The human blood proteome provides a holistic readout of health states through the assessment of thousands of circulating proteins. In this study, we present a pan-disease resource to enable the study of diverse disease phenotypes within a harmonized proteomics dataset. By profiling protein concentrations across 59 diseases and healthy cohorts, we identified proteins associated with age, sex, and body mass index, as well as disease-specific signatures. This study highlights shared and distinct protein patterns across conditions, demonstrating the power of a unified proteomics approach to uncover biological insights. The dataset, covering 8262 individuals and up to 5416 proteins, serves as an online resource for exploring disease-specific protein profiles and advancing precision medicine research.

New technologies enable single-cell transcriptome analysis, mapping genome-wide expression across the human body. Here, we present an extended analysis of protein-coding genes in all major human tissues and organs, combining single-cell and bulk transcriptomics. To enhance transcriptome depth, 31 tissues were analyzed using a pooling method, identifying 557 unique cell clusters, manually annotated by marker gene expression. Genes were classified by body-wide expression and validated through antibody-based profiling. All results are available in the updated open-access Single Cell Type section of the Human Protein Atlas for genome-wide exploration of genes, proteins, and their spatial distribution in cells.

Herbs are extensively utilized in Traditional Chinese Medicine (TCM) for lung and liver cancer treatment, but the mechanisms behind these herbs remain largely unknown. Here, high-throughput transcriptomic analysis technology was used to uncover molecular mechanisms of herbal treatment. Furthermore, we developed a compound recognition approach utilizing the LINCS L1000 database to identify potential treatment targets. Our results showed that among 14 herbs tested, Pulsatilla chinensis exhibited the strongest anticancer effects in A549 and Huh7 cells, followed by Bupleurum chinense, and Polyporus umbellatus. P. chinensis exerts its anticancer properties by downregulating cell cycle-related transcription factors, including E2F1 and TFDP1. Notably, the mechanisms of P. chinensis treatment differed between the two cell lines. In A549 cells, which possess wild-type p53, P. chinensis induced apoptosis through the regulation of the p53 pathway. In contrast, in Huh7 cells, which harbor mutant p53, the effect was mediated via the TNF-alpha/NF-kappa B signaling pathway. We also identified two drugs, AMG232 and Nutlin-3, that exhibited treatment effects similar to P. chinensis in A549 cells. Both drugs function as inhibitors of the MDM2-p53 interaction. Western blot analysis confirmed the alteration of the relevant proteins, aligning with our computational predictions. Furthermore, 23-hydroxybetulinic acid, a key active compound of P. chinensis, demonstrated the ability to inhibit the p53-MDM2 interaction by binding to the same pocket on the MDM2 protein.

Background Chronic liver disease due to alcohol-related liver disease and chronic viral hepatitis pose a substantial burden on healthcare systems. Chronic liver disease may predispose to hepatocellular carcinoma, for which therapeutic options are limited. This study aimed to explore the immune cell characteristics of the clinical conditions.Methods Explant liver samples were collected from 25 patients for bulk RNA sequencing and flow cytometry analysis. Immune cell populations were characterized by flow cytometry from isolated hepatic and peripheral mononuclear cells.Results Significant differences in immune cell characteristics were observed among patients with three clinical conditions. Viral hepatitis and peri-tumor samples exhibited higher hepatic B cell counts compared to alcohol-related liver disease. Additionally, chronic liver disease patients showed higher levels of CD57+ T cells, suggestive of T cell differentiation. Differential expression analysis identified several genes associated with immune regulation, including downregulation of CD27 and upregulation of granzyme B in ARLD, consistent with a highly differentiated phenotype. LAG3 and PDCD1 were upregulated in peri-tumor samples. The NK cell count was lower in peri-tumor liver specimens compared to ARLD, and an upregulation of TIGIT, an inhibitory marker, was observed in those peri-tumor specimens.Conclusion This study contributes to the understanding of immune dynamics in chronic liver disease among different etiologies. B lymphocytes are relatively reduced in alcohol-related liver disease compared to other groups, and T cells exhibit a more differentiated subtype. The peritumor microenvironment in HCC suggests a relatively diminished presence of NK cells and a potential tendency toward increased inhibitory characteristics.

