Cross talk between pyroptosis ferroptosis and anoikis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains therapy-resistant because alterations in p53, B-cell lymphoma 2 (BCL-2) family proteins, and oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) support apoptosis evasion. This review examines ferroptosis, pyroptosis, and anoikis, with anoikis resistance treated as a survival mechanism that must be overcome. Ferroptosis is driven by iron-dependent lipid peroxidation and restrained by glutathione peroxidase 4 (GPX4), making cysteine metabolism a potential vulnerability. Pyroptosis involves gasdermin-mediated membrane permeabilization and has both antitumor and tumor-promoting effects in PDAC. Anoikis is detachment-induced apoptosis; resistance to it supports dissemination through adhesion-associated signaling. Caspase-8, Yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), and endosomal sorting complex required for transport III (ESCRT-III) participate in the regulation of these processes. However, their shared involvement does not establish a coupled three-pathway circuit in pancreatic cancer. We distinguish direct pancreatic evidence from findings in other models and identify experiments needed to test functional interactions. Combinations involving ferroptosis induction, gasdermin-dependent killing, and restoration of anoikis remain hypotheses whose efficacy may depend on treatment order, substrate availability, and stromal context. Published focal adhesion kinase (FAK) combination data provide an early clinical reference point, but do not validate this sequence. We therefore emphasize comparative schedule testing, monitoring of persistent inflammation, and separate evaluation of candidate biomarkers before proposing a composite predictor. This evidence-based framework preserves the rationale for combination treatment while defining the limits of current mechanistic and clinical support. The “Triangle of Death” and staged death reprogramming in pancreatic ductal adenocarcinoma. Ferroptosis, pyroptosis, and anoikis resistance form an interconnected non-apoptotic death network coordinated by YAP/TAZ signaling, caspase-8, and ESCRT-III-mediated membrane repair. Ferroptosis is promoted by iron-dependent lipid peroxidation and accumulation of polyunsaturated fatty-acid-containing phospholipids, whereas GPX4 and system Xc−/SLC7A11 provide antioxidant protection. Pyroptosis proceeds through inflammasome- and caspase-dependent activation of gasdermins, resulting in membrane-pore formation and release of inflammatory mediators. Anoikis resistance is sustained by YAP/TAZ and integrin–FAK signaling, cytoskeletal remodeling, and epithelial–mesenchymal transition. In the desmoplastic, immunologically “cold” PDAC microenvironment, CAF-rich stroma, immunosuppressive cytokines, hypoxia, and limited immune infiltration permit compensatory rewiring between these pathways. The proposed staged strategy begins with ferroptotic priming through cysteine depletion or inhibition of system Xc−/GPX4, proceeds to pyroptotic licensing through restoration of gasdermin competence and chemotherapy-induced caspase activation, and culminates in collapse of anoikis resistance together with PD-1/PD-L1 immune-checkpoint blockade, promoting CD8+ T-cell activity and tumor elimination. This graphical abstract represents a conceptual therapeutic framework rather than a clinically validated treatment sequence. Abbreviations: ACSL4, acyl-CoA synthetase long-chain family member 4; AIM2, absent in melanoma 2; CAF, cancer-associated fibroblast; DAMPs, damage-associated molecular patterns; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; ESCRT-III, endosomal sorting complex required for transport III; FAK, focal adhesion kinase; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; GSDME, gasdermin E; GSH, glutathione; HDAC, histone deacetylase; HMGB1, high-mobility group box 1; IL, interleukin; NLRP3, NLR family pyrin domain-containing 3; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PDAC, pancreatic ductal adenocarcinoma; PUFA-PLs, polyunsaturated-fatty-acid-containing phospholipids; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; system Xc−, cystine/glutamate antiporter; TGF-β, transforming growth factor beta; YAP, Yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding motif.