{"doi":"10.1172/jci.insight.190780","title":"CDK12 regulates cellular metabolism to promote glioblastoma growth","abstract":"Glioblastoma IDH-wildtype is the most common and aggressive primary brain tumor in adults, with poor prognosis despite current therapies. To identify new therapeutic vulnerabilities, we investigated the role of CDK12, a transcription-associated cyclin-dependent kinase, in glioblastoma. Genetic or pharmacologic inactivation of CDK12 impaired tumor growth in patient-derived xenograft (PDX) models and enhanced the efficacy of temozolomide. Metabolic profiling using extracellular flux analysis and stable isotope tracing with U-¹³C-glucose and U-¹³C-glutamine showed that CDK12 inhibition disrupted mitochondrial respiration, resulting in energy depletion and apoptotic cell death characterized by caspase activation and Noxa induction. Mechanistically, we identified a direct interaction between CDK12 and GSK3β. CDK12 inhibition activated GSK3β, leading to downregulation of PPARD, a transcriptional regulator of oxidative metabolism. This CDK12/GSK3β/PPARD axis was required for glioblastoma cell proliferation and metabolic homeostasis. In vivo, CDK12 inhibition significantly extended survival without overt toxicity and induced complete tumor regression in a subset of animals. Strikingly, combined CDK12 inhibition and temozolomide treatment led to complete tumor eradication in all animals tested. These findings establish CDK12 as a key regulator of glioblastoma metabolism and survival, and provide strong preclinical rationale for its therapeutic targeting in combination with standard-of-care treatments.","journal":"JCI Insight","year":2025,"id":547147,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":634754,"name":"Chang Shu","orcid":"0000-0001-5619-0294","position":1,"is_corresponding":false},{"id":1251207,"name":"Qiuqiang Gao","orcid":"0009-0005-8738-2754","position":2,"is_corresponding":false},{"id":227799,"name":"Zhe Zhu","orcid":"0000-0002-5385-948X","position":3,"is_corresponding":false},{"id":395600,"name":"Hasan O. Akman","orcid":"0000-0003-4493-721X","position":4,"is_corresponding":false},{"id":245162,"name":"Mike‐Andrew Westhoff","orcid":"0000-0003-3256-7100","position":5,"is_corresponding":false},{"id":245163,"name":"Georg Karpel‐Massler","orcid":"0000-0001-8236-5369","position":6,"is_corresponding":false},{"id":245164,"name":"Markus D. Siegelin","orcid":"0000-0001-7113-3634","position":7,"is_corresponding":false},{"id":1249272,"name":"Jeong-Yeon Mun","orcid":null,"position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:36.567932Z","pmid":"40996961","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}