ceRNA-Mediated Regulation of Ferroptosis in the Lung Cancer Tumor Microenvironment: Molecular Mechanisms, Therapeutic Opportunities, and Research Gaps

Ferroptosis susceptibility in lung cancer is influenced by noncoding RNA regulation, metabolic defenses, and interactions among malignant, immune, and stromal cells. Recent reviews have established the major ncRNA pathways; the unresolved question is which reported interactions create a functional and therapeutically exploitable dependency. This structured narrative review evaluates ceRNA mechanisms separately from other ncRNA activities and proposes a framework linking three requirements: endogenous RNA competition, a consequential metabolic dependency, and a favorable response within the tumor ecosystem. Reported axes are organized by cystine supply, transsulfuration, lipid peroxide detoxification, iron storage, and oxidizable lipid availability. Convergence on SLC7A11 or GPX4 is distinguished from demonstrated network redundancy or treatment dependence. We examine how parallel antioxidant defenses, neighboring cells, and treatment state may uncouple RNA target engagement from ferroptotic death. The framework generates testable predictions for selecting combinations and distinguishing failed RNA competition, metabolic compensation, and microenvironmental protection. It also separates tumor killing from immune benefit, requiring preservation of cytotoxic lymphocyte and dendritic cell function. Evidence remains concentrated in non-small cell lung cancer, while small cell lung cancer requires independent validation. The contribution is an integrative and falsifiable interpretation of existing evidence, rather than a new experimentally validated mechanism or clinical selection algorithm.

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