Introduction: Ferroptosis, a recently identified form of regulated cell death, has gained attention due to its distinctive biochemical and morphological features. Unlike apoptosis or necrosis, ferroptosis is driven by iron, reactive oxygen species (ROS), and oxidative damage to phospholipids, leading to mitochondrial dysfunction and loss of membrane integrity. This cell death pathway is of interest because its dysregulation is linked to diseases like cancer and neurodegeneration, making understanding its mechanisms essential for therapeutic strategies.
Various signaling pathways and molecules regulate ferroptosis, and changes in its regulatory network can contribute to disease progression, especially cancer. Many cancer cells resistant to conventional chemotherapy are sensitive to ferroptosis inducers, suggesting that ferroptosis may inhibit tumor growth. This makes inducing ferroptosis a promising strategy in cancer therapy. Research shows that non-coding RNAs (ncRNAs) regulate ferroptosis either by directly targeting key regulatory molecules or by influencing upstream pathways. These ncRNAs often have tissue- and tumor-specific expression, highlighting their potential as therapeutic targets in cancer treatment.
Methods: The information presented in this review was gathered from various scientific databases, including PubMed, MDPI, ScienceDirect, BMC, NCBI, and Google Scholar. Relevant studies were identified based on their recent publication dates, relevance to the topic, and the provision of experimental or clinical evidence regarding the role of non-coding RNAs in ferroptosis.
Results: Non-coding RNAs (ncRNAs) are diverse RNA molecules that do not code for proteins but perform crucial regulatory functions. In fact, the majority of the mammalian genome is transcribed into ncRNAs. These molecules regulate processes like gene expression and RNA modifications. Based on their size and function, ncRNAs are categorized as short or long ncRNAs, both of which play roles in drug resistance and ferroptosis regulation.
MicroRNAs (miRNAs), a type of short ncRNA, regulate gene expression post-transcriptionally by binding to mRNAs and inhibiting their translation. Studies show miRNAs can prevent ferroptosis by reducing iron levels and ROS production. For example, miR-137 suppresses ferroptosis in cancer by downregulating a glutamate transporter, reducing the production of glutathione, an antioxidant that prevents ferroptosis. Conversely, miR-7-5p induces ferroptosis in hepatocellular carcinoma cells by inhibiting GPX4, an enzyme protecting cells from oxidative stress.
Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides long with diverse functions, including ferroptosis regulation in cancer cells. They interact with DNA, mRNA, miRNAs, and proteins. LncRNAs often exhibit tissue-specific expression, making them relevant for cancer research. For example, lncRNA MALAT1 promotes ferroptosis by increasing pro-apoptotic gene expression and activating the NF-κB pathway. LINC00336 prevents ferroptosis in lung cancer, contributing to tumor survival, while P53RRA induces ferroptosis by releasing the tumor suppressor protein p53.
Circular RNAs (circRNAs), a newly discovered type of ncRNA, form stable loops that resist degradation. Studies show that circRNAs regulate ferroptosis by acting as miRNA sponges in cancer cells. Like lncRNAs, circRNAs are tissue-specific, and their stability enhances their therapeutic potential. CircRNA PVT1 promotes resistance to ferroptosis in cancer by increasing SLC7A11 expression, a key regulator of the anti-ferroptosis pathway, while circ-TTBK2 in gastric cancer prevents ferroptosis by inhibiting miR-376a and upregulating SLC7A11.
Conclusion: Several ncRNA-based therapies are in development, though most are still in clinical trials. One of the primary challenges with ncRNA therapies is their specificity, delivery, and tolerability, as ncRNAs are unstable and difficult to deliver intracellularly. However, advances in RNA therapy design are addressing these issues, making clinical use more feasible. Targeting ncRNAs may offer a new therapeutic option for overcoming drug resistance and modulating ferroptosis in cancer therapy.
In conclusion, ferroptosis is a promising form of regulated cell death with potential therapeutic applications, particularly in cancer treatment. Its ability to suppress tumor growth makes it an exciting avenue for anti-cancer strategies. NcRNAs, through their regulation of ferroptosis, are critical in this process, highlighting their therapeutic importance. Despite challenges in delivering ncRNA-based therapies, recent advances provide hope for their future use. Further research into ferroptosis and ncRNAs could lead to innovative treatments for cancer.
Keywords: Ferroptosis, Non-coding RNAs, miRNA, lncRNA, Cancer