DOI: 10.1038/s41586-024-08136-yCentral Idea: This paper elucidates a novel mechanism for hypoxia-induced inflammatory cell death in cancer, specifically pyroptosis, mediated by a PTP1B-RNF213-CYLD-SPATA2 pathway. This pathway presents potential therapeutic targets for resistant hypoxic tumors.Key Concepts:Hypoxia and Cancer: Hypoxia within the tumor microenvironment promotes resistance to therapy and cancer recurrence. This paper focuses on the mechanisms of cell death in hypoxic cancer cells.PTP1B and RNF213 Regulation: Protein tyrosine phosphatase PTP1B and the E3 ubiquitin ligase RNF213 are key players. PTP1B inhibition activates RNF213, the mechanism of which is explored through RNF213 tyrosine phosphorylation (specifically at Tyr-1275) by ABL1/2 kinases and subsequent control of RNF213 oligomerization and RZ domain activation.CYLD/SPATA2 Ubiquitylation and Degradation: RNF213's RZ domain ubiquitylates and induces the degradation of CYLD/SPATA2, negative regulators of NF-kB. The role of RNF213’s RING domain in negatively regulating RZ activity is investigated.NF-kB Activation and NLRP3 Inflammasome: CYLD/SPATA2 degradation leads to NF-kB activation and induction of the NLRP3 inflammasome. This, coupled with hypoxia-induced endoplasmic reticulum (ER) stress, triggers pyroptotic cell death.Pyroptosis as Cell Death Mechanism: The paper establishes pyroptosis, a form of inflammatory programmed cell death, as the primary mechanism of cell death in hypoxic, PTP1B-deficient cancer cells, differentiated from other forms of cell death (apoptosis, necroptosis, ferroptosis). GSDMD and inflammatory caspase activity are examined as pyroptosis markers.In vivo Validation and Therapeutic Implications: The pathway is validated in vivo using xenograft models. The effects of PTP1B, CYLD, NLRP3 and RNF213 deletion/mutation on tumor growth are explored, highlighting potential therapeutic targets (PTP1B, CYLD/SPATA2, NLRP3).Further Research/Unanswered Questions:RNF213 Substrate Specificity: Fully characterize the substrate specificity of the RING and RZ domains of RNF213 and the interplay between the two domains.Role in Normal Tissues: Investigate the role of the PTP1B-RNF213 pathway in normal tissues under hypoxic conditions.MMD and Other Diseases: Further explore the implications of this pathway for Moyamoya disease (MMD), given the established role of RNF213, and for other inflammatory and autoimmune diseases.Therapeutic Development: Develop and test targeted therapies based on this pathway, including PTP1B and/or CYLD/SPATA2 inhibitors or NLRP3 inflammasome antagonists, for cancers and potentially other diseases.Mechanism of LUBAC Involvement: Further elucidate the mechanism by which LUBAC contributes to CYLD/SPATA2 degradation in this pathway and its relationship to RNF213 RZ domain activity.

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