Exploring Long Noncoding RNAs as Regulators of Tumor Ferroptosis: Advances and Challenges

ABSTRACT

Long noncoding RNAs (lncRNAs), a class of noncoding RNAs exceeding 200 nucleotides in length, play critical roles in regulating diverse biological processes and gene expression. Emerging evidence highlights their significant association with cancer occurrence, progression, prognosis, and therapeutic resistance, positioning lncRNAs as promising molecular targets for tumor detection and treatment. Ferroptosis, a regulated form of cell death characterized by the accumulation of iron‐dependent lipid peroxides, has gained attention as a potential therapeutic strategy for cancer, complementing existing modalities such as surgery, chemotherapy, radiotherapy, hormone therapy, and targeted molecular therapy. Recent research demonstrates that lncRNAs modulate ferroptosis in solid tumors, thereby influencing tumor cell invasion, metastasis, and proliferation. Inducing ferroptosis has been shown to inhibit tumor growth, reduce chemoresistance, and enhance radiotherapy efficacy. This review explores recent advancements in understanding the role of lncRNAs in tumor ferroptosis, with a focus on their involvement in iron metabolism and their potential as therapeutic targets in cancer combination therapies.

Long noncoding RNAs (lncRNAs) play pivotal roles in regulating gene expression and are closely associated with cancer progression, prognosis, and therapeutic resistance. This review highlights recent advancements in understanding how lncRNAs modulate ferroptosis, a regulated form of cell death characterized by iron‐dependent lipid peroxidation, influencing tumor invasion, metastasis, and proliferation. These findings suggest that targeting lncRNAs and ferroptosis could offer novel approaches for cancer therapy.

Abbreviations

ACSL4

acylcoenzyme A synthetase long‐chain family member 4

BC

breast cancer

Cys

cystine

Glu

glutamate

GPX4

glutathione peroxidase 4

GSH

glutathione

LC

lung cancer

Lip‐ROS

lipid reactive oxygen species

lncRNAs

long noncoding RNAs

LOX

lipoxygenase

LPCAT3

lysophosphatidylcholine acyltransferase 3

miRNAs

microRNAs

MLKL

mixed lineage kinase domain‐like proteins

PUFAPL

polyunsaturated fatty acid‐containing phospholipids

PUFAPLOOH

peroxidized polyunsaturated fatty acyl tail

PUFAs

polyunsaturated fatty acids

ROS

reactive oxygen species

SLC3A2

solute carrier family 3 member 2

SLC7A11

solute carrier family 7 member 11

System Xc‐

the cystine/glutamate antiport

Tf

transferrin

1. Introduction

GLOBOCAN 2020 provides estimates of cancer incidence and mortality from the International Agency for Research on Cancer, offering an update on the global cancer burden. In 2022, over 19.3 million new cancer diagnoses and nearly 10 million cancer‐related fatalities occurred worldwide. Among cancers in women, breast cancer (BC) has surpassed lung cancer (LC) to become the main cancer in women, with more than 2.3 million new cases (11.7%), followed by LC (11.4%), colorectal cancer (10.0%), prostate cancer (7.3%) and gastric cancer (5.6%). LC remains the leading cause of cancer deaths in women, accounting for about 1.8 million deaths (18%), followed by colorectal cancer (9.4%), liver cancer (8.3%), stomach cancer (7.7%) and female BC (6.9%) [1]. Malignant tumors have emerged as the primary cause of mortality in human health. Mutations or aberrant gene expression enable cells to sustain proliferative signaling, circumvent growth regulators, resist apoptosis, attain replicative immortality, promote angiogenesis, and initiate invasion and metastasis, culminating in cancer and progression [2]. Comprehending the mechanisms of tumorigenesis and investigating molecular targets with elevated specificity and sensitivity are crucial for cancer diagnosis and treatment [3].

Over 90% of the transcript products of the human genome consist of noncoding RNAs, which play a role in the regulation of gene expression at various levels. They govern fundamental biological processes, including growth, development, and organ function, while also playing a significant role in human diseases, particularly cancer [4]. Long noncoding RNA (lncRNA) is a kind of noncoding RNA exceeding 200 nucleotides in length and without protein‐coding capability [5]. LncRNAs provide significant biological activities, such as regulating gene expression, controlling the cell cycle, and participating in signal transduction networks [6]. The aberrant expression of lncRNA significantly contributes to carcinogenesis by modulating the proliferation, apoptosis, metastasis, and invasion of cancer cells [7].

