AP-2 Transcription Factors as Regulators of Ferroptosis: A Family-Wide Profiling in Diverse Cancer Contexts

TL;DR

This study explores how AP-2 transcription factors regulate ferroptosis, a type of cell death, across various cancers, revealing new connections between AP-2 and cancer prognosis.

Contribution

The paper provides the first family-wide analysis of AP-2's role in ferroptosis across multiple cancer types, identifying novel regulatory links and potential therapeutic targets.

Findings

AP-2 expression correlates with ferroptosis scores and prognosis in five cancer types.

Genes like LOX, PTGS2, and NQO1 are linked to AP-2 and may be involved in ferroptosis regulation.

AP-2-associated genes suggest new pathways involving redox and lipid metabolism in cancer cell death.

Abstract

Ferroptosis is an iron-dependent programmed cell death (PCD) implicated in cancer therapy response, yet its transcriptional control remains unevenly characterized and often centered on a limited subset of transcription factors (TFs) rather than systematically addressing TF families. The Activating enhancer-binding Protein-2 (AP-2) family of TFs is a plausible but understudied regulatory node linking oncogenic programs to ferroptosis, with prior research limited to AP-2α and AP-2γ, suggesting anti-ferroptotic and pro-tumorigenic roles. Thus, the present study aimed to provide a family-wide analysis of the relationships between AP-2 and ferroptosis across tumors in which this PCD type is considered biologically and clinically relevant. The research integrates ferroptosis gene modules with AP-2 targetomes, tumor–normal expression comparisons, survival stratification, ferroptosis scoring, cross-cohort functional analyses, and signaling pathway projection extending canonical ferroptosis circuits with AP-2–associated non-canonical elements. Consistent associations between AP-2 expression, prognosis, and ferroptosis score were observed in five tumor cohorts: cervical squamous cell carcinoma, glioblastoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, and thyroid carcinoma. In addition, cross-cohort clustering highlighted genes enriched in redox- and lipid-metabolism programs linked to apoptosis and autophagy-dependent death. Among the candidates emerging from these analyses, ferroptotic markers (LOX, PTGS2, and NQO1) and AP-2–linked nodes such as CD36, DUOX1, EPHA2, MUC1, PTPRC, SNAI2, and TP63 warrant targeted functional and binding validation to infer whether these associations reflect direct AP-2 regulatory mechanisms. Most importantly, AP-2–centered research appears to be a valuable area for guiding studies of tumor-specific ferroptosis vulnerability or resistance.

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