ABSTRACT The disease course in patients with advanced lung cancer with malignant serous effusions (ALC‐MSE) is complex, and treatment outcomes are difficult to predict; systematic studies on the tumor stem cell‐like characteristics and regulatory mechanisms of this condition are still lacking. Based on single‐cell transcriptomic data and the TCGA‐LUAD cohort, this study systematically analyzed the functional characteristics and key regulatory networks of malignant epithelial cells in severe lung cancer. Key findings include: epithelial cells in severe lung cancer exhibit significantly attenuated inflammation‐ and immunity‐related signaling pathways (including NF‐κB, TNF, and JAK–STAT signaling pathways), enhanced stem cell‐like properties, and metabolic reprogramming; we identified a highly stem‐like malignant epithelial cell subpopulation, represented by Cluster 3, which is enriched in stem‐like pathways such as Notch, Hippo, TGF‐β, and FoxO, and is accompanied by enhanced mitochondrial metabolism and stress adaptability; STMN1 is a key molecule regulating this stem‐like state, showing a significant positive correlation with stemness scores and mRNAi; cells with high STMN1 expression gain a survival advantage and may maintain their stemness by attenuating CAF/ECM signaling with other cells (COL1A1‐CD44), inhibiting complement activation and antigen presentation signaling (such as C3, ANXA1, and MHC‐II‐related molecules), and enhancing stemness niche signaling (MIF‐CD74/CD44). Furthermore, NELFE, MYBL2, FOXN3, POLR2A, and RAD21 were identified as potential upstream regulators of STMN1. In vitro experiments confirmed that, following induction of stem cell‐like properties, STMN1 was significantly overexpressed in lung adenocarcinoma cells, accompanied by upregulation of related stem cell markers (SOX2, NANOG, OCT4, and CD44). In summary, this study reveals a significantly enhanced stemness state in malignant epithelial cells in advanced lung cancer, accompanied by suppressed inflammatory signaling and enhanced metabolic adaptation, and identifies STMN1 as a key molecule driving stemness maintenance and disease progression.
ABSTRACT Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent pelvic pain disorder in men, yet effective pharmacotherapies remain limited. Emerging evidence suggests that oxidative stress and dysregulated iron metabolism contribute to the pathogenesis of CP/CPPS, with ferroptosis increasingly implicated in CP/CPPS‐related pathology. Qianlie Zhitong Formula (QLZTF) has shown therapeutic potential in treating CP/CPPS; however, its underlying mechanisms remain incompletely understood. This study integrated proteomics, metabolomics, and in vivo experiments to investigate the therapeutic mechanisms of QLZTF. A carrageenan‐induced rat model was established, and rats were randomly assigned to five groups: control, model, Qianliekang, low‐dose QLZTF, and high‐dose QLZTF. QLZTF significantly reduced inflammatory cytokines (TNF‐α, IL‐6, and IL‐1β), alleviated pain responses, and ameliorated prostate tissue injury. Proteomic analysis identified BCAT2, ALDH1B1, and ALDH2 as significantly upregulated proteins closely associated with ferroptosis. KEGG enrichment analysis of both proteomic and metabolomic data revealed that pantothenate and CoA biosynthesis and branched‐chain amino acid (BCAA) degradation pathways were significantly enriched. Integrated analysis indicated that QLZTF synergistically regulates these pathways, activates the BCAT2/ALDH axis, and inhibits ferroptosis, thereby alleviating inflammation, pain, and fibrosis in CP/CPPS. This study provides the first multiomics evidence for the anti‐ferroptotic mechanism of QLZTF.
