Cell adhesion molecules as emerging regulators of ferroptosis: mechanisms and therapeutic opportunities in cancer

Ferroptosis represents an iron-dependent form of regulated cell death, distinguished by the accumulation of lipid peroxides. This process holds significant implications for tumor progression and resistance to therapeutic interventions. Cell adhesion molecules (CAMs), which facilitate interactions between cells and between cells and the extracellular matrix, have emerged as pivotal regulators of ferroptosis sensitivity within the cancerous milieu. Accumulating evidence underscores the capacity of CAMs to modulate key ferroptotic pathways. This includes the system Xc^-/GSH/GPX4 antioxidant axis and iron metabolism through endocytic uptake mechanisms. Depending on the cellular context, CAMs can either promote or suppress ferroptosis. This review offers a systematic summary of the roles played by major CAM families-namely, the immunoglobulin superfamily, cadherins, and integrins-in the regulation of ferroptosis. Such regulation is achieved through diverse mechanisms, including signal transduction, lipid peroxidation, and iron homeostasis. Furthermore, we delve into the therapeutic potential of targeting CAMs, either as standalone treatments or in conjunction with ferroptosis inducers, as a novel and promising strategy for cancer management. These insights not only enhance our comprehension of the regulatory mechanisms governing ferroptosis mediated by CAMs but also pave the way for innovative combination therapies in the field of oncology.