The intersection of ferroptosis and non-coding RNAs: a novel approach to ovarian cancer

Abstract

Understanding the core principles of ovarian cancer has been significantly improved through the exploration of Ferroptosis, a type of cell death triggered by iron that leads to an increase in lipid peroxides. Current research has shed light on the critical functions of non-coding RNAs, such as circRNAs, lncRNAs, and miRNAs, in regulating ferroptosis in ovarian cancer. The aim of this paper is to comprehensively analyze how ncRNAs influence the development of ferroptosis in ovarian cancer cells. In-depth exploration is undertaken to understand the intricate ways in which ncRNAs regulate essential elements of ferroptosis, including iron management and lipid peroxidation levels. We also investigate their significant involvement in the progression of this type of cellular demise. It should be emphasized that ncRNAs can impact the synthesis of crucial proteins, such as GPX4, a key contributor to the cellular defense against oxidation, and ACSL4, involved in lipid formation. In addition, we examine the correlation between ncRNAs and well-known pathways associated with oxidative stress and cell death. The consequences of these discoveries are noteworthy, since focusing on particular ncRNAs could potentially render ovarian cancer cells more vulnerable to ferroptosis, effectively combating drug resistance problems. This discussion highlights the growing significance of ncRNAs in governing ferroptosis and their potential as useful biomarkers and treatment targets for ovarian cancer. We intend to promote additional research into the involvement of ncRNAs in controlling ferroptosis, based on current findings, with the ultimate goal of informing targeted therapeutic strategies and improving long-term treatment outcomes for individuals suffering from OC.

Introduction

Epithelial ovarian cancer (EOC) is the deadliest form of gynecological cancer, making up 70–80% of all OC cases. Its 5-year survival rate is typically no more than 45%, and in some cases, it is even lower [1]. Regarding progress in the medical field, the spread of EOC primarily happens through dissemination within the peritoneal cavity and through the lymphatic system, ultimately leading to the development of metastases in the omentum and peritoneum [2]. Hence, delving into uncharted pathways of EOC spread could offer a fresh approach to treating EOC in clinical settings.

The management of cancers specific to females is a significant hurdle, just like other types of cancer. Protecting healthy cells while targeting and destroying tumor cells is a crucial aspect of treating cancer. The identification of Regulated Cell Death (RCD) revealed the possibility of regulating the cellular death mechanism [3,4,5]. At first, RCD was thought to be solely caused by apoptosis, and numerous treatments were developed to induce apoptosis in cancerous cells. Nevertheless, recent findings have shown that tumor cells have varying levels of resistance to these drugs, emphasizing the necessity for alternative methods of treating cancer [6]. As a result, recent research has made efforts to focus on alternative cell death mechanisms to decrease cancer cell resistance to drugs that trigger apoptosis potentially.

The term ferroptosis refers to a specific type of RCD that is dependent on iron and iron-related mechanisms and pathways which was initially introduced in 2012 [7]. Ferroptosis inhibits the growth of tumors with RAS mutations. Further studies have shown a strong link between this process and the elimination of cancer cells [7, 8]. In ovarian cancer, upregulation of NRF2 and its target SLC7 A11 can lead to ferroptosis resistance by enhancing cystine uptake, supporting glutathione (GSH) biosynthesis, and ultimately protecting against lipid peroxidation [9, 10].

Ferroptosis relevance to OC lies in the unique metabolic and microenvironmental characteristics of OC cells, which often display elevated iron levels and dysregulated redox homeostasis—conditions that sensitize them to ferroptotic triggers [11, 12]. Moreover, accumulating evidence suggests that ferroptosis may play a pivotal role in overcoming resistance to conventional therapies, such as platinum-based chemotherapy, which remains a major clinical challenge in OC treatment [13, 14]. By exploiting this intrinsic vulnerability, ferroptosis-based strategies hold promises for enhancing the efficacy of existing treatments and improving patient outcomes. Therefore, understanding the role of ferroptosis in OC is not only scientifically compelling but also clinically significant. The conventional TP53/p53 tumor suppressor gene is responsible for controlling the RCD pathway, as it acts to suppress the activity of the cystine/glutamate antiporter/xCT/system Xc⁻ [15, 16]. A notable observation is that numerous tumor cells, despite their immunity to typical therapeutic methods, demonstrate susceptibility to ferroptosis. Therefore, triggering this type of cell death may aid in the elimination of these cells [17]. In addition, Ferroptosis has been linked to the implementation of immunotherapy, as it can be stimulated in cancer cells through T cells and the cytokine IFNG/IFNγ [18].

