The role of the NcRNA/ferroptosis axis in lung cancer: molecular mechanisms and potential therapeutic targets

Abstract

Lung cancer, the second most diagnosed malignancy globally, remains the leading cause of cancer-related deaths due to its aggressive nature and limited treatment success. Ferroptosis, a unique form of regulated cell death, is characterized by iron-dependent lipid peroxidation and oxidative stress, distinct from apoptosis and necrosis. It plays a dual role in cancer by promoting cell death while being suppressed in tumor progression. This suppression allows cancer cells, including lung cancer cells, to evade destruction, contributing to the disease's malignancy. However, ferroptosis-inducing agents have shown promise in targeting cancer cells resistant to conventional therapies, positioning ferroptosis as a therapeutic avenue in oncology. Non-coding RNAs (ncRNAs) emerge as pivotal regulators in this axis. These molecules, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), modulate ferroptosis-related pathways by targeting key regulators like GPX4, SLC7A11, and ACSL4. For instance, miRNAs can downregulate SLC7A11, enhancing sensitivity to ferroptosis, while lncRNAs can stabilize or suppress pathways that prevent lipid peroxidation. CircRNAs, acting as molecular sponges, influence ferroptosis by modulating miRNA activity. The deregulation of these ncRNAs in lung cancer underscores their significance in the disease's pathogenesis and progression. Understanding the ncRNA-ferroptosis axis offers a novel perspective in addressing this challenge. Therapeutic strategies targeting this axis aim to selectively induce ferroptosis in tumor cells while sparing normal cells, enhancing treatment specificity and efficacy. Furthermore, combining ncRNA-based therapeutics with ferroptosis inducers provides a promising framework for overcoming drug resistance and improving outcomes. This review highlights comprehensive insight into the molecular mechanisms and therapeutic potential of the ncRNA-ferroptosis axis that could pave the way for more effective lung cancer treatments.

Keywords: Circular RNAs (circRNAs); Ferroptosis; Long non-coding RNAs (lncRNAs); Lung cancer; MicroRNAs (miRNAs); Non-coding RNAs (ncRNAs).