Ferroptosis-related LncRNAs in diseases.

The discovery of ferroptosis originated from the identification of system xc- which was first reported in 1980 [ 27 ]. System xc- was identified as an antiporter that exchanges intracellular glutamate for extracellular cystine on the cell membrane, consisting of solute carrier family 7 member 11 (SLC7 A11) and solute carrier family 3 member 2 (SLC3 A2). Under the transport of system xc-, glutamate and cysteine are exchanged in and out of cells, leading to synthesize GSH through the catalysis of glutathione synthetase (GS) and glutamate cysteine ligase (GCL) [ 28 ]. In 2003, the Stockwell laboratory identified a cell death pattern distinct from apoptosis using erastin, which targets cancer cells harboring RAS gene mutations [ 29 ]. However, the authors did not name this mode of cell death at that time. Five years later, their laboratory [ 30 ] reported that a compound Ras selective lethal 3 (RSL3) could induce cell death like erastin and demonstrated that this cell death pathway can be inhibited by iron chelators and antioxidants, suggesting its association with iron and reactive oxygen species (ROS). Based on the foundational understanding of the mechanisms of the control of ROS and the regulation of iron [ 8 ], this type of cell death was termed “ferroptosis” in 2012: an iron-dependent form of nonapoptotic cell death [ 6 ]. Studies conducted over the next decade demonstrated that ferroptosis is ultimately driven by specific lipid peroxidation, primarily determined by lipid metabolism, ROS, and iron regulation [ 8 ]. The main components of ferroptosis are shown in Fig.  2 , core lipid peroxidation regulated by three interrelated factors: lipid metabolism, ROS antioxidant defense, and iron regulation. Fig. 2 Critical features of ferroptosis. The core incentive of ferroptosis is lipid peroxidation, typically involving polyunsaturated fatty acids (PUFAs), which are regulated by three related factors: lipid metabolism, ROS antioxidant defense, and iron regulation. Ferroptosis is monitored by two systems, one mediated by GPX4 and primarily catalyzing the reduction of lipid peroxides. The other set is dominated by non-GPX4 enzymes, mainly by scavenging free radicals to inhibit ferroptosis through antioxidant pathways. PUFA, polyunsaturated fatty acid; ROS, reaction oxygen species; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; POR, p450 oxidoreductase; ALOXs, lipoxygenases; FSP1, ferroptosis suppressor protein; GCH1, GTP cyclohydrolase 1; DHODH, dihydroorotate dehydrogenase; BH4, tetrahydrobiopterin; GPX4, glutathione peroxidase 4; GS, glutathione synthetase; GCL, glutamate cysteine ligase Critical features of ferroptosis. The core incentive of ferroptosis is lipid peroxidation, typically involving polyunsaturated fatty acids (PUFAs), which are regulated by three related factors: lipid metabolism, ROS antioxidant defense, and iron regulation. Ferroptosis is monitored by two systems, one mediated by GPX4 and primarily catalyzing the reduction of lipid peroxides. The other set is dominated by non-GPX4 enzymes, mainly by scavenging free radicals to inhibit ferroptosis through antioxidant pathways. PUFA, polyunsaturated fatty acid; ROS, reaction oxygen species; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; POR, p450 oxidoreductase; ALOXs, lipoxygenases; FSP1, ferroptosis suppressor protein; GCH1, GTP cyclohydrolase 1; DHODH, dihydroorotate dehydrogenase; BH4, tetrahydrobiopterin; GPX4, glutathione peroxidase 4; GS, glutathione synthetase; GCL, glutamate cysteine ligase Polyunsaturated fatty acids (PUFAs) are highly prone to peroxidation due to the presence of extremely weak C-H bonds between adjacent C = C double bonds [ 31 ]. Under the catalysis of lysophosphatidylcholine acyltransferase 3 (LPCAT3) [ 32 ] and acyl CoA synthase long-chain family member 4 (ACSL4) [ 33 ], free PUFA combines with phosphatidyl ethanolamine (PE) to generate polyunsaturated fatty acid phospholipids (PUFA-PL) [ 34 , 35 ]. PUFA-PL is sensitive to ROS and converts to peroxidized PUFA-PL-OOH, which induces ferroptosis [ 36 ]. ROS-mediated PUFA-PL peroxidation is associated with iron regulation, including labile iron pool and iron-dependent enzymes. In the Fenton reaction, 1 mol of H 2 O 2 reacts with 1 mol of Fe 2+ to generate 1 mol of Fe 3+ , 1 mol of OH − plus 1 mol of hydroxyl radical. After Fe 3+ reduction to Fe 2+ in cells, iron-binding complexes will be preferentially formed to participate in diverse physiological and biochemical reactions. Excess Fe 2+ will accumulate in the cell, creating an unstable iron ion pool that engages in the Fenton reaction to generate free radicals and induce ROS. Iron-dependent enzymes, including lipoxygenases (ALOXs) [ 31 ] and cytochrome P450 reductase (POR) [ 37 ], are recruited to generate hydrogen peroxide, the substrate of the Fenton reaction. PUFA-PL-OOH-driven ferroptosis is monitored by two systems, one mediated by glutathione peroxidase 4 (GPX4), which catalyzes the reduction of phospholipid peroxides. It was found that selenoprotein GPX4 converts PUFA-PL-OOH to PUFA-PL-OH, and inhibition of this activity will lead to the accumulation of PUFA-PL-OOH in the cell membrane and promote ferroptosis [ 38 ]. The other surveillance system is GPX4-independent and mediated by enzymes that produce metabolites with free radical-trapping antioxidant activity (non-GPX4 surveillance system). Currently, three non-GPX4 surveillance systems have been identified, namely FSP1/CoQ10, DHODH/CoQ10, and GCH1/BH4. Ferroptosis suppressor protein 1 (FSP1), formerly known as apoptosis-inducing factor mitochondrial 2 (AIFM2) [ 39 ], and dihydrolactate dehydrogenase (DHODH) [ 40 ] are a class of coenzyme Q (CoQ) oxidoreductases that can reduce CoQ to CoQH2, directly reducing the generation of free radicals and halting the propagation of lipid peroxides. GTP cyclohydrolase 1 (GCH1) scavenges free radicals and inhibits ferroptosis by producing the lipophilic antioxidant tetrahydropterin (BH4) [ 41 , 42 ].

The therapeutic potential of FRlncRNAs lies in its specific targeting of miRNAs or proteins, influencing ferroptosis gene expression and potentially offering novel treatments for diseases. While these studies are still in the early stages and face challenges, they hold promise for future clinical applications. The most promising avenue for targeted interventions is ferroptosis-related stem cell-derived exosomal lncRNAs. Sun Z et al. described that lncRNA TUG1 from human urine-derived stem cells (USCs)-derived exosomes (USC-Exo) regulated the stability of ACSL4 and the treatment of USC-Exo ameliorated kidney injury in I/R injury-induced acute kidney injury mouse models [ 215 ]. Zhang JK et al. showed that lncRNA Mir9-3 hg from bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSCs-Exo) suppressed cardiomyocyte ferroptosis in ischemia–reperfusion mice and the treatment of BMSCs-Exo attenuates I/R-induced cardiac injury [ 217 ]. Zhang L et al. found that lncRNA TUBB6/NRF2 pathways were activated by human umbilical cord mesenchymal stem cell-derived exosomes (HUCMSC-Exo) and the administration of HUCMSC-Exo suppressed traumatic brain injury-induced inflammation and ferroptosis after traumatic brain injury [ 260 ]. Shao C et al. investigated the exosomes derived from mesenchymal stem cells (MSC-Exo) for cell therapy of acute spinal cord injury. They showed that lncRNA lncGm36569 was enriched in the MSCs-Exo and acted as a competitive RNA of miR-5627-5p to induce FSP1 upregulation, enhancing repair of neurological function in the acute spinal cord injury mouse model [ 261 ]. Aside from stem cell-derived exosomal lncRNAs, other FRlncRNA strategies are developed for therapeutic intervention. Based on the previous findings that lncRNA metallothionein 1D pseudogene (MT1DP) aggravates oxidative stress by repressing antioxidation, Gai C et al. assembled nanoparticles combined with folate (FA)-modified liposome (FA-LP), erastin, and lncRNA MT1DP (E/M@FA-LPs) and proved that E/M@FA-LPs had a favorable therapeutic effect on NSCLC xenografts by MT1DP competitively sponging miR-365a-3p and thus regulating the expression of NRF2 protein [ 262 ].

