Succinylation of TAGLN2 at K40 drives lipid oxidative stress resistance and TMZ chemoresistance via redox reprogramming in Glioblastoma.

Temozolomide (TMZ) resistance constitutes a primary cause of clinical treatment failure in glioblastoma (GBM). Targeting oxidative cell death to reverse glioma chemoresistance has emerged as a promising novel therapeutic strategy, whereas the core molecular mechanisms linking this oxidative cell death process to TMZ resistance remain poorly defined. Here, we identify that lysine 40 succinylation of TAGLN2 serves as a core driver enabling glioma cells to evade oxidative cell death and acquire TMZ resistance. Notably, this succinylation shows a correlation with CPT1A expression, which may regulate the succinyl-CoA metabolic environment to indirectly influence TAGLN2 succinylation. Mechanistically, TAGLN2-K40 succinylation blocks MARCH1-mediated ubiquitin-proteasome degradation to sustain TAGLN2 protein stability. It further inhibits PP2A activity to trigger the activation of PI3K/AKT/GSK-3β signaling, which subsequently promotes downstream activation of β-catenin and NRF2, upregulates GPX4 expression, and ultimately restrains oxidative cell death and reinforces TMZ resistance. Moreover, we constructed a cell-penetrating peptide targeting TAGLN2-K40 succinylation, which inhibits glioma growth. This work provides novel therapeutic targets and combinatorial regimens to overcome GBM chemoresistance.