Multi-omics profiling of oxeiptosis-associated biomarkers in cancer

Oxeiptosis is a form of regulated cell death that is independent of caspases and is generally considered to be non-inflammatory. This process is triggered by reactive oxygen species and involves the Kelch-like ECH-associated protein 1 (KEAP1)-phosphoglycerate mutase family member 5 (PGAM5)-apoptosis-inducing factor mitochondria-associated 1 (AIFM1) signaling pathway. This review critically assesses the potential of oxeiptosis-related molecules and multi-omics signatures as biomarkers in human cancers, highlighting their analytical validity and future perspectives in the field of translational laboratory medicine. Other factors, such as KEAP1, PGAM5, and AIFM1, are not unique to oxeiptosis but are also involved in the regulation of other forms of cell death, including antioxidant signaling, mitophagy, and apoptosis. Concurrently, AIFM1 may need to be dephosphorylated at serine 116 (Ser116), PGAM5 must be activated, oxidative stress is required, and there must be no activation of caspases, although this pathway profile is not analytically validated. While many composite signatures exhibit hypothesis-generating potential for prognostic stratification, molecular subtyping, and prediction of therapeutic responsiveness, most have not yet been prospectively validated and are at risk of data set overlap, overfitting, algorithm instability, and poor inter-cohort transportability. Preanalytical variability, specimen stability, assay standardization, normalization, inter-platform concordance, and undefined clinical performance thresholds are other factors that limit translation. In summary, the current state of oxeiptosis-related biomarkers is not clinically validated and has a low level of translational readiness. To achieve future progress, standardized definitions of analytic measures, multicenter validation, and prospective clinical utility must be demonstrated.