Chronic hepatic injury and inflammation from various causes can lead to fibrosis and cirrhosis, potentially predisposing to hepatocellular carcinoma. The molecular mechanisms underlying fibrosis and its progression remain incompletely understood. Using a proteo-transcriptomics approach, we analyze liver and plasma samples from 330 individuals, including 40 healthy individuals and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease. Our findings reveal dysregulated pathways related to extracellular matrix, immune response, inflammation, and metabolism in advanced fibrosis. We also identify 132 circulating proteins associated with advanced fibrosis, with neurofascin and growth differentiation factor 15 demonstrating superior predictive performance for advanced fibrosis(area under the receiver operating characteristic curve [AUROC] 0.89 [95% confidence interval (CI) 0.81–0.97]) compared to the fibrosis-4 model (AUROC 0.85 [95% CI 0.78–0.93]). These findings provide insights into fibrosis pathogenesis and highlight the potential for more accurate non-invasive diagnosis.

Parkinson’s disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson’s disease and Alzheimer’s disease animal models and the cognitive functions in Alzheimer’s disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson’s disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson’s Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson’s disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson’s disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson’s disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson’s disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson’s disease patients as recently shown in Alzheimer’s disease patients.

Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.

Background Clear cell renal carcinoma (ccRCC) is the predominant form of kidney cancer, but the prognostic value of expression quantitative trait loci (eQTLs) remains underexplored, particularly in Asian populations. Objective We analyzed whole-exome sequencing and RNA sequencing data from 100 Japanese ccRCC patients to identify eQTLs. Multiple Cox proportional hazard models assessed survival associations, with validation in the Cancer Genome Atlas ccRCC cohort (n = 287). Results We identified 805 eGenes and 4,558 cis-eQTLs in the Japanese cohort. Survival analysis revealed a total of 9 eGenes significantly associated with overall survival (FDR < 0.05). Further exploratory analysis were performed using 158 eGenes and 711 eQTLs (p-value <0.05) as potential prognostic signals. Among these, 223 eQTLs regulating 54 eGenes showed consistent prognostic effects at both expression and genetic levels. Cross-population validation identified eight eQTLs regulating 11 eGenes with reproducible survival associations across ethnicities, including a missense mutation in ERV3–1 and regulatory variants near ANKRD20A7P. These variants demonstrated consistent allelic effects on both gene expression and patient survival in both cohorts.

Pyruvate kinase is a key regulator in hepatic glucose metabolism, encoded by the gene pyruvate kinase liver/red blood cells (PKLR). Systems biology-based approaches, including metabolic and gene co-expression networks analyses, as well as genome-wide association studies (GWAS), have led to the identification of PKLR as a pivotal gene influencing liver metabolism in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Here, we review the critical role of PKLR in MASLD and HCC progression and examine the effects of PKLR modulation both in vitro and in vivo. We also discuss the development of therapeutic strategies for patients with MASLD and HCC by modulating PKLR, highlighting its promising future in a broader range of liver diseases.

Background: Cancer is one of the leading causes of mortality worldwide, highlighting the urgent need for a deeper molecular understanding and the development of personalized treatments. The present study aims to establish a solid association between gene expression and patient survival outcomes to enhance the utility of the Human Pathology Atlas for cancer research. Methods: In this updated analysis, we examined the expression profiles of 6918 patients across 21 cancer types. We integrated data from 10 independent cancer cohorts, creating a cross-validated, reliable collection of prognostic genes. We applied systems biology approach to identify the association between gene expression profiles and patient survival outcomes. We further constructed prognostic regulatory networks for kidney renal clear cell carcinoma (KIRC) and liver hepatocellular carcinoma (LIHC), which elucidate the molecular underpinnings associated with patient survival in these cancers. Findings: We observed that gene expression during the transition from normal to tumorous tissue exhibited diverse shifting patterns in their original tissue locations. Significant correlations between gene expression and patient survival outcomes were identified in KIRC and LIHC among the major cancer types. Additionally, the prognostic regulatory network established for these two cancers showed the indicative capabilities of the Human Pathology Atlas and provides actionable insights for cancer research. Interpretation: The updated Human Pathology Atlas provides a significant foundation for precision oncology and the formulation of personalized treatment strategies. These findings deepen our understanding of cancer biology and have the potential to advance targeted therapeutic approaches in clinical practice. Funding: The Knut and Alice Wallenberg Foundation ( 72110), the China Scholarship Council (Grant No. 202006940003).