Recent studies have established a significant correlation between programmed cell death mechanisms, including apoptosis, necrosis, autophagy, pyroptosis, and necroptosis, and the proliferation, migration, and treatment resistance of BC cells [8]. Ferroptosis is a form of cell death marked by the accumulation of iron‐dependent lipid reactive oxygen species (Lip‐ROS) [9]. It represents a novel kind of cell death, distinct from the established four major types: apoptosis, necroptosis, autophagy, and pyroptosis [10]. Research indicates that ferroptosis plays a significant role in the onset and advancement of various human diseases, including cancers, and is intricately linked to their therapy [11]. The induction of ferroptosis in tumor cells might significantly impede tumor progression and offer a novel therapeutic option, particularly for treatment‐resistant malignancies [12, 13, 14, 15].

This paper evaluates the study advancements of lncRNA associated with ferroptosis in cancer, offering theoretical support for the enhancement of BC treatment and the creation of targeted therapies.

2. Structural Characteristics of lncRNA

LncRNA is a type of RNA transcript exceeding 200 bases in length, ranging from 200 to 100,000 nucleotides. It bears structural similarities to messenger RNA but lacks significant protein‐coding capability due to the absence of an open reading frame in its sequences. Extensive data indicate that the majority of identified lncRNAs are transcribed by RNA polymerase II and possess mRNA‐like features, including a polyadenylated tail and promoter structure following enzymatic cleavage and processing [16], most lncRNAs are localized in the nucleus, with some specifically found in the cytoplasm, and many are retained in various subcellular organelles, being ubiquitously transcribed in eukaryotic cells. They consist of highly conserved promoter sequences, introns, or exon sequences encompassing the majority of the “k4‐K36” domain. It possesses a secondary structure [17, 18]. The secondary structure comprises a double stem configuration and a 3′‐terminal cloverleaf structure [19, 20]. The tertiary structure of lncRNA remains undetermined by existing research. The architecture of lncRNA is dispersed and lacks a cohesive core, potentially resembling the structure of telomerase RNA [21]. The majority of lncRNAs lack the capacity for protein translation. While they cannot be converted into proteins, they are crucial in gene coding processes, including transcriptional, posttranscriptional, and epigenetic levels. They participate in the activation, transcriptional modulation, and interference of proto‐oncogenes. It also plays a crucial part in the growth, development, and demise of organisms [22, 23, 24].

2.1. Mechanism of Action of lncRNA

LncRNAs demonstrate developmental and tissue‐specific expression patterns and are linked to several biological processes, including alternative splicing, protein activity regulation, modified protein localization, and epigenetic regulation. Certain lncRNAs may serve as precursors for short RNAs and as instruments for the silencing of microRNAs (miRNAs). Research indicates that lncRNA can function as a competitive inhibitor of miRNA cavernosum, specifically miRNA, so diminishing the concentration of miRNA [25]. LncRNA primarily fulfills four molecular functions: signaling, baiting, guiding, and scaffolding. LncRNAs can act as signaling molecules, demonstrating tissue selectivity in response to particular stimuli. LncRNA can function as a decoy for miRNA targets and can also attach to certain proteins, inhibiting the reaction of their downstream sequences. LncRNA can recruit chromatin‐modifying enzymes or other proteins to target genes and regulate gene expression by forming protein complexes. Common chromatin‐modifying enzymes include histone‐modifying enzymes and DNA methyltransferases, such as lncRNA HOTAIR recruiting PRC2 and LSD1 complexes, which catalyze H3K27me3 and remove H3K4me2, respectively, and repress target gene expression. LncRNAs can modulate gene expression in cells, influence protein localization, and are integral to the creation of cellular substructures or protein complexes. LncRNA can modulate the activity and location of proteins through protein interactions. Furthermore, lncRNAs modulate gene transcription and enhance gene expression by attracting transcription factors to the promoters of their target genes (Figure 1). Multiple studies have shown that lncRNAs are involved in nuclear transport, regulation of protein function, transcriptional interference, and gene regulation [26]. As cancer research advances, numerous scientists have discovered that lncRNA influences the expression of genes associated with the cell cycle, survival, and metastasis [27]. Additionally, lncRNAs function as oncogenes and tumor suppressor genes, inhibiting tumor incidence and progression [28]. Consequently, lncRNAs are intricately associated with cancer [29] (Table 1).

