Necrotic Cells Alter IRE1α-XBP1 Signaling and Induce Transcriptional Changes in Glioblastoma

Abstract

Necrosis is a characteristic feature of glioblastoma multiforme (GBM) and is closely associated with tumor-associated inflammation and poor clinical outcomes. However, the molecular consequences of necrotic cell death on endoplasmic reticulum (ER) stress signaling in GBM cells remain unclear. In this study, we examined the effects of necrotic cells on the ER stress signaling and unfolded protein response (UPR) in human glioblastoma cell lines. Exposure to necrotic cells reduced IRE1α phosphorylation and increased unspliced XBP1 (XBP1u) accumulation, without affecting PERK or ATF6 pathways. These changes were accompanied by enhanced IκBα phosphorylation and impaired autophagic degradation. Treatment with ER stress inducers failed to reverse XBP1u accumulation, and reduced phosphorylation of PKAc was observed together with decreased IRE1α activation. Transcriptomic analysis and quantitative reverse transcription PCR (qRT-PCR) revealed that necrotic cell-induced XBP1u was associated with altered expression of XBP1-related genes, while XBP1 knockdown produced similar transcriptional changes and enhanced the effects of necrotic cell treatment. These findings suggest that necrotic cells impair canonical IRE1α-XBP1 signaling and induce transcriptional reprogramming in glioblastoma cells, which may contribute to tumor progression. © 2026 by the authors.