Recently, FRlncRNAs have been extensively investigated as they could play a major role in the control of cancer progression (Fig.  3 ) and non-malignant diseases (Fig.  4 ). The mechanism by which FRlncRNAs regulate the progression of cancer through targeted proteins or miRNAs is gradually being elucidated. An increasing number of reports have established signatures of FRlncRNAs for cancer prognosis through bioinformatics analysis from online databases. The mechanisms by which FRlncRNAs mediate tumor drug resistance have now been documented. The functions of FRlncRNAs in non-malignant diseases can now be therapeutically addressed. In sum, lipid metabolism, ROS, and iron regulation mediated by FRlncRNAs are critically involved in the occurrence and development of diseases. Fig. 3 FRlncRNAs that regulate cancer progression. HCC, hepatocellular carcinoma; BC, bladder cancer; RCC, renal cell carcinoma; PCa, prostate cancer; TNBC, Triple-negative breast cancer; LUAD, Lung adenocarcinoma; ESCC, esophageal squamous cell cancer; CRC, colorectal cancer; OSCC, oral squamous cell carcinoma; NSCLC, non-small cell lung cancer; EC, endometrial cancer; BRCA, breast cancer; GC, gastric cancer; PC, pancreatic cancer Fig. 4 FRlncRNAs that regulate non-malignant diseases. PD, Parkinson’s disease; MI, myocardial infarction; CH, cardiac hypertrophy; I/R, ischemia–reperfusion; SAE, sepsis-associated encephalopathy; DR, diabetic retinopathy; DN, diabetic nephropathy; ARC, age-related cataract; AD, Alzheimer's disease; aortic dissection; IH, intracerebral hemorrhage FRlncRNAs that regulate cancer progression. HCC, hepatocellular carcinoma; BC, bladder cancer; RCC, renal cell carcinoma; PCa, prostate cancer; TNBC, Triple-negative breast cancer; LUAD, Lung adenocarcinoma; ESCC, esophageal squamous cell cancer; CRC, colorectal cancer; OSCC, oral squamous cell carcinoma; NSCLC, non-small cell lung cancer; EC, endometrial cancer; BRCA, breast cancer; GC, gastric cancer; PC, pancreatic cancer FRlncRNAs that regulate non-malignant diseases. PD, Parkinson’s disease; MI, myocardial infarction; CH, cardiac hypertrophy; I/R, ischemia–reperfusion; SAE, sepsis-associated encephalopathy; DR, diabetic retinopathy; DN, diabetic nephropathy; ARC, age-related cataract; AD, Alzheimer's disease; aortic dissection; IH, intracerebral hemorrhage These findings provide the basis for future exploiting the diagnostic and therapeutic potential of FRlncRNAs. One goal is to establish more robust FRlncRNA cancer prognostic signatures. So far, some lncRNAs, such as AP003555.1 , ZFPM2-AS1, MKLN1-AS, and AC099850.3 , have been identified as key players in multiple predictive models. FRlncRNAs may exhibit organ-specificity, for example, AP003555.1 and AC010973.2 for prognosis of CRC [ 49 , 52 , 53 , 103 – 105 ], and ZFPM2-AS1 and MKLN1-AS for HCC [ 54 , 58 , 111 , 112 ]. It is thus anticipated that more reliable FRlncRNA prognostic signatures will be established for different types of cancer. The second goal could be focused on monitoring FRlncRNA activities in vivo. Fluorescent probes can be used to monitor various biologically related molecules and microenvironments during ferroptosis at the cellular, tissue, and in vivo levels [ 263 ]. However, due to the lack of specific probes, imaging ferroptosis in patients remains a critical unresolved issue. A distinct, ferroptotic-like, necrotic cell death has recently been reported occurring in vivo during wounding of the Drosophila embryo using live imaging [ 264 ]. Unfortunately, this real-time imaging technology, which does not require probes, is not yet suitable for clinical application in patients. Thus, the development of future technologies may enable the in vivo detection of ferroptosis and facilitate further investigation into the roles of FRlncRNAs in diseases. Another direction is to apply FRlncRNAs in clinical development. Although research reports from the past 3 years have shown that FRlncRNAs can interfere with drug resistance and that FRlncRNAs in stem cell-derived exosomes could potentially treat diseases such as ischemia–reperfusion, the enormous potential of FRlncRNAs in treating diseases remains largely unexplored. Nonetheless, it is worth reiterating that targeting lncRNAs is a promising method for treating various diseases [ 265 ]. A better understanding of the mechanisms associated with FRlncRNA-mediated diseases, improvements in delivering FRlncRNAs to target cells, reducing the immunogenicity of lncRNA drugs, and ensuring a significant clinical response will significantly promote the application of FRlncRNAs in therapeutic applications.