FIGURE 1.

LncRNAs interact with proteins to regulate the mechanism of transcription.

TABLE 1.

LncRNA plays a role in breast cancer metastasis, invasion, and proliferation through RNA‐protein interactions.

LncRNA	Function of regulation	Binding protein	Molecular mechanisms
UCA1	Breast cancer cell growth and tumorigenesis	hnRNP I	hnRNP I enhanced p27 (Kip1) translation by interacting with p27 mRNA, but the interaction between UCA1 and hnRNP I inhibited p27 expression by competitive inhibition
NKILA	Metastasis and invasion of breast cancer cells	NF‐κB	NKILA is upregulated by NF‐B and binds to NF‐B/IB, thereby inhibiting IKK‐induced phosphorylation of IB and NF‐B activation
LINC01133	Breast cancer cell proliferation, invasion and metastasis	EZH2	Binding of LINC01133 to EZH2 inhibited the transcription of SOX4
LINC02273	Invasion and metastasis of breast cancer cells	hnRNPL	hnRNPL‐LINC02273 promotes breast cancer metastasis by regulating the expression of AGR2
LncRNA NONHSAT028712 (Lnc712)	Breast cancer Cell proliferation	HSP90	Lnc712 interacts with HSP90 and participates in breast cancer proliferation through the Cdc37‐CDK2 pathway
DSCAM‐AS1	Breast cancer Cell proliferation	YBX1	DSCAM‐AS1 interacts with YBX1 to reduce transcriptional activation of FOXA1 and ER
MaTAR25 (LINC01271)	Breast cancer cell proliferation, invasion and metastasis	PURB	MaTAR25 interacts with PURB to regulate Tns1 to promote breast cancer metastasis
LCPAT1	Breast cancer cell proliferation, invasion and metastasis	RBBP4	LCPAT1 interacts with RBBP4 to activate MFAP2 transcription to promote BC progression
MNX1‐AS1	Breast cancer cell proliferation, invasion and metastasis	Stat3	MNX1‐AS1 binds to Stat3 and upregulates Stat3 phosphorylation by enhancing the interaction between p‐JAK and Stat3
Linc00668	Breast cancer cell metastasis	SND1	Linc00668 interacted with SND1 to promote SMAD2/3/4 transcription
HUMT	Proliferation, metastasis, and lymphangiogenesis in triple‐negative breast cancer	YBX1	HUMT interacts with YBX1 to promote FOXK1 expression
AC073352.1	Migration and invasion, angiogenesis of breast cancer cells	YBX1	AC073352.1 interacted with YBX1 to promote BC metastasis, and AC073352.1 could act as an exosomal lncRNA to induce angiogenesis in HUVEC
NR2F1‐AS1 (NAS1)	Lung metastasis of breast cancer cells is regulated by dormancy, which promotes EMT and cell invasion	PTBP1	NAS1 binds to NR2F1 mRNA and recruits the RNA‐binding protein PTBP1 to facilitate the internal ribosome entry site (IRES)‐mediated translation of NR2F1, resulting in NR2F1 repression of ΔNp63 transcription. ΔNp63 knockdown leads to epithelial‐mesenchymal transition, reduced tumorigenicity, and enhanced dormancy of lung cancer cells
MIR200CHG	Proliferation and invasion of breast cancer cells	YB‐1	MIR200CHG binds to YB‐1 and inhibits its ubiquitination and degradation. It regulates tumor cell proliferation, invasion and drug resistance by affecting the ubiquitination and phosphorylation of serine 102 of YB‐1. In addition, MIR200CHG partially affected the expression of miR‐200c/141‐3p encoded by its intronic region
ARHGAP5‐AS1	Breast cancer cell migration	SMAD7	ARHGAP5‐AS1 interacts with the PY motif of SMAD7 protein to negatively control the TGF‐signaling pathway and inhibit breast cancer cell migration
AATBC	Migration and invasion of breast cancer cells	YBX1	AATBC interacts with YBX1 to inhibit the phosphorylation of YAP1, thereby activating the Hippo signaling pathway and promoting the migration and invasion of breast cancer cells
PHACTR2‐AS1 (PAS1)	Breast cancer growth and metastasis	Vigilin, SUV39H1	PAS1 forms a triple complex with the RNA‐binding protein vigilin and the histone methyltransferase SUV39H1. PAS1 interacts with the RNA‐binding protein vigilin to maintain its stability. Meanwhile, PAS1 recruits SUV39H1 to trigger H3K9 methylation of PH20, leading to its silencing
THOR	Breast cancer cell proliferation, migration and invasion	hnRNPD	THOR stabilizes its target mrnas, including pyruvate dehydrogenase kinase 1 (PDK1), by increasing hnRNPD protein levels by binding to hnRNPD protein and maintaining hnRNPD protein stability by inhibiting the proteasome‐dependent degradation pathway, Furthermore, the downstream PI3K‐AKT and MAPK signaling pathways were activated to regulate breast cancer cell proliferation and metastasis
Uc003xsl.1	Breast cancer growth and metastasis	NF‐κB	Uc003xsl.1 directly binds to nuclear transcription factor NF‐B to inhibit NKRF, thereby inhibiting NKRF on NF‐B‐mediated IL‐8 transcription. Activation of the NF‐B/IL‐8 axis promotes breast cancer progression
TGFB2‐AS1	Breast cancer growth and metastasis	SMARCA4	TGFB2‐AS1 interacts with SMARCA4, the core subunit of the SWI/SNF complex, and blocks access of the complex to its target promoter in cis and trans, thereby represses the expression of target genes TGF2 and SOX2, ultimately leading to the inhibition of breast cancer progression
LncRNA FGF13‐AS1	Breast cancer cell proliferation, invasion and metastasis	IGF2BP1	FGF13‐AS1 directly interacts with IGF2BPs and reduces the stability of IGF2BPs on Myc mRNA
Linc00514	Breast cancer cell proliferation, invasion and M2 polarization of macrophages	JAK2, STAT3	LINC00514 interacted with JAK2 and STAT3 and increased pSTAT3 expression activates Jagged1‐mediated Notch signaling pathway

