Ping Xia

Plant‐derived polyphenols possess broad anti‐inflammatory activities and may benefit chronic inflammatory diseases. XuanBi is a traditional Chinese medicine formula containing orally absorbable polyphenolic constituents and is used to treat rheumatoid arthritis (RA). This study investigated its absorbable components and potential mechanisms associated with synovial inflammatory hyperplasia. XuanBi was evaluated in collagen‐induced arthritis (CIA) rats and rheumatoid arthritis synovial fibroblasts (RASFs). Constituents in the decoction and rat serum were characterized by high‐performance liquid chromatography coupled with quadrupole‐Orbitrap mass spectrometry (HPLC‐Q‐Orbitrap‐MS). Predicted targets were intersected with synovial differentially expressed proteins (DEPs), followed by network pharmacology, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and experimental validation. Twenty‐six absorbable constituents were identified, including catechin, quercetin, baicalein, and wogonin, together with 14 candidate proteins associated with RA synovial pathology. Enrichment analysis implicated extracellular matrix (ECM)–receptor interaction, focal adhesion, and interleukin‐17 (IL‐17) signaling. Medium‐ and high‐dose XuanBi reduced joint swelling, synovial hyperplasia, and inflammatory infiltration in CIA rats. In RASFs, XuanBi inhibited proliferation, migration, and invasion. It also downregulated fibronectin 1 (FN1) and caveolin 1 (CAV1), reduced phosphorylation of SRC, focal adhesion kinase (FAK), and FYN, decreased integrin alpha 2b (ITGA2B) ⁺ /integrin beta 1 (ITGB1) ⁺ cells, and reduced interleukin‐1 beta (IL‐1β), interleukin‐6 (IL‐6), tumor necrosis factor alpha (TNF‐α), matrix metallopeptidase 3 (MMP3), and matrix metallopeptidase 9 (MMP9). Overall, XuanBi exerted anti‐inflammatory and anti‐synovial‐hyperplasia effects in experimental RA, accompanied by changes in proteins associated with these pathways, supporting the potential involvement of these pathways and warranting further mechanistic and clinical investigation.

Peroxiredoxins (PRDXs) are thiol-specific antioxidant enzymes that maintain cellular redox balance and regulate signaling pathways. They participate in the development of cancer, neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, and infectious diseases. In cancer, PRDXs are frequently overexpressed and promote tumor progression, metastasis, and treatment resistance through interactions with oncogenic pathways. In neurodegenerative and cardiovascular diseases, by contrast, they support cell survival by limiting oxidative damage. Therapeutic strategies directed at PRDXs include small-molecule inhibitors, activators, and gene therapy. PRDX inhibitors sensitize tumor cells to oxidative damage, whereas PRDX activators confer neuroprotection; the principal obstacles are achieving isoform specificity and limiting off-target effects. Here we review the structure and biology of the PRDX family, its isoform- and context-dependent functions across these disease settings, and the evidence supporting PRDXs as therapeutic targets and prognostic biomarkers.

While the histone lysine methyltransferase (KMT) family responsible for posttranslational modification has been reported to regulate multiple diseases progression like tumor and cardiovascular disease, its role in renal fibrosis progression is not completely understood. Here, via TGF‐β‐treated HK‐2 cells and an in vivo unilateral ureteral obstruction mice model, the histone lysine methyltransferase family was screened and the upregulated expression of KMT5a was identified in these renal fibrosis models. Interference assays using lentivirus transfection in HK‐2 cells and transgenic mice displayed that KMT5a silencing in HK‐2 cells impeded macrophage chemotaxis. Moreover, in vivo, transgenic KMT5a knockout inhibited macrophage infiltration, which contributed to the suppression of renal fibrosis progression. Mechanistically, by immunoprecipitation assays and mass spectrometry, we discovered that KMT5a could interact with and stabilize the transcription factor IRF3 to regulate macrophage chemotaxis and infiltration in renal tissues, which accelerated renal fibrosis progression. Notably, we confirmed that a small molecular inhibitor of KMT5a, UNC0379, reduced IRF3 protein levels and macrophage chemotaxis, thus suppressing renal fibrosis, in vitro and in vivo. Therefore, this study presented KMT5a as a mediator of renal fibrosis progression, an effect that was reversed by the KMT5a inhibitor UNC0379, which provided evidence of a novel target and potential drug for inhibiting renal fibrosis progression.

Background: In chronic kidney disease (CKD), there is evidence of loss of function and fibrosis in the progression of tubular epithelial cells; however, the cellular heterogeneity and underlying molecular mechanisms are not well defined. Knowledge of the diversity among tubular cells is essential for precision medicine therapy. Methods: We subjected renal cells from CKD patients to single‐cell RNA sequencing with a focus on tubular epithelial populations. Through unsupervised clustering, a computational pipeline that includes metabolic pathway scoring and pseudotemporal trajectory inference combined with machine learning classification, our analysis enabled the characterization of intratumoral cellular diversity and metabolic states coupled to differentiation trajectories. We analyzed segment‐specific markers (SLC34A1, SLC5A2, LRP2, CUBN, ALDOB, and GATM) and metabolic enzymes (glycolysis and TCA cycle enzymes) in cell subsets. Results: Tubular cells showed marked heterogeneity and metabolic reprogramming from oxidative phosphorylation to glycolysis, clustering as OXPHOS‐high, glycolytic, dormant, and intermediate cell states. The expression of segment‐specific markers was differentially retained and lost, reflecting maintenance of fate as well as dedifferentiation. Pseudotemporal analysis demonstrated progressive cellular transitions driven by the expression of critical genes such as MALAT1 and ANXA1. Proximal tubule cells constituted ∼70% of the profiled cells with different transcriptomic signatures. Moderate classification results were obtained using a machine learning approach (ROC AUC = 0.673). Conclusions: This work furnishes a molecular atlas of tubular epithelial cell heterogeneity in CKD, highlighting metabolic reprogramming and transdifferentiation as key processes driving tubular dysfunction and fibrosis. These results also revealed potential therapeutic targets to retain tubular function and ameliorate the progression of CKD.