Recent findings suggest that the ferroptosis flux can be controlled through various ncRNA molecules, including miRNAs, circRNAs, and lncRNAs, which all have significant impacts [19, 20]. Together with ferroptosis, the related non-coding RNA molecules controls iron and amino acid metabolism, which affects the flow of ferroptosis [21]. Moreover, ncRNAs are also responsible for controlling the metabolism of ROS, and it is widely acknowledged that the buildup of lipid ROS within cells is a significant trigger for ferroptosis [22]. When the ROS levels increase moderately in cells, it can prompt cell growth, survival, and cancer formation. However, ncRNAs can control ROS levels to maintain a balanced redox state, which can prevent ferroptosis once the ROS levels decrease [19]. Ultimately, ferroptosis involves in the formation and growth of cancer, and its effects can be influenced by ncRNAs, which can determine whether cancer advances or is inhibited.

Ferroptosis and ovarian cancer

The research revealed that OC tissues with a high grade of plasma cytosis exhibited significantly higher amounts of iron when compared to benign ovarian tissues, suggesting a correlation between OC and heightened levels of iron within the cells [23, 24]. Furthermore, scientists discovered that the compound sodium molybdate can cause an increase in intracellular LIP levels in OC cells [25]. It is discovered that Ferroptosis-associated Cell death (FAC) increases the amount of iron inside OC cells, ultimately hindering their growth and replication [26]. Key ferroptosis-related genes include GPX4 (glutathione peroxidase 4), which acts as a central inhibitor of ferroptosis by reducing lipid hydroperoxides, and SLC7 A11, a component of the cystine/glutamate antiporter system Xc⁻, which maintains intracellular glutathione levels necessary for GPX4 function [27, 28]. ACSL4 (acyl-CoA synthetase long-chain family member 4) promotes the incorporation of polyunsaturated fatty acids into membrane phospholipids, thereby enhancing lipid peroxidation and susceptibility to ferroptosis [29]. TFRC (transferrin receptor) and FTH1 (ferritin heavy chain 1) are involved in iron uptake and storage, respectively, and play crucial roles in regulating iron homeostasis—a key determinant of ferroptotic sensitivity [30]. Dysregulation of these genes has been implicated in cancer progression and therapy resistance, particularly in tumors with high metabolic demands, such as ovarian cancer, making them potential targets for ferroptosis-based therapeutic strategies [28].

Mitochondrial Fe²⁺/Fe³⁺ homeostasis plays a critical role in regulating ferroptosis susceptibility in ovarian cancer cells. Mitochondria are central hubs for iron metabolism, responsible for synthesizing iron–sulfur clusters and heme while also maintaining a delicate balance between ferrous (Fe²⁺) and ferric (Fe³⁺) iron [31,32,33]. Disruptions in this balance, particularly mitochondrial iron overload, can lead to an accumulation of labile Fe²⁺, which readily participates in Fenton chemistry, generating reactive oxygen species (ROS) that promote lipid peroxidation—hallmarks of ferroptosis [34, 35]. In ovarian cancer, mitochondrial iron overload has been observed to prime cells for ferroptotic death by enhancing oxidative stress and overwhelming antioxidant defenses, particularly when GPX4 activity is compromised [36, 37]. The expression of mitochondrial iron transporters, such as mitoferrin- 1/2 and the downregulation or dysfunction of mitochondrial ferritin (FtMt), which normally buffers excess iron, can further exacerbate this vulnerability [38, 39]. Overall, mitochondrial iron dysregulation not only contributes to the metabolic plasticity of ovarian cancer cells but also creates a susceptibility window for ferroptosis-based therapies.