3. Overview of Ferroptosis

3.1. Concept of Ferroptosis

Ferroptosis is a novel method of cell death introduced by Dixon et al. in 2012. Lipid peroxidation is induced by the Fenton reaction, facilitated by ferrous (Fe²⁺) or ferric (Fe³⁺) ions, resulting in an increase in reactive oxygen species (ROS) within cells. The most perilous hydroxyl radical is generated by hydrogen peroxide, which induces cellular apoptosis [30]. Ferroptosis is a gene‐regulated kind of cell death closely associated with many intracellular metabolic pathways. Iron metabolism influences intracellular iron accumulation, lipid metabolism dictates lipid peroxidation outcomes, and amino acid metabolism is integral to the antioxidant defense system, all of which directly impact the onset and progression of ferroptosis and cellular sensitivity to this form of cell death [31].

3.2. Attributes of Ferroptosis

Ferroptosis is a novel kind of programmed cell death that differs from apoptosis, necrosis, and autophagy in terms of biochemistry, morphology, and genetics, exhibiting distinct morphological and biochemical traits [32]. The morphological features primarily include mitochondrial shrinkage, reduction or absence of mitochondrial cristae, increased mitochondrial membrane density, rupture of the mitochondrial membrane, and normal nuclear morphology as observed under an electron microscope. However, there is an absence of chromatin condensation [33]. The primary biochemical characteristics include elevated iron and Lip‐ROS levels, reduced glutathione (GSH), inactivation of glutathione peroxidase 4 (GPX4), and diminished mitochondrial membrane potential [34]. During ferroptosis, polyunsaturated fatty acids (PUFAs) in the cell membrane generate Lip‐ROS through the catalysis of lipoxygenase (LOX) and iron. The elimination of Lip‐ROS is mostly conducted by GPX4. Inhibition of the cystine/glutamate antiport (System Xc‐) prevents the import of cystine into cells and obstructs the synthesis of GSH. The GSH‐dependent inactivation of GPX4 results in the accumulation of intracellular Lip‐ROS, subsequently inducing oxidative damage to cells [35]. Consequently, the suppression of System Xc‐, depletion of GSH, and inactivation of GPX4 are critical factors that trigger ferroptosis in cells. Moreover, ferroptosis is independent of apoptotic proteins, does not utilize energy, and lacks apoptotic signals. Simultaneously, there is an absence of cytoplasmic and organelle enlargement, cell membrane rupture, and intracellular autophagosome formation.

