{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:59:18Z","timestamp":1789516758905,"version":"build-2803163510"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Clear cell renal cell carcinoma (ccRCC) remains a clinically challenging malignancy due to late diagnosis and limited therapeutic options. This study aimed to investigate the role of DNER in the progression of ccRCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bioinformatic analyses were integrated with experimental validation. Metabolism-related candidate genes were systematically screened to identify hub genes closely associated with metabolic pathway activity and immune cell infiltration. Both in vitro and in vivo functional assays were performed, along with mechanistic studies focusing on DNER-interacting proteins and downstream signaling pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Bioinformatic analysis revealed that lipid metabolism and energy metabolism are key metabolic pathways significantly affecting the prognosis of ccRCC patients. Through systematic screening, DNER was identified as a hub gene strongly correlated with both metabolic pathway activity and immune cell infiltration. Functional experiments demonstrated that DNER promotes ccRCC cell proliferation both in vitro and in vivo. Mechanistically, DNER physically interacts with JAK2 and activates the JAK2\/STAT3 signaling pathway, leading to STAT3 nuclear translocation and subsequent direct transcriptional upregulation of the glycolytic enzymes LDHA and PKM, thereby enhancing glycolytic flux. The increased lactate production drives macrophage polarization toward a pro-tumorigenic M2-like phenotype, establishing a signaling cascade that links tumor cell-intrinsic metabolic reprogramming to immunosuppressive microenvironment remodeling. Preliminary evidence also suggests that DNER overexpression may be associated with enhanced sensitivity of ccRCC cells to the PARP inhibitor Olaparib, although the underlying mechanism requires further investigation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>In conclusion, DNER drives ccRCC progression by coupling glycolytic reprogramming with immunosuppressive microenvironment formation via the JAK2\/STAT3 signaling axis, and may represent a potential therapeutic target for ccRCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1799104","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T06:10:07Z","timestamp":1779430207000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["DNER drives glycolytic reprogramming in renal cell carcinoma by 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