Targeting PPARα activation sensitizes glioblastoma cells to temozolomide and reverses acquired resistance by inhibiting H3K18 lactylation

Jun 11, 2025Acta pharmacologica Sinica

Activating PPARα may make glioblastoma cells more sensitive to temozolomide and reverse drug resistance by blocking a specific gene modification

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Abstract

TMZ resistance in glioblastoma cells is associated with upregulated H3K18 lactylation and inactivated PPARα.

TMZ-resistant glioblastoma cells showed increased levels of H3K18 lactylation and elevated extracellular acidification rate (ECAR) and lactate.
Lactate treatment was found to time-dependently increase H3K18 lactylation in sensitive glioblastoma cells.
TMZ activated PPARα in sensitive glioblastoma cells through DNA damage-induced p38 MAPK activation, but PPARα was inactivated in resistant cells.
Activated PPARα upregulated ACOX1, which inhibited lactate-mediated H3K18 lactylation and enhanced PPARα activation through a specific pathway.
Targeting PPARα activation with gemfibrozil or GW7647 sensitized TMZ-resistant glioblastoma cells and reversed their resistance by reducing H3K18 lactylation.

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Temozolomide (TMZ) is an alkylating agent recommended as the first-line pharmaceutical for glioblastoma (GBM), but its efficacy is limited by the development of acquired resistance in GBM cells. TMZ resistance is regulated by multiple factors such as MGMT upregulation and metabolism reprogramming, its underlying mechanism still remains elusive. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor regulating the metabolism of lipid and glucose, while histone 3 lactylation at lysine on position 18 (H3K18la) could promote cancer cells' resistance to therapeutic drugs. In this study we investigated the role of PPARα in regulating H3K18la and TMZ sensitivity in glioblastoma (GBM) cells. We established TMZ-resistant U87TR, U251TR, and U118TR cells by treating the parental U87, U251, and U118 cells with increased dosages of TMZ until the cells could resist TMZ (200 μM). We found that in TMZ-resistant cells, H3K18la level was apparently upregulated accompanied by increased ECAR (extracellular acidification rate) and intracellular lactate levels, whereas lactate (20 mM) time-dependently upregulated H3K18la in U87 and U251 cells. We found that PPARα was activated by TMZ in U87, U251, and U118 cells, but was inactivated when the cells became resistant to TMZ. In TMZ-sensitive glioma cells, TMZ triggered PPARα activation by causing DNA DSBs-dependent p38 MAPK activation. The activated PPARα upregulated its downstream signal ACOX1, which not only inhibited lactate-mediated H3K18 lactylation by promoting ROS-dependent PKM2 downregulation, but also reversely enhanced PPARα activation through ROS-activated ASK1/p38 MAPK pathway. In GBM cells resistant to TMZ, PPARα and p38 MAPK were both inactivated, but H3K18 lactylation was obviously upregulated. Targeting activation of PPARα with gemfibrozil or GW7647 not only sensitized GBM cells to TMZ but also effectively reversed the acquired resistance of GBM cells to TMZ by suppression of H3K18 lactylation through upregulation of ACOX1. Taken together, PPARα contributed to TMZ-induced growth arrest in GBM cells by inhibiting lactate-mediated H3K18 lactylation, targeting activation of PPARα may be a new strategy to improve the treatment effect of TMZ against GBM.

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Targeting PPARα activation sensitizes glioblastoma cells to temozolomide and reverses acquired resistance by inhibiting H3K18 lactylation

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