3.3. The Molecular Drivers of Ferroptosis

Ferroptosis is closely related to various biological processes such as iron metabolism, lipid metabolism, and glutathione metabolism. Among them, intracellular iron accumulation and lipid peroxidation are two key signals in the process of ferroptosis [36]. Ferric iron (Fe³⁺) attaches to transferrin (Tf), and the resulting complex is internalized by the cell via endocytosis. Subsequently, Fe³⁺ is reduced to divalent iron (Fe²⁺). Conversely, polyunsaturated fatty acids (PUFA) in the cell membrane generate polyunsaturated fatty acid‐containing phospholipids (PUFAPL) through the activity of Acylcoenzyme A synthetase long‐chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) [37]. Subsequently, PUFAPL synthesizes phospholipid with peroxidized polyunsaturated fatty acyl tail (PUFAPLOOH) by the Fe²⁺ mediated Fenton reaction, which also triggers excessive ROS generation. Excessive PUFAPLOOH and ROS may compromise the cell membrane and trigger ferroptosis [38].

Several previously described types of programmed cell death are centered on executive proteins, considering the method of occurrence. Apoptosis is mostly executed by the caspase protein family, pyroptosis is predominantly regulated by the gasdermins family, and necroptosis is chiefly handled by mixed lineage kinase domain‐like proteins (MLKL) [39]. As a unique mode of cell death, ferroptosis depends on the confrontation between the executive system and defense buffer system. The main regulatory factors of ferroptosis include GPX4, FSP1, NRF2, and p53, among which GPX4 is the key protein affecting ferroptosis [38]. The standard function of GPX4 relies on GSH. GSH is generated from glutamate (Glu), cysteine, and glycine, with its synthesis reliant on the normal functioning of System Xc‐, which facilitates the import of cystine (Cys) into the cell and the export of glutamate from the cell [40]. System Xc‐ is the upstream node of the GPX4/GSH axis, which is a heterodimer of two subunits, solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2) [32]. Inhibition or depletion of GPX4, GSH, and System Xc‐ can facilitate the advancement of ferroptosis (Figure 2).

FIGURE 2.

Schematic of the regulatory mechanism of ferroptosis.

3.4. Advancements in the Study of Ferroptosis‐Associated lncRNAs in Tumors

Ferroptosis significantly influences the proliferation of some tumor cell types, including pancreatic ductal cell carcinoma and hepatocellular carcinoma. Investigating the regulatory processes associated with ferroptosis in tumors is crucial for comprehending and treating neoplasms. Currently, the majority of chemotherapy agents function by triggering apoptosis in neoplastic cells. If apoptosis is circumvented, chemoresistance will ensue. Ferroptosis, a novel kind of programmed cell death, possesses distinct properties and demonstrates significant potential in tumor treatment via ferroptosis inducers and inhibitors [41]. The activation of the ferroptosis pathway can induce the death of cancer cells [42], especially in the case of drug resistance to enhance the sensitivity of chemotherapy drugs. For example, cisplatin combined with the ferroptosis inducer erastin can significantly improve the antitumor activity, showing that ferroptosis plays an important role in cancer treatment [43]. A multitude of studies has validated that ferroptosis can serve as a novel target for tumor suppression, hence providing a new avenue for clinical tumor treatment [44].

3.4.1. Breast Tumor

BC is a malignant neoplasm with the greatest incidence and fatality rates among women globally. It not only impacts the exterior perception of women but also poses a significant threat to their life and health. A substantial body of evidence indicates that the prevalence of BC has been rising in recent years, with a notable tendency towards younger age groups, while advancements in BC research have plateaued. Therefore, it is imperative to explore new avenues for BC treatment.

LncRNAs regulating ferroptosis in BC cells. Qi et al. [45] found that the long‐chain noncoding RNA PGM5P3‐AS1 stabilized the expression of the target gene microtubule‐associated protein light chain C by binding to the RNA‐binding protein NOP58, which promoted ferroptosis and inhibited the malignant progression of triple‐negative BC. Zhang et al. [46] found that LNC00460 promoted BC cell proliferation and inhibited ferroptosis through the miR‐320a/MAL2 axis. Li et al. [47] found that POU2F2‐mediated upregulation of lncRNA PTPRG‐AS1 inhibited ferroptosis in BC through the miR‐376c‐3p/SLC7A11 axis. Wang et al. [48] found that RUNX1‐IT1 promoted the occurrence and development of BC by regulating the IGF2BP1/GPX4 axis. Fan et al. [49] found that lncRNA FASA promoted tumor ferroptosis by regulating PRDX1 phase separation. Mao et al. [50] found that lncRNA P53RRA can participate in the ferroptosis process by regulating the expression of P53, thereby mediating tumor resistance.

