Glioblastoma (GBM) is the most aggressive primary brain malignancy in adults, characterized by extensive intratumoral heterogeneity, near-universal recurrence, and profound resistance to current standard-of-care therapy. The Stupp regimen comprising maximal safe resection followed by concurrent radiotherapy and temozolomide (TMZ) established in 2005 confers a median overall survival of approximately 14–15 months, an outcome that has not substantially improved despite decades of clinical investigation. A fundamental contributor to therapeutic failure is the dependency of conventional treatments on apoptosis, a regulated cell death (RCD) modality frequently evaded in GBM through epigenetic silencing, mismatch repair deficiency, and anti-apoptotic signalling hyperactivation. Furthermore, apoptosis is immunologically quiescent, failing to engage the immunosuppressive GBM tumor microenvironment (TME) in a therapeutically meaningful manner. 7,8 Emerging evidence from non-CNS cancer models and inflammatory systems has drawn attention to inflammatory-regulated cell death modalities pyroptosis, necroptosis, and their potential convergence within the PANoptosis framework as candidate mechanisms capable of circumventing apoptotic resistance while eliciting immunologically relevant damage-associated molecular pattern (DAMP) release. PANoptosis refers to a regulated cell death process characterized by concurrent or functionally interdependent engagement of pyroptotic, apoptotic, and necroptotic pathways, coordinated through a multimolecular PANoptosome complex incorporating innate immune sensors such as ZBP1, kinases including RIPK1 and RIPK3, and the caspase-8/FADD regulatory axis. This review synthesizes current mechanistic evidence for apoptotic, necroptotic, and pyroptotic pathways in GBM, evaluates natural compounds reported to engage these pathways in GBM models, and critically assesses the applicability of the PANoptosis framework to glioblastoma biology. Available data indicate that individual RCD pathway markers phosphorylated MLKL, cleaved gasdermin D, and executioner caspase activation have each been observed in GBM experimental systems. However, simultaneous, mechanistically validated co-activation of all three executioner pathways within a single GBM model, as required for definitive PANoptosis designation, has not yet been established. Natural compounds including shikonin, osthole, and curcumin-based formulations, demonstrate capacity to engage specific RCD pathways in GBM cell lines, with shikonin and osthole providing the most direct evidence for necroptosis-dominant execution. The translational application of PANoptosis-oriented strategies in GBM faces specific challenges including RIPK3 promoter hypermethylation, blood-brain barrier permeability constraints, risk of neuroinflammatory sequelae, and absence of validated biomarkers for patient stratification. This review identifies critical experimental and clinical gaps and frames the mechanistic and translational priorities necessary to advance this field.
Ramanathan et al. (Fri,) studied this question.