Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1–3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.

Toll-like receptor 4 (TLR4)-tumor necrosis factor receptor 6 (TRAF6) signaling is activated in atherosclerosis (AS), inducing inflammatory mediators. Because miR-146a, a TLR4 microRNA (miRNA), can regulate TLR4 signaling during inflammatory responses, this study investigated the effects of aerobic exercise on TLR4-targeted miRNAs in AS. Apolipoprotein E-null mice fed a high-fat diet for 12 weeks were separated into 3 groups: (i) no treatment (AS), (ii) statin treatment (AD), or (iii) aerobic exercise (AE). Plaques and foam cells were observed in the untreated control and statin groups, respectively, but not in the AE group. Reduced angiotensin II (Ang II) and endothelin 1 (ET1) levels were observed in the AE group. Both treatment groups significantly altered the expression of inflammatory cytokine expression and reduced vascular TLR4 levels. Increased miR-146a and miR-126 and reduced miR-155 levels were observed in both treatment groups (all, P<0.001). miR-146a interacted with the 3' untranslated region of the TRAF6 gene, reducing its expression. Thus, aerobic exercise and statins may induce miR-146a expression, thereby reducing vascular TRAF and TLR4 signaling and vascular inflammatory injury in AS. Further analysis of this pathway may provide insight into the protective effects of aerobic exercise on vascular disease as well as new therapeutic targets.

Chemotherapy and targeted therapy are the major treatments for gastric cancer (GC), but drug resistance limits its effectiveness. Here, we profile the proteome of 206 tumor tissues from patients with GC undergoing either chemotherapy or anti-HER2-based therapy. Proteome-based classification reveals four subtypes (G-I–G-IV) related to different clinical and molecular features. MSI-sig high GC patients benefit from docetaxel combination treatment, accompanied by anticancer immune response. Further study reveals patients with high T cell receptor signaling respond to anti-HER2-based therapy; while activation of extracellular matrix/PI3K-AKT pathway impair anti-tumor effect of trastuzumab. We observe CTSE functions as a cell intrinsic enhancer of chemosensitivity of docetaxel, whereas TKTL1 functions as an attenuator. Finally, we develop prognostic models with high accuracy to predict therapeutic response, further validated in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemotherapy and targeted therapy in GC.