Moreover, ferroptosis‐related lncRNAs have been reported to predict the prognosis and outcome of BC [51]. This elucidates additional information regarding the function of lncRNAs and offers clinical targets for oncological treatment. Numerous studies examine the association between ferroptosis and noncoding RNA in BC; however, current research primarily emphasizes the expression of molecular relationships and the potential of noncoding RNA in forecasting ferroptosis and tumor prognosis. We anticipate the development of small molecule drugs that target ferroptosis‐related noncoding RNA to offer further therapeutic strategies for BC.

3.4.2. Lung Tumor

LC holds the highest position in the global age‐standardized incidence and mortality rates of malignant neoplasms. In 2020, around 2.2 million new LC cases and 1.8 million fatalities occurred globally. The absence of distinct clinical manifestations and diagnostic indicators for early LC results in most patients missing optimal treatment opportunities, leading to a 5‐year survival rate of under 17%. Investigating the incidence and developmental mechanisms of LC is crucial for early clinical diagnosis, targeted therapy, and prognostic assessment [52].

LncRNAs regulating ferroptosis in LC cells. Wang et al. [53] used LC PC9, A549, and H358 cell lines to study the mechanism of lncRNA LINC00336 regulating ferroptosis and found that LINC00336 was localized in the nucleus and that overexpression of the LSH gene could induce upregulation of LINC00336 transcription level. It is highly expressed in both lung adenocarcinoma cell lines and lung squamous cell lines. Chao et al. [54] studied the molecular mechanism of lncRNA MT1DP regulating ferroptosis and found that MT1DP could inhibit the antioxidant response of cells by inhibiting the expression of miR‐365a‐3p and eventually lead to the activation and aggravation of the oxidative stress response of cells.

Recent advancements in genomics research have positioned lncRNAs as a novel avenue for understanding the mechanisms behind LC development and enhancing clinical diagnosis and treatment. LncRNAs play a pivotal role across the entirety of fundamental research and clinical practice of LC, encompassing the malignant transformation of normal bronchoalveolar epithelial cells, local and distant tumor spread, early clinical diagnosis, and the development of targeted therapies. It unequivocally illustrates the significant potential of lncRNAs as novel biomarkers.

3.4.3. Gastric Tumor

Gastric cancer, a prevalent malignant tumor in the digestive tract, has a consistently high fatality rate throughout the year. The insidious indications of early stomach cancer frequently lead to later stages, resulting in the loss of surgical intervention opportunities. Consequently, other therapeutic modalities must be employed to eradicate cancer cells, thereby enhancing patients' quality of life and extending their survival duration.

LncRNAs regulating ferroptosis in gastric cancer cells. Qu et al. [55] studied a novel lncRNA DACT3‐AS1. In vitro and in vivo experiments showed that DACT3‐AS1 is one of the exosome components of cancer‐related fibroblasts (CAFs) and can spread to gastric cancer cells. Enhancing the sensitivity of gastric cancer cells to oxaliplatin by targeting the miR‐181a‐5p/sirtuin 1 (SIRT1) axis inhibits cell proliferation, migration, and invasion. LASTR can inhibit the ferroptosis of gastric cancer cells and promote their proliferation and migration [56]. Under hypoxic conditions, PMAN could regulate SLC7A11 through ELAVL1 [57], and CBSLR could coregulate CBS with YTHDF2, reducing the ASCL4 protein methylation level, protein polyubiquitination, and protein degradation [58]. It also inhibited ferroptosis and promoted the proliferation of cancer cells.

In gastric cancer, several intracellular chemicals, such as amino acids, noncoding RNAs, and peptides, regulate ferroptosis. Ferroptosis is significant in gastric cancer treatment since it uncovers novel drug resistance pathways and modulates tumor cell sensitivity to chemotherapy resistance. Nonetheless, the regulating mechanism of ferroptosis in gastric carcinogenesis requires additional investigation.

3.4.4. Liver Tumor

Liver cancer is a highly lethal malignancy and the primary cause of mortality among males. The prevalent risk factors for liver cancer include liver cirrhosis, tobacco use, and obesity, among others. The aberrant expression of ferroptosis‐related lncRNAs modulates ferroptosis in hepatocellular carcinoma cells, influencing the proliferation, metastasis, and prognosis of cancer cells.