Completely inhibiting the production of GPX4 in ovarian cancer cells was found to effectively induce ferroptosis and the resulting cell death. This suggests that interfering with iron regulation during the initial phases of ovarian cancer may hinder its advancement. Furthermore, the presence of ROS in the mitochondria has the potential to trigger the opening of the mitochondrial permeability transition pore, resulting in damage to DNA and ultimately the process of apoptosis [12, 40,41,42]. Tesfay et al. revealed that cells of ovarian cancer demonstrate elevated levels of SCD1 [43]. Blocking SCD1 could potentially modify lipid processing and heighten the susceptibility of OC cells to compounds that induce ferroptosis (Fig. 1). Research has revealed a correlation between OC and the atypical manifestation of FRGs, which presents new possibilities for the management of OC. Wang et al. [44] demonstrated that eriodictyol effectively combats cancer by regulating the survival of cells, influencing ferroptosis, and managing mitochondrial function in ovarian cancer cells. This is achieved through the Nrf2/HO- 1/NQO1 pathway [45]. Based on recent studies, the administration of lidocaine and ropivacaine has been observed to facilitate the occurrence of ferroptosis in ovarian cancer cells [46, 47]. Studies have demonstrated that curcumin possesses the ability to impede the proliferation of tumors. More specifically, a specific form of curcumin, known as NL01, has been validated in its ability to trigger ferroptosis by activating the HCAR1/MCT1 pathway. This ultimately results in a more potent suppression of tumor progression [48]. Furthermore, the breakdown of p53 by MEX3 A is responsible for the proliferation of ovarian cancer, as it circumvents the natural ability of p53 to suppress tumor growth. This indicates that inhibiting MEX3 A could be a viable approach for treating ovarian cancer that expresses wild-type p53 [49]. In addition, it was discovered by scientists that the use of SPIO-Serum can trigger ferroptosis in ovarian cancer cells, demonstrating the potential of nanomaterials as a treatment for this disease through ferroptosis induction [50]. A new investigation has uncovered that MAP 30, a protein extracted from bitter melon seeds, has dual capabilities of fighting against ovarian cancer and overcoming resistance to chemotherapy [51]. Despite notable advancements in the detection of OC in recent times, there exists a considerable deficiency in accurately diagnosing and predicting the outcome for those suffering from this disease. In a research endeavor, a prognostic grading system for ovarian cancer was constructed by conducting a thorough examination of biological factors, including five elements associated with ferroptosis—ALOX12, CD44, ACACA, SLC7 A11, and FTH1 [52]. In addition, Li and colleagues conducted a thorough examination of the relationship between immune system infiltration and the occurrence of ferroptosis. After that, they developed a ground-breaking E-FRG scoring system consisting of 15 FRGs. This can serve as a highly efficient method for predicting the chances of survival for individuals who have been diagnosed with ovarian cancer [53]. Studies have shown that lncRNAs can to control the behavior of both healthy and cancerous cells [54]. Several pieces of research have suggested that lncRNAs have the potential to exert regulatory influences on cancer by means of inducing ferroptosis [55]. Research has uncovered the influential role of lncRNAs in triggering ferroptosis and regulating related signaling pathways. These molecules have a pivotal role in governing cancer mechanisms that involve ferroptosis [56, 57]. Zheng et al. discovered and verified a cluster of nine lncRNAs associated with FRLs that possess prognostic significance, a finding that has not been previously documented in OC [58]. The risk assessment system, which was developed and verified using nine different functional response levels, has been confirmed as a standalone predictor. It is expected to be a useful resource for predicting the future condition of OC patients.

Fig. 1

Processes of ferroptosis in ovarian cancer are complex and involve multiple pathways. One significant pathway is the systemic Xc⁻–GSH–GPX4 pathway, which functions to safeguard cells against ferroptotic cell death. Moreover, Nrf2 influences this pathway by increasing the levels of CBS, which in turn reinforces the effects of the systemic Xc⁻–GSH–GPX4 pathway. In addition, the heightened expression of FZD7 can activate P63, a cancer-causing agent, which in turn stimulates the production of GPX4 and ultimately inhibits ferroptosis. TAZ has a significant impact on the regulation of ferroptosis by managing ANGPTL4 levels, which in turn influences the function of NOX2. In addition, YAP promotes ferroptosis by controlling SKP2. Furthermore, researchers have discovered that the administration of sodium molybdate can enhance the presence of LIP, thereby augmenting the mechanism of ferroptosis in OC

