{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:46:43Z","timestamp":1782820003838,"version":"3.54.5"},"reference-count":147,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"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>\n                      Deregulation of cellular metabolism is a hallmark of cancer, in which tumour cells upregulate glycolysis and preferentially ferment glucose to lactate in the \u2018Warburg effect\u2019. Tumour-specific upregulation of hexokinase 2 (\n                      <jats:italic>HK2<\/jats:italic>\n                      ), which catalyses the first rate-limiting step of glycolysis, is a key driver of this phenotype and represents a promising therapeutic target in glioblastoma. Here, we sought to identify HK2-associated tumour processes that could serve as therapeutic co-targets by profiling the transcriptomic consequences of\n                      <jats:italic>HK2<\/jats:italic>\n                      knockdown (HK2KD) in model established glioblastoma cell lines and patient-derived short-term cell cultures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Glioblastoma cell lines and patient-derived short-term cell cultures were subjected to HK2KD using\n                      <jats:italic>HK2<\/jats:italic>\n                      -targeted siRNA. Glycolytic activity was assessed using the Seahorse Glycolytic Stress Test, and transcriptomic changes were analysed by RNA sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HK2KD was associated with reduced glycolytic activity in high-\n                      <jats:italic>HK2<\/jats:italic>\n                      -expressing models as well as extensive transcriptional remodelling. Integrative analysis using RNA sequencing, gene ontology and pathway enrichment, protein-protein interaction networks, and transcriptome-based perturbation matching indicated coordinated modulation of inflammatory, immune-associated and angiogenesis-linked gene programmes, including cytokine, chemokine and pro-angiogenic signalling axes. Notably, inflammatory pathway responses diverged markedly between independent glioblastoma models, representing a central finding of this study and highlighting context-dependent immunometabolic transcriptional changes following HK2KD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings suggest that HK2KD is associated with transcriptional changes extending beyond glycolytic pathways, linking metabolic activity to immunological and angiogenic transcriptional networks in a model-dependent manner. Although functional effects on the tumour microenvironment were not directly assessed, this study provides a transcriptomic framework for understanding how\n                      <jats:italic>HK2<\/jats:italic>\n                      targeting may be associated with changes in tumour-associated signalling pathways, with potential implications for stratified metabolic and combination therapeutic strategies in glioblastoma.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1842240","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:38:33Z","timestamp":1781588313000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["HK2 knockdown is associated with context-dependent inflammatory and angiogenesis-related transcriptional programmes in glioblastoma cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Christopher","family":"Edwards","sequence":"first","affiliation":[{"name":"University of Wolverhampton, Faculty of Science and Engineering","place":["Wolverhampton, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Richards","sequence":"additional","affiliation":[{"name":"University of Wolverhampton, Faculty of Science and Engineering","place":["Wolverhampton, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hafid Omar","family":"Al-Hassi","sequence":"additional","affiliation":[{"name":"University of Wolverhampton, Faculty of Science and Engineering","place":["Wolverhampton, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surya Prakash","family":"Shivakumar","sequence":"additional","affiliation":[{"name":"University of Wolverhampton, Faculty of Science and Engineering","place":["Wolverhampton, United 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