Atlas of the Plasma Proteome in Health and Disease in 53,026 Adults

      Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure

       Comprehensive Discovery and Functional Characterization of the Noncanonical Proteome

       Proteomic Changes Upon Treatment with Semaglutide in Individuals with Obesity

      Chip-Tip: A Highly Sensitive Single-Cell Proteomics Technology

       Longitudinal Serum Proteome Mapping Reveals Biomarkers for Healthy Ageing and Related Cardiometabolic Diseases

       Integrated Proteogenomic Characterization of Ampullary Adenocarcinoma

       Multi-omics Reveals the Cellular and Molecular Features of Decidualization Resistance in Patients with a History of Severe Preeclampsia

Large-scale proteomic studies deepen our understanding of the mechanisms of health and disease and provide an important scientific basis for precision medicine. On 9 January, a cross-disciplinary study by the teams of Jin-Tai Yu and Ying Mao at Huashan Hospital, Fudan University, together with the teams of Wei Cheng and Jian-Feng Feng at the Institute of Science and Technology for Brain-Inspired Intelligence, appeared on the opening cover of Cell. Analysing plasma proteomic data from 53,026 individuals — covering 2,920 plasma proteins alongside 406 prevalent diseases, 660 incident diseases identified during follow-up and 986 health-related traits, over a median follow-up of 14.8 years — the study revealed 168,100 protein–disease associations and 554,488 protein–phenotype associations. More than 650 proteins were associated with at least 50 diseases, and more than 1,000 proteins showed sex and age differences, demonstrating considerable potential for disease discrimination (area under the curve [AUC] > 0.80 for 183 diseases). After integrating protein quantitative data, 474 causal proteins were identified, offering 37 drug repurposing opportunities and 26 safety-validated targets. The study establishes an open protein–phenotype resource (https://proteome-phenome-atlas.com/) that helps to elucidate the biological mechanisms of disease and accelerates the development of disease biomarkers, predictive models and therapeutic targets.

Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure

Compared with people without HIV, people living with HIV face a higher risk of heart failure and left atrial remodeling. Although the mechanism remains unclear, inflammatory responses and premature senescence are likely to be key factors. A research team at Johns Hopkins University analysed plasma proteomic and cardiac magnetic resonance imaging data from two independent study populations, revealing potential similarities between HIV-associated immune dysfunction and aging-related immune dysfunction that may lead to atrial remodeling and clinical heart failure. The team further found that plasma proteomic signatures may partly reflect or drive HIV-associated atrial remodeling, and that many of these signatures are associated with the timing of incident heart failure in an independent community cohort of older adults without HIV. This proteomic signature was statistically enriched in immune checkpoint proteins, tumour necrosis factor signalling, Ephrin signalling and extracellular matrix organization, identifying possible shared pathways between HIV and aging that give rise to heart failure risk.

Systematic identification and functional characterization of noncanonical translation products (such as novel peptides) deepens our understanding of the human genome and offers new insights into cell biology. The team of Ai-Fu Lin at the Fourth Affiliated Hospital of Zhejiang University School of Medicine constructed a micropeptide open reading frame reference database and developed an ultrafiltration-based mass spectrometry identification system to map the gastric cancer micropeptide landscape; based on CRISPR functional screening, AI structural modelling and the micropeptide–protein interaction network (mPPI), they developed a framework for predicting micropeptide function, providing important tools and data resources for micropeptide research. Using this micropeptide mass spectrometry system, the researchers identified 8,945 previously unannotated micropeptides in gastric cancer clinical samples and cell lines and constructed the gastric cancer micropeptidome; notably, 50.3% of the micropeptides originated from non-coding RNAs (ncRNAs) previously thought to lack coding capacity. CRISPR screening based on cell proliferation further revealed that 1,161 ncRNA-derived micropeptides were significantly associated with gastric cancer cell proliferation, with more than 80% of them promoting cancer. To verify the authenticity and reliability of the micropeptide library, the researchers adopted a multi-level, tiered validation strategy including micropeptide-tag plasmid construction, polysome profiling, Flag-knock-in technology and antibody preparation. They also validated the interactomes of four representative micropeptides — pep1-nc-OLMALINC, pep5-nc-TRHDE-AS1, pep-nc-ZNF436-AS1 and pep2-nc-AC027045.3 — together with their subcellular localization and functions, and used animal models and clinical samples to illustrate their potential clinical value as markers and targets in gastric cancer treatment. Overall, by building a human micropeptide ORF reference library and developing an ultrafiltration-based micropeptide mass spectrometry identification system, this study successfully mapped the human gastric cancer micropeptide landscape and established a structure–interaction-based framework for predicting micropeptide function, systematically screening and identifying functional micropeptides. This not only provides important tools and data resources for micropeptide research, but also offers a significant complement to the human functional genome and proteome, as well as a theoretical basis for the development of gastric cancer targets and drugs.

Obesity and type 2 diabetes are common chronic diseases that can be effectively managed with semaglutide. Yet the systematic impact of semaglutide on the human proteome — particularly its mechanisms of action beyond weight regulation — remains poorly studied. A research team from Denmark used large-scale proteomic analysis to examine serum samples from two randomized, double-blind, placebo-controlled phase 3 clinical trials (STEP 1 and STEP 2). Using the SomaScan® platform to measure the relative abundance of more than 6,400 unique proteins, they revealed the mechanisms through which semaglutide acts on weight regulation, glucose metabolism, lipid metabolism and inflammatory pathways, and further explored its potential value for cardiovascular protection and drug repurposing. This study not only provides an important basis for a deeper understanding of the pharmacological mechanisms of semaglutide, but also highlights the broad application prospects of proteomics technology in disease mechanism research and drug development.