Ferroptosis-inducing therapies represent a novel and promising avenue for enhancing the efficacy of current ovarian cancer (OC) treatments, particularly in overcoming resistance to platinum-based chemotherapy and PARP inhibitors. Preclinical studies have demonstrated synergistic effects when ferroptosis inducers are combined with standard OC therapies. For instance, the use of erastin or RSL3—well-known ferroptosis inducers—has been found to sensitize OC cells to cisplatin by depleting glutathione and inactivating GPX4, thereby enhancing oxidative stress and promoting cell death in platinum-resistant models [59,60,61]. Furthermore, recent studies suggest that PARP inhibition can indirectly promote ferroptosis by impairing DNA repair and redox homeostasis, creating a metabolic vulnerability that can be exploited by ferroptosis inducers [62, 63].

Non-coding RNAs and ovarian cancer

The rise of advanced genome sequencing and array technology has enabled the recording of about 90% of the human genome [64]. Although the human genome contains around 3 billion base pairs, only about 2% of it is used to produce proteins—roughly 20,000 in total. The remaining majority of the genome (98%) is transcribed into non-coding RNAs (ncRNAs), which do not code for proteins but play essential regulatory and structural roles within the cell [65]. These include circRNAs, miRNAs, lncRNAs, and other types of RNAs [64, 66]. A lncRNA is formed by over 200 nucleotides and is modified with a cap and poly(A) tail [67]. MiRNA, which is a short RNA made up of 17–22 building blocks, acts as a controller in controlling the activity of genes in different parts of the body [68,69,70]. CircRNA varies in length from a few hundred to several thousand nucleotides, in many different species. [71, 72]. Furthermore, ncRNAs typically exhibit a distinct pattern of expression specific to a particular cell type, tissue, or stage of development [73,74,75,76,77,78].

In recent years, studies have emphasized the considerable influence of ncRNAs on various cellular pathways implicated in the progression of OC. These pathways encompass a diverse array of tasks, including cell growth, apoptosis, movement, resistance to drugs, angiogenesis, and alterations in metabolic activities [79,80,81,82]. Studying ncRNAs as predictive indicators could potentially advance the field of precision medicine for OC patients. Gaining more knowledge on the role of ncRNAs in controlling OC resistance and metastasis to chemotherapy offers potential for innovative treatments that could enhance the outlook for patients. Furthermore, OC encompasses a wide range of histological subtypes with two main categories: EOC, which accounts for 90% of cases, and non-epithelial OC, which makes up the remaining 10% [83]. The most prevalent type of EOC is the high-grade serous OC, making up around 52% of cases. Other types include ovarian clear cell carcinoma (6%), endometrioid ovarian cancer (10%), low-grade serous ovarian cancer (5%), and mucinous ovarian cancer (6%) [83, 84]. In OC that is not associated with epithelial tissue, the occurrence of germ cell tumors and sex cord stromal tumors is limited to a mere 3% and 2% of all cases, respectively [84]. Presently, research on ncRNAs primarily focuses on EOC. A thorough analysis of miRNA expression patterns can enhance the classification of EOC subtypes, presenting potential for detecting clinically relevant markers that can enhance stratification and diagnosis of OC [85]. According to news research, ncRNAs displayed discrepancies in their levels of expression between various subtypes of OC. A notable instance of this was miR-483-5p, which demonstrated contrasting levels of expression in non-serous and serous EOC, with a notable elevation in serous EOC [85]. It is showed that HGSOC exhibits an increased expression of exosomal miR- 1290 compared to other types of ovarian cancer, highlighting the diverse expression profiles of miRNAs amongst distinct subtypes of OC. This suggests that targeting specific miRNAs could potentially lead to personalized treatments and better diagnosis for individual patients [86]. Further analyses are required for future inquiries to fully understand the subject matter.