LncRNAs regulating ferroptosis in hepatocellular carcinoma cells. Qi et al. [59] found that GABPB1‐AS1 could inhibit GABPB1 translation, down‐regulate PRDX5 expression, and inhibit the antioxidant capacity of cells, thereby promoting ferroptosis and inhibiting cancer cell proliferation in erastin‐treated HCC cells. Some studies have suggested that HULC can regulate ferroptosis‐related gene ATF4 through miR‐3200‐5p, and LINC01134 can up‐regulate GPX4 expression through NRF2, both of which inhibit ferroptosis and promote cancer cell proliferation [60, 61]. He et al. [62] found that PVT1 could inhibit GPX4 by binding to miR‐214‐3p, promote ferroptosis, and inhibit the proliferation of hepatocellular carcinoma cells after ketamine treatment.

The rapid development of LncRNA in the field of cancer has attracted more and more attention. Through the organic combination of lncRNA and epigenetics, a more comprehensive understanding of RNA can be obtained. As a unique mode of cell death, ferroptosis has also attracted wide attention in the field of cancer research and become a hot spot in tumor treatment. Although there are a variety of treatment options for liver cancer, their effects are not good and there are still some difficulties in the treatment. Therefore, an in‐depth understanding of the regulatory network between ferroptosis and lncRNAs in liver cancer and providing a scientific basis for precise treatment of liver cancer still has great research prospects and development potential.

3.4.5. Other Types of Cancer

Ferroptosis‐associated lncRNAs are implicated in the onset and progression of several malignancies, including pancreatic, renal, prostate, and bladder cancers. Pancreatic cancer is a malignant neoplasm of the digestive system characterized by a challenging diagnosis and unfavorable prognosis. Long noncoding RNAs can suppress ferroptosis in pancreatic cancer. For example, Tang et al. [63] found that high expression of SLCO4A1‐AS1 was identified as a new molecule mediating ferroptosis resistance in vitro, which was helpful to evaluate the prognosis, molecular characteristics, and treatment mode of patients with ferroptosis. In addition, kidney cancer, prostate cancer, and bladder cancer are common urinary system tumors. Up‐regulated lncRNAs can affect ferroptosis in renal and prostate cancer through SLC7A11. For example, SLC16A1‐AS1 can regulate SLC7A11 by targeting miR‐143‐3p to inhibit ferroptosis and promote the proliferation and metastasis of renal cancer cells [64]. Luo et al. [65] found that up‐regulated RP11‐89 could target miR‐129‐5p to regulate the ferroptosis‐related gene PROM2, thereby inhibiting ferroptosis and promoting bladder cancer cell proliferation (Table 2).

TABLE 2.

LncRNAs associated with tumor ferroptosis.

