Pyrroline-5-carboxylate reductase (PYCR) is pivotal in converting pyrroline-5-carboxylate (P5C) to proline, the final step in proline synthesis. Three isoforms, PYCR1, PYCR2, and PYCR3, existed and played significant regulatory roles in tumor initiation and progression. In this study, we first assessed the molecular and immune characteristics of PYCRs by a pan-cancer analysis, especially focusing on their prognostic relevance. Then, a kidney renal clear cell carcinoma (KIRC)-specific prognostic model was established, incorporating pathomics features to enhance predictive capabilities. The biological functions and regulatory mechanisms of PYCR1 and PYCR2 were investigated by in vitro experiments in renal cancer cells. The PYCRs’ expressions were elevated in diverse tumors, correlating with unfavorable clinical outcomes. PYCRs were enriched in cancer signaling pathways, significantly correlating with immune cell infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI). In KIRC, a prognostic model based on PYCR1 and PYCR2 was independently validated statistically. Leveraging features from H&E-stained images, a pathomics feature model reliably predicted patient prognosis. In vitro experiments demonstrated that PYCR1 and PYCR2 enhanced the proliferation and migration of renal carcinoma cells by activating the mTOR pathway, at least in part. This study underscores PYCRs’ pivotal role in various tumors, positioning them as potential prognostic biomarkers and therapeutic targets, particularly in malignancies like KIRC. The findings emphasize the need for a broader exploration of PYCRs’ implications in pan-cancer contexts.

Klebsiella pneumoniae (K. pneumoniae) is a leading cause of hospital- and community-acquired lower respiratory infections (LRI). The emergence of antimicrobial resistance (AMR), especially carbapenem-resistant strains (CRKP), poses a serious global health threat. Using Global Burden of Disease (GBD) 2021 data, we estimated AMR-related mortality for K. pneumoniae-associated LRI across regions from 1990 to 2021. Joinpoint regression analysis identified temporal trends. Global mortality declined overall, with a 70% reduction in under-5 deaths but a doubling among adults over 70 years. Deaths associated with and attributable to AMR decreased by 18.9% and 4.5%, respectively. The age-standardized mortality rate (ASMR) fell by nearly 50%. In contrast, the mortality burden associated with carbapenem resistance increased markedly, with AMR-associated deaths rising by 157% and disproportionately affecting high-burden regions such as Sub-Saharan Africa and South Asia. Despite overall progress, the increasing mortality burden associated with carbapenem resistance in K. pneumoniae-associated LRI poses a critical and persistent global health threat.

Xylene is a common industrial solvent that includes three isomers: o-xylene, m-xylene, and p-xylene. Long-term exposure to low doses of xylene in the environment has been linked to a higher risk of lung cancer. However, the molecular mechanisms behind this link are still not fully understood. In this study, we used a combination of network toxicology and molecular docking to investigate how xylene may contribute to the development of non-small cell lung cancer (NSCLC). We first identified 115 potential target genes related to xylene exposure by searching several public databases, including CHEMBL, STITCH, GeneCards, and OMIM. Further screening using the STRING platform and Cytoscape analysis highlighted five core targets: IL1A, H3C13, ITGAM, CCR5, and COMT. We utilized scRNA-seq data to analyze the expression patterns of core targets across distinct cell subpopulations, the majority of core targets were expressed in immune cells. We then performed GO and KEGG pathway enrichment analysis. These results showed that the five target genes are mainly involved in cancer-related pathways, such as ECM-receptor interaction, focal adhesion, chemical carcinogenesis, and the PI3K-Akt signaling pathway. Molecular docking results confirmed that xylene isomers have strong binding affinities with the proteins encoded by these genes. This suggests that xylene may disrupt important cellular signals and promote tumor growth. In conclusion, our study provides new insight into how xylene might cause NSCLC at the molecular level. It also shows the usefulness of network toxicology in evaluating health risks from environmental chemicals. These findings may help guide future efforts in prevention and treatment strategies.

Severe Klebsiella pneumoniae pneumonia is associated with substantial mortality and is characterized by intense systemic inflammation that coexists with a failure to control infection. The cellular changes underlying the transition from effective host defense to immune dysfunction remain incompletely defined. Here, we constructed a severity‐focused single‐cell transcriptomic atlas of 708,894 peripheral blood mononuclear cells from 100 individuals (54 healthy controls, 23 patients with mild disease, and 23 patients with severe disease), complemented by plasma protein measurements and flow cytometry. Mild disease was characterized by a relatively coordinated peripheral immune response, with preserved monocyte regulatory and tissue‐repair programs, preserved cytotoxic lymphocyte activity, and coordinated interactions between T follicular helper cells and B cells. Severe disease showed marked monocyte inflammation together with widespread disruption of adaptive immune responses. Classical monocytes expanded and showed increased expression of S100A8/A9/A12 , accompanied by enhanced TLR4–MYD88 signaling and elevated plasma S100 proteins. These changes were accompanied by impaired dendritic cell antigen presentation, expansion of immunoregulatory monocyte states resembling monocytic myeloid‐derived suppressor cells, cytotoxicity‐ and exhaustion‐associated changes in CD8 ⁺ T cells and natural killer cells, hyperactivated yet poorly coordinated CD4 ⁺ T cell states, and weaker B cell receptor signaling despite plasma cell expansion. These findings delineate a severity‐associated peripheral immune state characterized by monocyte‐centered inflammatory signatures and features of altered adaptive immune coordination, and provide a basis for future mechanistic investigation of monocyte‐derived S100 alarmins and severity‐associated myeloid remodeling.

Background: Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. It reduces quality of life and increases the risk of complications such as stroke. Although progress has been made in understanding its pathogenesis, the key cellular subtypes and therapeutic targets remain unclear. Methods: We applied single‐cell transcriptomics to identify critical cellular subtypes in AF. High‐dimensional weighted gene co‐expression network analysis (hdWGCNA) and machine learning were used to screen AF‐related genes. Mendelian randomization (MR) and colocalization analyses were performed to assess causal relationships between these genes and AF. Results: Single‐cell analysis showed a significant increase in macrophages in AF, especially SPP1‐expressing macrophages, which may drive AF onset and progression. HdWGCNA identified AF‐related gene modules. Three genes, LRCH1, RSRC2 and VAMP2, were found to be causally associated with AF. MR analysis confirmed their significant causal effects. Conclusions: The accumulation of SPP1‐expressing macrophages may drive the onset and progression of AF. Furthermore, LRCH1, RSRC2, and VAMP2 were identified as key causal genes for AF, providing novel insights into its molecular mechanisms and potential therapeutic targets.