The figure titled "Regulatory Mechanisms Linking OvCa and Immune Cell Function via ncRNAs" provides a comprehensive explanation of how ncRNAs impact the functioning of immune cells in relation to OvCa. These findings highlight the significance of ongoing research in detecting ncRNA-mediated immune alterations in the OvCa tumor microenvironment. Such investigations may offer valuable insights, diagnostic approaches, and potential treatment targets for OvCa (Fig. 2).

Fig. 2

Behavior and existence of immune cells within the TME of ovarian cancer is impacted by both noncoding RNAs and exosomes that contain miRNAs. These specific noncoding RNAs and exosomes are responsible for controlling the activities of different immune cells, including APCs, CAFs, CD3-expressing T cells, CD8-expressing T cells, CD4-expressing T cells, MDSCs, NK cells, and TAMs

Ferroptosis and microRNAs in ovarian cancer

The process of miRNA biogenesis commences by either the transcription of miRNA genes through RNA polymerase II or III, occurring either prior to or concurrently with transcription [87] (Fig. 3). About half of the total number of recognized miRNAs originate from gene sequences, with the majority coming from introns but some also originating from exons. The other miRNAs are created from non-gene areas of the genome and transcribed separately [88]. The transcription of certain miRNAs results in clusters, which in turn form families of genes with similar seed sequence and genomic position [89]. The MicroRNA-induced silencing complex (miRISC) is a complex composed of AGO proteins and miRNA guide. They bind to specific regions on the target mRNA, called MREs, to effectively silence the targeted mRNA [90, 91]. The level of resemblance between miRNA and MRE is the deciding factor for whether there will be AGO2-mediated mRNA cleavage or if the miRISC complex will hinder translation and eventually cause the mRNA to break down. Moreover, in cases where the miRNA and MRE are an exact match, this not only triggers mRNA cleavage and activates the AGO2 endonuclease, but it also leads to self-degradation of the miRNA due to the formation of an RNA duplex [90, 92]. After the miRNA binds to the target mRNA inside the RISC complex, it can reduce gene expression in two different ways. One method involves stopping the translation process through repression, preventing the ribosomes from turning the target mRNA into useful proteins. Another approach is to enhance the removal of the poly(A) tail and initiate the decapping of the target mRNA, causing it to break down and preventing the formation of proteins [93]. The vast majority of interactions between miRNAs and their target sites in animal cells do not involve a perfect match. This is because there are often mismatches in the central region, which can hinder the effectiveness of AGO2, the main protein responsible for carrying out the functions of miRNAs [94]. AGO2 is not a singular entity, but rather a key player in the intricate process of RNA interference, similar to its counterparts AGO 1, 3, and 4 found in humans. The miRNA's "seed" sequence located at its 5′end (composed of nucleotides 2–8) often engages in interactions with the target sequences (known as MREs). By enhancing the base pairing at the 3′end, the strength and longevity of this interaction can be improved, resulting in a more precise and enduring bond [95, 96].

Fig. 3

Diagram illustrates the various stages of the miRNA biogenesis pathway, including both the usual and alternative routes. Beginning with the transcription of primary miRNAs by RNA polymerase II/III, the process involves the involvement of the Drosha–DGCR8 complex and Dicer. Ultimately, mature miRNAs are produced and are responsible for controlling gene expression through the action of the miRISC

One miRNA has the capability to target several regions due to the restriction of pairing only to the"seed sequence". This ability allows miRNAs to effectively control multiple gene networks, making them influential regulators of essential cellular functions, such as growth, specialization, cell death, and even ferroptosis (Table 1) [97].

Table 1 Summary of important ncRNAs in regulation of ferroptosis in ovarian cancer

In previous statements, it has been established that GPX4 controls ferroptosis and can be specifically influenced by miRNAs in the context of cancer, resulting in its degradation or inhibition of translation. In addition, certain miRNAs have been found to specifically target and impact the ferroptosis pathway, as shown in Fig. 4. [98]. Zhuang et al. studied the effects of miR-375-3p on cardiac fibrosis using both an I/R rat model and a cell model induced by angiotensin II. Their findings indicate that this miRNA facilitates the progression of cardiac fibrosis by suppressing the activity of 15-LOX-1 enzyme and promoting ferroptosis [99]. In the absence of GPX4, lipid peroxidation progresses unimpeded through self-propagating chain reactions. The peroxidation of polyunsaturated fatty acids (PUFAs) is particularly critical in this process and is regulated primarily by lipoxygenases (LOXs) and GPX4 during ferroptosis [100]. Without GPX4 to terminate these chain reactions by reducing lipid hydroperoxides to lipid alcohols, peroxidation spreads rapidly throughout cellular membranes [100].

