PKA signaling meets ferroptosis: A new perspertive in cancer treatment

Emerging evidence highlights ferroptosis - a recently identified iron-dependent form of regulated cell death - as a promising therapeutic approach for tumor suppression and treatment optimization. Notably, Protein Kinase A (PKA), a central upstream kinase orchestrating cellular signaling cascades, has been shown to modulate ferroptosis through phosphorylation-mediated regulation of downstream effectors. The strategic integration of PKA-targeted therapies with ferroptosis induction represents a novel paradigm for effectively inhibiting tumorigenesis, impeding cancer progression, and overcoming therapeutic resistance. This comprehensive review systematically examines recent advances in elucidating the molecular mechanisms through which PKA signaling modulates ferroptosis pathways. By analyzing the regulatory interplay between PKA-mediated phosphorylation events and ferroptosis execution mechanisms, we aim to provide valuable insights for developing synergistic therapeutic strategies. The convergence of PKA pathway modulation and ferroptosis activation may fundamentally transform current treatment modalities, offering enhanced specificity and efficacy in cancer management. These innovative perspectives not only deepen our understanding of cell death regulation in malignant cells but may also significantly advance both fundamental research and clinical translation of combination therapies targeting PKA and ferroptosis pathways. Such interdisciplinary approaches hold particular promise for addressing the persistent challenges of tumor heterogeneity and adaptive resistance in cancer treatment.