Targeting ferroptosis through kinase signaling: The roles of MAPK and AMPK pathways in cancer therapy.

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical mechanism in tumor suppression and a promising target for cancer therapy. As a reversible and dynamic post-translational modification, phosphorylation orchestrated by protein kinases serves as a pivotal regulatory layer in the ferroptotic process. This review systematically delineates the roles of two major kinase families- mitogen-activated protein kinases (MAPKs) and Adenosine 5'-monophosphate-activated protein kinase (AMPK)-in the initiation, execution, and modulation of ferroptosis. We discuss how MAPK subfamilies, including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase (ERK5), regulate iron metabolism, lipid peroxidation, and antioxidant responses through context-dependent signaling cascades. In parallel, AMPK acts as an energy-sensing hub that influences ferroptosis via lipid metabolic reprogramming and the control of glutathione peroxidase 4 (GPX4) expression. We further explore the dual implications of ferroptosis in tumor biology, highlighting its role as a barrier to cancer progression and the adaptive resistance mechanisms evolved by tumor cells. Finally, we evaluate the therapeutic potential of targeting kinase-mediated ferroptosis, offering insights into combination strategies involving kinase inhibitors and ferroptosis inducers, and addressing the challenges and future directions for translating these insights into clinical oncology.