Type of tumor	LncRNAs	Cellular localization	Change	Target	Potential regulatory mechanisms	References
Breast cancer	PGM5P3‐AS1	Cytoplasm	Down	NOP58, MAP1LC3C	Promote ferroptosis and suppress TNBC cell proliferation and migration	[45]
	LINC00460	Cytoplasm	Up	miR‐320a/MAL2	Promotes the proliferation of breast cancer cells and inhibits ferroptosis	[46]
	PTPRG‐AS1	Cytoplasm	Up	miR‐376c‐3p/SLC7A11	Inhibition of ferroptosis in breast cancer	[47]
	RUNX1‐IT1	Cytoplasm	Up	IGF2BP1/GPX4	Inhibition of ferroptosis to promote breast cancer death	[48]
	LncFASA	Cytoplasm	Down	PRDX1	Promotes tumor ferroptosis	[49]
	P53RRA	Cytoplasm	Down	G3BP1, P53	Promotes cell cycle arrest, apoptosis, and ferroptosis	[50]
Lung cancer	LINC00336	Nucleus	Up	miR‐6852/ELAVL1	Inhibition of ferroptosis in lung cancer by competing endogenous RNA	[53]
	MT1DP	Cytoplasm	Down	miR‐365a‐3p/NRF2	Increase the sensitivity of erastin‐induced ferroptosis in non‐small cell lung cancer cells	[54]
Gastric cancer	DACT3‐AS1	Cytoplasm	Down	miR‐181a‐5p/sirtuin 1	Inhibition of cell proliferation, migration and invasion	[55]
	LASTR	Cytoplasm	Up	SART3	Promote the adaptability of cancer cells	[56]
	PMAN	Cytoplasm	Up	ELAVL1, SLC7A11	Enhance ferroptosis resistance of gastric cancer cells	[57]
	CBSLR	Cytoplasm	Up	YTHDF2/CBS	Protect the GC after hypoxia induced cells from death, the influence of iron to produce resistance	[58]
Liver cancer	GABPB1‐ AS1	Cytoplasm	Up	PRDX5	Inhibition of tumor ferroptosis	[59]
	HULC	Cytoplasm	Up	miR‐3200‐5p/ATF4	Mediates ferroptosis in hepatocellular carcinoma	[60]
	LINC01134	Nucleus	Up	Nrf2/GPX4	Through oxidation stress way reduce cell viability and cell apoptosis, thereby enhancing OXA resistance of hepatocellular carcinoma (HCC)	[61]
	PVT1	Nucleus	Up	miR‐214‐3p/GPX4	Regulates the process of ketamine inhibiting the viability and inducing ferroptosis of hepatocellular carcinoma cells	[62]
Pancreatic cancer	SLCO4A1‐AS1	Cytoplasm	Up	SLC7A11	Promotes tumorigenesis and mediates ferroptosis resistance	[63]
Kidney cancer	SLC16A1‐AS1	Nucleus	Up	miR‐143‐3p/SLC7A11	Promotes tumorigenesis and ferroptosis resistance	[64]
Bladder cancer	RP11‐89	Cytoplasm	Up	miR‐129‐5p/prom2	Promotes tumorigenesis and ferroptosis resistance	[65]

In conclusion, the application of cancer therapy based on the ferroptosis molecular regulation mechanism still has great research prospects and development potential.

4. Expectation

Recent research indicates that lncRNAs influence solid tumors, including lung, liver, and stomach cancers, by altering ferroptosis, proliferation, and metastasis of cancer cells. The ongoing advancement of research and technology enables comprehensive verification of the expression, phenotypic, and downstream regulatory mechanisms of lncRNAs in tumor cells and tissues. The results derived from molecular mechanism validation are the most compelling. Moreover, numerous unidentified lncRNAs modulate ferroptosis‐related genes in malignancies or influence ferroptosis through other molecular processes. A multitude of bioinformatics publications have undergone initial screening, and elucidating the specific relationship between them and ferroptosis may be the focal point of forthcoming research.

In recent years, the majority of research initiatives concerning cancers have focused on identifying differentially expressed lncRNAs, validating phenotypes, and investigating downstream processes. The discovery of ferroptosis has liberated researchers from solely focusing on innate traits like proliferation, invasion, and metastasis. Currently, there is a tendency to integrate ferroptosis with apoptosis and autophagy.

Cancer is a significant cause of mortality among humans globally. Despite significant advancements in tumor treatment over the past decades, the resistance of malignancies to therapeutic agents and the elevated likelihood of recurrence necessitate further exploration of tumor therapies. Furthermore, new cancer data indicate that tumor incidence remains stable, suggesting a stagnation in tumor research. Recent research has increasingly demonstrated that ferroptosis effectively eradicates cancer cells resistant to other forms of cell death and improves tumor cell sensitivity to antitumor treatments, including chemotherapy and radiotherapy. Nevertheless, the majority of reported ferroptosis inducers remain in the preclinical phase, necessitating further investigation into their efficacy, targets, drug resistance, and potential adverse effects. Furthermore, there is a paucity of research regarding the interplay between lncRNA and ferroptosis in tumor regulation. Consequently, a comprehensive examination of the novel paradigm of lncRNA in conjunction with ferroptosis, clarification of the ferroptosis mechanism, and exploration of innovative ferroptosis‐based therapeutic approaches are imperative in the forthcoming years, as they will offer potential strategies and insights for tumor treatment and the development of effective and safe targeted pharmaceuticals. In conclusion, elucidating the precise mechanism of lncRNA‐ferroptosis in cancer, targeting various nodes within the ferroptosis regulatory network, and integrating with alternative therapeutic approaches are anticipated to be effectively and judiciously implemented in the future, thereby facilitating personalized cancer treatment.

Author Contributions

Gang Li: writing – original draft. Bing Wang: writing – original draft. Lisha Ye: writing – review and editing. Guohua Wang: writing – review and editing.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.