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However, the precise molecular metabolic mechanisms remain poorly understood. Here, we found that palmitic acid (PA) accumulates in hypoxic pseudopalisading regions of GBM and drives the formation of mesenchymal (MES) GBM and the hypoxia myeloid\u2010derived macrophages (MDM) subpopulation, establishing an interactive tumor\u2010promoting niche that fuels GBM recurrence. Maechanistically, PA induces ZDHHC12\u2010mediated palmitoylation of lactate dehydrogenase A (LDHA) at cysteine 163. This enhances LDHA enzymatic activity, promoting glycolytic reprogramming that reinforces the MES phenotype and confers resistance to chemoradiotherapy. Concurrently, palmitoylation facilitates the exosomal sorting of LDHA, which is internalized by MDMs, inducing their polarization into an immunosuppressive, glycolytic hypoxia\u2010MDM subset, which cooperatively shapes an immunosuppressive pseudopalisading niche with MES glioma stem cells to promote GBM recurrence. Critically, we identified the small molecule Rutin as a potent inhibitor of LDHA\u2010Cys163 palmitoylation, thereby re\u2010sensitizing GBM to chemoradiotherapy. This study defines a metabolic circuit in recurrent GBM driven by crosstalk between PA\u2010activated MES\u2010GBM cells and hypoxia\u2010MDMs. The small molecule Rutin disrupts this circuit, re\u2010sensitizing GBM to chemoradiotherapy and offering a promising strategy to overcome post\u2010treatment recurrence.<\/jats:p>","DOI":"10.1002\/advs.77536","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:40:10Z","timestamp":1790599210000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting LDHA Palmitoylation Sensitizes GBM to Chemoradiotherapy via Suppressing Palmitic Acid Induced Glycolytic Reprogramming"],"prefix":"10.1002","author":[{"given":"Zijie","family":"Gao","sequence":"first","affiliation":[{"name":"Shandong Key Laboratory of Brain Health and Function Remodeling Department of Neurosurgery Qilu Hospital of Shandong University Jinan Shandong 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