ABSTRACT Bone metastasis of lung adenocarcinoma (LUAD) directly leads to poor prognosis. This study aimed to dissect the stromal landscape of LUAD with bone metastases. Unsupervised clustering of scRNA‐seq data from LUAD patients with bone metastasis identifies stromal subsets. Pseudotime analysis combined with CytoTRACE stemness scoring reconstructs mesenchymal stromal cell (MSC) differentiation trajectories, while CellChat characterizes cell–cell communication networks among MSC subpopulations. Differentially expressed genes (DEGs) specific to functionally distinct MSC subsets are subjected to LASSO‐Cox regression for construction of a prognostic RiskScore model, which is validated in independent bulk RNA‐seq cohorts regarding overall survival, immune cell infiltration, and drug sensitivity. A distinct high‐stemness MSC C1 subpopulation is localized at the bifurcation point of two divergent differentiation trajectories toward a matrix‐remodeling fate and a secretory, immunomodulatory phenotype. The RiskScore model stratifies patients into low‐ and high‐risk groups with divergent overall‐survival outcomes. Reduced infiltration of cytotoxic lymphocytes is observed in high‐risk patients, and higher drug sensitivity within the high‐risk subgroup. In vitro assays verify that LDHA knockdown impairs proliferation and migration in A549 cells. This study provides a rationale for targeting stroma‐derived genes in risk‐adapted therapy.
ABSTRACT The nanocomposites based on aminopropylsilanol (Si~NH 2 ) and polylysine‐anatase (Ans/PL) nanoparticles bearing DNAzymes (Dz) and oligodeoxyribonucleotides (ON) can effectively inhibit the replication of the influenza A/H5N1 virus in cell culture. Nanocomposites based on both types of nanoparticles exhibit high activity. The Dz‐containing nanocomposites exhibited higher antiviral activity than those containing ON, reducing influenza A/H5N1 virus production by 3.5 log versus 2.4–3.0 log, respectively. Notably, the effect of Dz incorporated into the nanoparticles was an order of magnitude higher than that of unbound Dz transfected with lipofectamine. Nanocomposites carrying control DNA fragments that are not specific to the influenza A virus genome have practically no antiviral activity, indicating the specificity of the proposed nanocomposites. It was demonstrated that the antiviral efficacy of the nanocomposites is primarily determined by the activity of DNA delivered into cells, which can be varied by altering either the nanocomposite concentration or its capacity for DNA fragments. All of the proposed nanocomposites can be considered as potential antiviral drugs.
ABSTRACT In the present study, a series of curcumin analogs (A1–P3) were designed and synthesized for the inhibition of prostate cancer cells by targeting androgen receptor (AR). All synthesized compounds were structurally characterized by 1 H NMR, 13 C NMR, and high‐resolution mass spectrometry (HRMS). In vitro cytotoxicity assays demonstrated that multiple compounds exhibited comparable or improved cytotoxicity against AR‐positive 22Rv1 cells as compared to dimethylcurcumin (DMC, ASC‐J9). Among these compounds, compounds A2, A3, B1–B3, D1, F1, F3, G1, G3, H1, and P3 possessed higher selectivity toward prostate cancer cells as compared to DMC. Compounds O1–O3, A1–A3, B1–B3, F1, F3, G1, I1, and P3 exhibited lower cytotoxicity against AR‐negative PC‐3 cells than those against 22Rv1 cells. Based on the cytotoxicity results, the structure–activity relationships were analyzed. In the AR protein suppression assay, compounds O1–O3, A1–A3, and I1 exhibited similar inhibitory effects on both full‐length AR (AR‐FL) and AR splice variant 7 (AR‐V7) as compared to DMC, while compound P3 exhibited significantly enhanced AR‐FL suppression effect as compared to DMC. In comparison, compounds B2, B3, F1, and F3 exhibited reduced AR‐FL and AR‐V7 suppression effects as compared to DMC; B1 and G1 exhibited no significant suppression effect on AR‐FL and AR‐V7, suggesting that these compounds might inhibit prostate cancer cells by multiple mechanisms. Molecular docking simulations further confirmed that compounds O1–O3, A1–A3, I1, and P3 displayed high targeting ability to AR. The probable binding modes of these compounds to AR were also revealed. By modifying the molecular structure of curcumin, this study identified several compounds (A2, A3, P3) with high inhibitory activity and selectivity against castration‐resistant prostate cancer cells by targeting AR‐FL and AR‐V7. These three compounds are promising new candidates for castration‐resistant prostate cancer drug discovery.