Chip-Tip: A Highly Sensitive Single-Cell Proteomics Technology

Current single-cell proteomics technologies typically identify only 1,000 to 2,000 proteins per cell; this limited depth of coverage constrains the study of complex biological questions such as cellular heterogeneity, making the development of new technologies with higher sensitivity and broader coverage an urgent priority. Recently, Dr. Zilu Ye of the Institute of Systems Medicine, Chinese Academy of Medical Sciences / Suzhou Institute of Systems Medicine, together with Professor Jesper Olsen of the University of Copenhagen, developed a highly sensitive single-cell proteomics technology called Chip-Tip. The technology can identify more than 5,000 proteins in a single HeLa cell and detect post-translational modifications without additional enrichment. The team applied Chip-Tip to analyse the single-cell proteomes of tumour cells stimulated with 5-fluorouracil and of induced pluripotent stem cells undergoing differentiation, successfully identifying protein markers and achieving precise quantification. This shows that Chip-Tip has outstanding sensitivity and can be used to discover cell-specific markers and potential therapeutic targets. The technology provides a leaner and more efficient tool for exploring the diversity of post-translational modifications and the regulatory mechanisms at the single-cell level, which not only helps us better understand fundamental biological principles but also opens up new possibilities for biomedical research. Chip-Tip is expected to become an important means of decoding the complex dynamic changes inside cells and advancing personalized medicine.

Longitudinal Serum Proteome Mapping Reveals Biomarkers for Healthy Ageing and Related Cardiometabolic Diseases

Aging is an inevitable natural process in the course of life, accompanied by the gradual decline of physical function and a marked increase in susceptibility to disease. Although a variety of physiological measurements, functional assessments and high-throughput omics technologies are now widely used to estimate biological age, fully uncovering the complex biological mechanisms behind aging remains a major challenge. Recently, a research team at Westlake University performed longitudinal proteomic analysis of 7,565 serum samples from 3,796 middle-aged and older adults, identifying 86 protein markers closely associated with the aging process; these markers were significantly associated with 32 clinical traits and the incidence of 14 major categories of age-related chronic disease. Using machine learning algorithms, the team further selected 22 key proteins from the 86 markers to construct a proteomic healthy aging score (PHAS) capable of predicting cardiometabolic disease risk. This study not only reveals serum proteomic biomarkers associated with human aging, but also provides a valuable proteomic perspective for exploring the underlying mechanisms of aging. More importantly, the protein markers identified are expected to become important tools for monitoring and predicting cardiometabolic diseases related to aging, pointing in a new direction for the promotion of healthy ageing.

Ampullary adenocarcinoma (AMPAC) is a rare, heterogeneous malignant tumour that usually arises in the region of the ampulla of Vater. Owing to its unclear aetiology, extremely low incidence and complex anatomy, AMPAC has long presented numerous challenges in clinical and pathological research. Recently, the teams of Chen Ding at the Human Phenome Institute of Fudan University, Ying-Yong Hou at the Department of Pathology of Zhongshan Hospital, Fudan University, and Yu Liu at Shanghai Children's Medical Center affiliated to Shanghai Jiao Tong University, performed a comprehensive proteogenomic analysis of 198 samples from Chinese patients with AMPAC and from duodenal patients. Genomic data indicated that 4q deletion leads to fatty acid accumulation and cell proliferation. Proteomic analysis revealed three distinct clusters (C-FAM, C-AD and C-CC), of which the C-AD cluster was the most aggressive, was associated with the worst prognosis and was characterized by the formation of focal adhesions. Immune clustering defined three immune clusters and revealed that immune clusters M1 (macrophage-infiltrated) and M3 (DC-infiltrated) showed higher immune scores than the M2 cluster (CD4+ T cell-infiltrated), and were associated with poor prognosis, possibly because tumour cells secrete IL-6 and the effects that follow. Through comprehensive proteogenomic analysis, this study provides a deeper understanding of AMPAC and new insights into potential therapeutic directions for the disease.

Endometrial decidualization resistance (DR) is associated with a range of gynaecological and obstetric diseases. Researchers in Spain used a multi-omics strategy to investigate in depth the cellular and molecular features of decidualization resistance in patients with a history of severe preeclampsia (sPE). Morphological analysis found significant anatomical abnormalities in the endometrial glands of these patients, which digital tissue section analysis further confirmed. Single-cell RNA sequencing (scRNA-seq) showed that, compared with controls, the endometrial cell composition of sPE patients changed markedly, presenting a stromal mosaic state in which proliferative stromal cells (such as MMP11- and SFRP4-positive cells) coexist with IGFBP1-positive decidualized cells, together with an epithelial mosaic state and the loss of decidualization-associated epithelial–stromal transition. Cell–cell communication network analysis revealed abnormal cross-talk between specific cell types involving key signalling pathways such as endoglin, WNT and SPP1. Spatial transcriptomics validated the DR-associated features in a replication cohort. Laser capture microdissection/mass spectrometry analysis further confirmed several of the scRNA-seq findings in a second replication cohort, in particular the loss of stromal-to-epithelial transition at the level of signalling pathways, indicating that the response to steroid hormones, especially oestrogen, is disrupted. These findings provide new insights into the pathological mechanisms of DR in the context of sPE.