Fig. 4

Visual depiction of miRNAs that affect the process of ferroptosis either by promoting or inhibiting it. This figure presents the main miRNAs that regulate ferroptosis by targeting crucial elements of its pathways, such as enzymes involved in lipid metabolism, antioxidant systems, and regulators of iron metabolism. These miRNAs have an impact on cellular susceptibility to ferroptosis, ultimately affecting cell survival and the progression of various tumors

Lipoxygenases, especially 12/15-LOX, play a core role in lipid peroxidation by directly catalyzing the oxidation of PUFAs. The activity of these enzymes becomes particularly damaging in the context of GPX4 deficiency, as there is no counterbalancing mechanism to neutralize the resulting lipid peroxides. In addition, phosphatidylethanolamine binding protein 1 (PEBP1) can form complexes with 15-LOX to further promote ferroptosis in the absence of GPX4 protection [100].

The system Xc⁻/GSH/GPX4 axis represents an integrated antioxidant system, where each component depends on the others. While miRNAs can directly target GPX4, the consequences extend beyond just GPX4 inactivation. As lipid peroxidation accelerates due to GPX4 deficiency, GSH is rapidly consumed in futile attempts to neutralize ROS through other glutathione-dependent mechanisms. This depletion of GSH further compromises the remaining GPX4 activity, as GSH is an essential cofactor for GPX4 function [101, 102]. The result is a downward spiral of antioxidant capacity, where GSH depletion leads to further GPX4 inactivation, which in turn accelerates lipid peroxidation and more GSH consumption.

In their study, Fan et al. showed that the blockage of miR- 15a- 5p leads to a decrease in ferroptosis by regulating GPX4. As a result, this reduces the intensity of myocardial damage in instances of acute myocardial infarction [103]. The suppression of miR-1224 has been shown to mitigate damage to the heart caused by hypoxia/reoxygenation, through the increase of GPX4 [104]. GPX4 involves in the occurrence of ferroptosis. Altering the expression of certain miRNAs, such as miR- 375-3p, miR-1224, and miR-15a-5p, has the potential to safeguard cardiomyocytes and reduce heart damage by elevating GPX4 levels and decreasing ferroptosis. Furthermore, the proper functioning of the antioxidant system relies on the existence of SLC7 A11, which is a crucial part of the Xc⁻ transporter [105].

Liu et al. conducted a study, where they used the exosome inhibitor GW4869 to suppress the release of cardiac fibroblast-derived exon-miR-23a-3p. This inhibition led to an increase in SLC7 A11 expression and ultimately decreased ferroptosis in H9c2 cardiomyocytes. Their findings suggest that inhibiting miR-23a-3p could potentially prevent the progression of atrial flutter [106]. The statement posits that suppressing miR-23a-3p leads to a rise in levels of cystine and GSH within cells, effectively counteracting ROS and providing a potential treatment for atrial fibrillation. This is due to the fact that GLS2, an enzyme responsible for producing glutamate, can trigger an excess of ROS within mitochondria. within the cell, effectively preventing the harmful effects of ROS in treating atrial fibrillation. This effect is achieved through the activity of GLS2, which accelerates the production of glutamate and promotes ROS build-up in the mitochondria [107]. Myocardial infarction often results in cardiomyocyte death and pathological changes that can ultimately lead to heart failure [108]. Zhou et al., proved that miR-190a-5p inhibits GLS2 and controls the quantities of reactive oxygen species, malondialdehyde, and ferric ions in H9c2 cells, effectively hindering ferroptosis in cardiomyocytes and offering a safeguard against myocardial infarction [109]. MiR-190a-5p reduces lipid peroxidation by suppressing the expression of GLS2 mRNA, ultimately protecting against ferroptosis and decreased susceptibility to myocardial infarction. ATG5, a protein involved in autophagy, has also been proposed to hinder ferroptosis by inhibiting autophagy and promoting lipid breakdown [110]. Tang et al. revealed that elevated levels of miR-30 d lead to increased ferroptosis following a heart attack, as it targets and suppresses ATG5 [111]. Consequently, there could potentially be an interaction between ferroptosis and autophagy. This is particularly important due to the prevalence of cardiovascular disease globally. Finding ways to reduce the death of cardiomyocytes and repair damaged cardiac tissue is an urgent matter in clinical practice [112]. Ferroptosis greatly reduces the beneficial effects of ischemia/reperfusion (I/R) injury on the heart, but inhibiting it results in a reduced level of inflammation and limits the extent of left ventricular remodeling following I/R injury [113]. The most common types of heart conditions seen in medical settings include myocardial infarction, atherosclerosis, arrhythmia, and heart failure. The development of these diseases heavily relies on the process of ferroptosis [114]. miRNAs contribute to the process of ferroptosis by controlling the antioxidant system and lipid oxidation. The current body of research suggests that an increase in miRNA levels can lead to ferroptosis-related damage in cardiomyocytes. However, due to the multifaceted nature of miRNAs, there is a need for further investigation to uncover additional information and insights.

