Histone H4K8 lactylation promotes glioblastoma progression by inducing NUPR1-mediated autophagosome‒lysosome fusion

<b>Rationale:</b> Glioblastoma (GBM), an aggressive malignant brain tumour associated with a dismal prognosis, is characterized by metabolic reprogramming that drives tumour progression, with the Warburg effect being a central contributor. This effect not only causes significant lactate buildup but also fuels lactylation, a novel post-translational modification implicated in the development of gliomas and various other cancers. Nevertheless, the exact molecular mechanisms by which lactylation promotes GBM progression remain largely elusive. <b>Methods:</b> Lactylation levels in normal brain and GBM tissues were analysed using immunohistochemistry, immunofluorescence, and Western blotting. Glycolysis inhibitors and LDHA/LDHB knockdown were used to modulate histone lactylation in subsequent <i>in vitro</i> and <i>in vivo</i> experiments assessing GBM cell proliferation, invasion, and migration. CUT&Tag and RNA sequencing were used to identify H4K8la target genes, and NUPR1 expression was validated via ChIP‒qPCR and Western blotting. Autophagic flux was examined using transmission electron microscopy, EGFP-mCherry-LC3B probes, and LysoTracker staining. The therapeutic effects of NUPR1 inhibitor ZZW-115 were evaluated in both cellular and animal models. <b>Results:</b> Histone lactylation, notably that of H4K8la, was markedly increased in GBM cells. Targeting lactate metabolism and lactylation levels attenuated GBM malignancy <i>in vitro</i> and <i>in vivo</i>. Genome-wide analysis revealed H4K8la enrichment at promoter regions, where it transcriptionally activated the autophagy regulator NUPR1. Functionally, NUPR1 enhanced protective autophagy via autophagosome‒lysosome fusion. Pharmacological inhibition of NUPR1 with ZZW-115 suppressed GBM growth by impairing autophagic flux, demonstrating therapeutic potential. <b>Conclusion:</b> In summary, this study defines the functional and prognostic significance of histone lactylation in the progression of GBM. We identified the H4K8la-NUPR1 axis as a key regulatory pathway that mediates protective autophagy and developed targeted therapeutic strategies to disrupt this pathway. These findings provide novel insights into epigenetic regulation and targeted therapy for GBM.