets, revealing new opportunities for drug repurposing including Trodelvy for endometrial cancer.
A landmark study led by Professor Guo Tiannan of Westlake University (搜索)'s School of Medicine has produced the highest-resolution and most comprehensive spatial map of the human proteome ever constructed, a breakthrough that promises to transform drug development from "exploring a black box" into a process guided by a detailed molecular atlas.
Published in the journal Nature, the research analyzed nearly 3,000 human tissue samples covering 58 normal tissue types and 25 types of cancer. The team conducted quantitative analyses of more than 13,000 proteins, generating what researchers described as the most detailed spatial atlas of the human proteome to date. All data have been made publicly available through an open-access database for researchers worldwide.
A Technological Leap in Proteomics
To enable this large-scale endeavor, Guo's team developed a proteomics analysis platform based on data-independent acquisition mass spectrometry (DIA-MS) capable of processing extremely small tissue samples. Using the new method, researchers can perform standardized proteomic analyses with tissue samples as small as a sesame seed. According to Westlake University (搜索), the approach increases analytical speed by approximately tenfold while significantly reducing experimental costs, laying the technical foundation for large-scale, high-throughput proteomics research.
After years of sample collection and experimental work, the team established a database containing 15,332 proteins and conducted precise quantitative analyses of 13,609 of them. The samples were obtained from nine post-mortem adult donors, nine post-mortem fetal donors, eight healthy individuals, and 1,015 cancer patients.
Mapping the Continuum from Health to Disease
The researchers employed t-SNE visualization and trajectory analysis to investigate how fetal, tumor, paired non-tumor, and healthy adult samples relate to one another. Their analysis revealed that protein profiles placed these tissue types along a continuum reflecting increasing tissue differentiation, with notable exceptions in brain and liver samples.
Brain tissues across fetal, tumor, paired non-tumor, and normal adult states showed relatively stable protein profiles with fewer developmental shifts. In contrast, liver tissues exhibited much larger changes, which the authors linked to the liver's adaptive plasticity. While proteins involved in RNA processing were most abundant in fetal tissues, those linked to antibody-based immunity predominated in adult tissues.
Tissues with specialized biological functions formed distinct molecular clusters. For example, the semicircular canals and cochlea grouped separately, while functionally related tissues including the brain, spinal cord, and peripheral nerves clustered closely together. Across 36 tissues overlapping with Human Protein Atlas data, the team identified 832 proteins uniquely enriched in their dataset, including pannexin 3 (PANX3 (搜索)) detected at particularly high levels in the cochlea and confirmed using synthesized peptides.
Implications for Drug Safety and Repurposing
The analysis linked 2,598 drugs to 402 proteins that were especially abundant in certain tissues, with the liver containing most of these targets. Cytochrome P450 2C8 (CYP2C8 (搜索)), a liver-enriched enzyme involved in drug metabolism, was targeted by 302 drugs. The researchers highlighted gemfibrozil as a potent CYP2C8 inhibitor that can raise concentrations of co-administered drugs and increase the risk of adverse effects. Triclosan exposure was also noted for its targeting of thyroid peroxidase, an enzyme essential for thyroid hormone production, with potential implications for thyroid function.
In the oncology domain, the team identified 8,940 differentially expressed proteins (DEPs) across 25 cancer types, of which 2,878 were specific to a single cancer type. Testicular carcinomas (搜索) showed increased expression of tissue-specific proteins, suggesting these tumors may exploit intrinsic germ-cell growth programs.
The researchers screened 77 upregulated DEPs shared among tumors that were targeted by 36 biomolecular drugs, mostly receptor tyrosine kinase inhibitors, evaluated in 2,084 clinical trials. Notably, the findings suggest that Trodelvy, an antibody-drug conjugate approved for triple-negative breast cancer (搜索), could be explored for endometrial cancers (搜索) because both trophoblast cell surface antigen 2 (TROP2 (搜索)) and DNA topoisomerase 1 (TOP1 (搜索)) are upregulated in the disease. The team also identified potential new targets such as TYROBP (搜索), which could be investigated as a shared antibody-drug conjugate target, though its myeloid expression requires careful toxicity evaluation.
A New Era for Precision Medicine
Guo emphasized that the findings could help transform drug development by enabling researchers to identify potential drug targets more accurately, making the process more precise and efficient. The map could also help scientists uncover new therapeutic targets for existing medicines, opening new possibilities for drug repurposing.
The study provides a comprehensive human protein atlas spanning healthy and tumor tissues that deepens understanding of tumor pathophysiology. By unraveling health- and disease-specific alterations in fetal and adult tissues, the dataset could help advance research into human development, tissue biology, and drug discovery. The researchers noted that future studies should include larger samples of individuals across different ages and tumor types to validate the findings.