Pancancer transcriptomic profiling identifies key PANoptosis markers as therapeutic targets for oncology

Area of Science:

• Immunology
• Oncology
• Computational Biology

Background:

• Resistance to programmed cell death (PCD) is a key feature of cancer, hindering effective treatment.
• Complex interactions within PCD pathways, including PANoptosis, obscure the roles of individual molecules.
• PANoptosis, an innate immune-mediated inflammatory PCD, integrates components from various cell death pathways.

Purpose of the Study:

• To systematically evaluate the pancancer clinical significance of PANoptosis using a computational framework.
• To identify potential targetable biomarkers within the PANoptosis pathway for cancer therapy.

Main Methods:

• Development of a systematic computational framework to analyze PANoptosis gene expression.
• Assessment of the prognostic impact of PANoptosis genes across multiple cancer types.
• In vitro validation of a therapeutic strategy targeting ZBP1 in melanoma cells.

Main Results:

• High PANoptosis gene expression was associated with poor prognosis in low-grade glioma (LGG) and kidney renal cell carcinoma (KIRC).
• Specific genes like ZBP1, CASP2, CASP3, CASP4, CASP8, and GSDMD showed negative prognostic effects in LGG.
• Conversely, high PANoptosis gene expression correlated with better outcomes in skin cutaneous melanoma (SKCM), with ZBP1, NLRP1, CASP8, and GSDMD showing positive prognostic effects.

Conclusions:

• PANoptosis plays a complex and context-dependent role in cancer prognosis.
• Key PANoptosis genes (e.g., ZBP1, GSDMD) represent potential therapeutic targets for specific cancers.
• Targeting PANoptosis, as demonstrated by ZBP1 activation in melanoma, can induce cell death and improve outcomes.