Glioblastoma (GBM) remains a highly aggressive and therapy-resistant brain tumor, with

limited benefit from the current standard-of-care regimen combining surgery, radiotherapy, and

temozolomide (TMZ). Overcoming chemoresistance therefore represents a critical unmet

clinical need.

Here, we investigate the anticancer potential of hydroalcoholic extract from leaves of Succisa

pratensis and its ability to enhance TMZ efficacy in GBM models. Treatment with Succisa

pratensis markedly reduced cell proliferation and migration while significantly increasing

sensitivity to TMZ. Integrated multi-omics analyses revealed extensive metabolic rewiring,

characterized by suppression of central carbon metabolism and activation of stress-adaptive

pathways.

Mechanistically, we identify the Pregnane X Receptor (PXR), a key regulator of drug

metabolism and chemoresistance, as a central node affected by treatment. Although Succisa

pratensis increased PXR expression, this was not accompanied by induction of canonical

downstream targets, including MDR1 and ALDH1A1, indicating a functional impairment of

PXR transcriptional activity. Consistently, pharmacological inhibition of PXR using the

antagonist SPA70 further potentiated the cytotoxic effects of Succisa pratensis and TMZ.

Docking analyses suggest that specific secondary metabolites, including apigenin-derived

compounds, may interact with the PXR ligand-binding domain, providing a potential molecular

basis for this effect.

Collectively, our findings indicate that Succisa pratensis enhances TMZ efficacy by inducing

metabolic vulnerability and functionally impairing PXR signaling. These results highlight the

therapeutic potential of plant-derived metabolites as adjuvant strategies to overcome

chemoresistance in glioblastoma.