Ferroptosis and Non-Coding RNA Regulation in Cancer Systems

Ferroptosis represents a distinct form of regulated cell death, characterised by the iron-dependent peroxidation of polyunsaturated fatty acids in cellular membranes. Unlike apoptosis or necroptosis, it is driven by the collapse of antioxidant defences such as system x_c^–-mediated cystine import and glutathione peroxidase 4 activity, culminating in uncontrolled lipid peroxidation and cell demise. Within cancer systems, ferroptosis is both a vulnerability and an adaptive mechanism: some tumours co-opt iron uptake and redox pathways to resist cell death, while others display intrinsic ferroptotic susceptibility amenable to therapeutic targeting. Non-coding RNAs, including microRNAs, long non-coding RNAs and circular RNAs, have emerged as pivotal modulators of this process. They exert epigenetic and post-transcriptional control over key ferroptotic regulators, influencing iron metabolism, lipid handling and reactive oxygen species homeostasis. For instance, certain long non-coding RNAs act as molecular sponges for microRNAs that would otherwise repress lipid oxidising enzymes, whereas microRNAs can directly target transcripts encoding ferroptosis suppressors such as SLC7A11 or GPX4. Mapping these ncRNA-ferroptosis networks has unveiled novel biomarkers and therapeutic targets, laying the groundwork for precision oncology strategies that exploit ferroptotic death to overcome drug resistance across diverse malignancies.

Research from Nature Portfolio

An early mechanistic study uncovered the role of an antisense long non-coding RNA in sensitising hepatocellular carcinoma cells to erastin-induced ferroptosis. The antisense transcript downregulates a key transcription factor by inhibiting its translation, leading to reduced levels of the peroxidase PRDX5. As a result, the antioxidant defence is compromised, lipid peroxidation escalates and tumour cell viability is diminished. Clinical correlations indicated that high expression of the antisense RNA improves overall survival, highlighting its potential as both a prognostic marker and a therapeutic target in liver cancer.

Ferroptosis and Non-Coding RNA Regulation in Cancer Systems publication trend

The graph below shows the total number of articles in ferroptosis and non-coding rna regulation in cancer systems across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: A regulated form of cell death driven by iron-dependent lipid peroxidation.

Non-coding RNA (ncRNA): RNA molecules that do not encode proteins but regulate gene expression at multiple levels.

MicroRNA (miRNA): Small ncRNAs of about 22 nucleotides that bind target mRNAs to repress translation or promote degradation.

Long non-coding RNA (lncRNA): Transcripts longer than 200 nucleotides involved in chromatin remodelling, transcriptional and post-transcriptional regulation.

Competing endogenous RNA (ceRNA): RNAs that sequester microRNAs through shared binding sites, modulating the availability of miRNAs for other targets.

Glutathione peroxidase 4 (GPX4): A central antioxidant enzyme that reduces lipid hydroperoxides and prevents ferroptotic cell death.

Lipid peroxidation: Oxidative degradation of polyunsaturated fatty acids in membranes, leading to cell damage and death.

References

1. LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells. Scientific Reports (2019).
2. Epigenetic modification of ferroptosis by non-coding RNAs in cancer drug resistance. Molecular Cancer (2024).
3. Competing endogenous RNA networks and ferroptosis in cancer: novel therapeutic targets. Cell Death & Disease (2024).