Iron is a vital trace element for almost all living organisms, including humans. Iron metabolism operates through a highly controlled system that maintains a balance between iron absorption and excretion [ 1 ]. Due to its importance, iron levels in organisms are finely regulated, and excessive iron can damage the organism through various mechanisms, inducing a unique form of cell death known as ferroptosis. Ferroptosis is a type of regulated cell death (RCD) that is iron dependent and driving by lipid peroxidation. This is different to other forms of RCD such as apoptosis, autophagy, necroptosis, and pyroptosis, and as such ferroptosis is associated with different cell morphology, biochemistry, and genetics [ 2 – 4 ]. Under normal circumstances, ferroptosis primarily manifests as morphological changes in mitochondria, including reduced or absent mitochondrial cristae, increased membrane density, rupture of mitochondrial outer membrane, and significantly smaller mitochondria [ 5 – 7 ]. Ferroptosis is a novel type of programmed cell death that is iron dependent and driven by lipid peroxidation [ 8 ]. However, ferroptosis and other forms of RCD are not independent of each other. Studies have shown that cell apoptosis can be transformed into ferroptosis under certain conditions, and ferroptosis promotes cell sensitivity to apoptosis [ 9 , 10 ]. It was found that activation of autophagy could degrade ferritin and induce ferroptosis in cancer cells [ 11 ] and ferroptosis coexisted with necroptosis to work as two complementary forms of cell death [ 12 ]. The primary biochemical characteristics of ferroptosis include the aggregation of intracellular lipid peroxide and reduced glutathione (GSH) levels [ 8 ]. In addition, ferroptosis is considered a form of inflammatory cell death in immunology, characterized by the release of damage-associated molecular patterns (DAMPs) and lipid oxidation products [ 2 , 8 ]. Since its discovery, increasing evidence has shown that ferroptosis is associated with many diseases such as neurodegenerative and cardiovascular diseases, ischemia/reperfusion (I/R) injury, and cancer [ 13 – 17 ]. Following the completion of the Encyclopedia of DNA Elements (ENCODE) [ 18 ], it has been revealed that nearly 90% of genes in eukaryotic genomes can be transcribed into RNA. Still, only 1–2% of transcribed genes are translated into proteins, and most genes are transcribed as noncoding RNAs (ncRNAs) [ 19 , 20 ], including long noncoding RNAs (lncRNAs) which are ncRNAs with a transcript length of more than 200 nt. Unlike messenger RNAs (mRNAs), which encode proteins, lncRNAs play a crucial role in the epigenetic regulation of gene expression at both the transcriptional and post-transcriptional levels [ 21 ], serving as scaffolds, guides, decoys, and miRNA sponges [ 22 ] (Fig.  1 ). Fig. 1 Schematic diagram of the four main regulatory mechanisms of lncRNAs. 1: As scaffolds, lncRNAs can bring together multiple proteins to form ribonucleoprotein complexes, enabling information exchange and integration between different signaling pathways. 2: As miRNA sponges, lncRNAs can sponge specific miRNAs to block the interaction between miRNA and mRNA. 3: As guides, lncRNAs can bind with proteins and then locate protein complexes to specific DNA sequences to regulate gene expression. 4: As decoys, lncRNAs can bind to DNA-binding proteins (such as transcription factors), thereby blocking the action of the protein molecule and regulating the expression of downstream genes Schematic diagram of the four main regulatory mechanisms of lncRNAs. 1: As scaffolds, lncRNAs can bring together multiple proteins to form ribonucleoprotein complexes, enabling information exchange and integration between different signaling pathways. 2: As miRNA sponges, lncRNAs can sponge specific miRNAs to block the interaction between miRNA and mRNA. 3: As guides, lncRNAs can bind with proteins and then locate protein complexes to specific DNA sequences to regulate gene expression. 4: As decoys, lncRNAs can bind to DNA-binding proteins (such as transcription factors), thereby blocking the action of the protein molecule and regulating the expression of downstream genes An increasing number of lncRNAs have been identified as regulators of ferroptosis. The role of LncRNA in ferroptosis [ 23 ] and ferroptosis-related lncRNAs (FRlncRNAs) in cancer therapy have been reviewed elsewhere [ 24 – 26 ]. However, the unique role of FRlncRNAs in cancer prognosis, the close association between FRlncRNAs and non-malignant diseases, and the promising application for targeted interventions on FRlncRNAs have not yet been summarized. Here, we provide a brief review of the discovery of ferroptosis and describe the crucial mechanisms driving this process, as well as recent advances in identifying the role of FRlncRNAs in diseases, particularly in cancer prognosis, mechanisms associated with malignancy, drug resistance, and other conditions.