Crosstalk between ion homeostasis and lipid peroxidation: Mechanisms and translational opportunities in regulated cell death

The expanding landscape of regulated cell death (RCD)—encompassing ferroptosis, cuproptosis, pyroptosis, and apoptosis—has revealed a highly interconnected signaling network rather than strictly isolated pathways. A critical missing link in decoding this mechanistic crosstalk is the dysregulation of subcellular ion homeostasis. Here, we systematically review how the spatiotemporal interplay between transition metals (e.g., Fe²⁺, Cu⁺) and classical ions (e.g., Ca²⁺, K⁺, Cl⁻) dictates cell fate. Moving beyond single-ion paradigms, we highlight lipid peroxidation as the primary biochemical convergence hub where metal-catalyzed oxidative stress and channel-mediated organelle dysfunction intersect. Furthermore, we contextualize these ionic derangements within specific pathophysiological microenvironments, particularly focusing on how hypoxia, acidosis, and metabolic exhaustion re-wire ion channel repertoires in cardiovascular ischemia/reperfusion injury and the tumor immune microenvironment. By interrogating the dual role of ion-driven RCD in both tumor cells and anti-tumor immunity, we expose novel therapeutic vulnerabilities. Finally, we outline emerging precision strategies—including multiplexed in vivo biosensors, spatial transcriptomics, and stimuli-responsive nanomedicine—designed to spatiotemporally manipulate ion fluxes. This review provides an actionable conceptual framework for targeting the ion homeostasis-lipid peroxidation axis, ultimately guiding the development of disease-modifying therapies across oncology, cardiology, and neurology.