TRIM25 promotes temozolomide resistance in glioma by regulating oxidative stress and ferroptotic cell death via the ubiquitination of keap1

Resistance to temozolomide (TMZ) remains an important cause of treatment failure in patients with glioblastoma multiforme (GBM). TRIM25, as a tripartite motif-containing (TRIM) family member, plays a significant role in cancer progression and chemoresistance. However, the function of TRIM25 and its precise mechanism in regulating GBM progression and TMZ resistance remain poorly understood. We found that the expression of TRIM25 was upregulated in GBM, and it was associated with tumor grade and TMZ resistance. Elevated TRIM25 expression predicted a poor prognosis in GBM patients and enhanced tumor growth in vitro and in vivo. Further analysis revealed that elevated TRIM25 expression inhibited oxidative stress and ferroptotic cell death in glioma cells under TMZ treatment. Mechanistically, TRIM25 regulates TMZ resistance by promoting the nuclear import of nuclear factor erythroid 2-related factor 2(Nrf2) via keap1 ubiquitination. Knockdown of Nrf2 abolished the ability of TRIM25 to promote glioma cell survival and TMZ resistance. Our results support the targeting of TRIM25 as a new therapeutic strategy for glioma.

Automated summary

TRIM25 overexpression in glioblastoma is associated with tumor grade and temozolomide resistance. Elevated TRIM25 expression predicts poor prognosis and enhances tumor growth. Mechanistically, TRIM25 promotes TMZ resistance by facilitating nuclear import of Nrf2 via keap1 ubiquitination. Targeting TRIM25 could be a potential therapeutic strategy for glioma.