The inhibition of ferroptosis in ovarian cancer is accomplished by specifically targeting the ACSL4 gene with the use of miR-424 - 5p. An upregulation of ACSL4 or a decrease in miR-424 - 5p expression results in the enhancement of lipid peroxidation and subsequent ferroptosis as miR-424 - 5p directly binds to the 3'-UTR of ACSL4 and further suppressed the expression of this gene. In contrast, with the overexpression of ACSL4 or a decrease in miR-424 - 5p, there is a reversal of the reduction in lipid peroxidation and ferroptosis [115, 116]. Lidocaine effectively prohibits the upregulation of SLC7 A11 by miR-382 - 5p. The application of this anesthetic drug induces an increase in miR-382 - 5p levels, causing a hindrance in SLC7 A11 expression. These results highlight the potential of Lidocaine in targeting breast and ovarian cancer cells by exploiting this process [117].

Ferroptosis and long non-coding RNAs in ovarian cancer

LncRNAs, make up another subgroup of ncRNAs and regulate gene expression. They do this by binding to DNA, mRNA, proteins, or miRNA transcripts and impacting transcription, translation, and post-translational processes [118, 119]. In the past, lncRNAs were characterized by their lack of ability to code for proteins. Nevertheless, through modern computational methods, it has been discovered that lncRNA sequences may contain ORFs which could indicate their potential to code for proteins [120]. Moreover, studies have demonstrated a significant connection between specific lncRNAs and the formation and spread of cancer cells and ribosomes, indicating the potential for these lncRNAs to contain coding sequences for small peptides [121].

Recent research has demonstrated that approximately 40% of lncRNAs and pseudogene RNAs in human cells are translated, as evidenced by ribosome profiling analyses. This was further supported by mass spectrometry data, which showed the presence of small peptides encoded by lncRNAs [122, 123]. For example, the lncRNA HOXB–AS3 (HOXB cluster antisense RNA 3) can produce a 53-amino acid peptide which inhibits the growth of colon cancer cells [124]. Ren et al., found that CTBP1–DT lncRNA induced ovarian cancer cell cisplatin resistance via encoding DDUP protein. DDUP maintained RAD18/RAD51 C and RAD18/PCNA complexes at the sites of DNA damage which led to the dual RAD51 C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms and further development of cisplatin resistance in this cancer [125].

Significantly, lncRNAs that have been translated into proteins tend to be found predominantly in the cytoplasm, while lncRNAs that have not been translated remain largely in the nucleus [122]. The translation capability of lncRNAs found in the cytoplasm is comparable to that of mRNAs, indicating that they are actively involved in ribosomal activities. Nevertheless, the effectiveness of the peptides derived from lncRNAs is still uncertain as they may just be undesirable byproducts that are prone to instability [123]. Assessing the coding potential of lncRNAs poses significant difficulties as their structures closely resemble those of mRNAs. Furthermore, analyzing lncRNAs is a complicated task as their coding regions can be located within introns or overlap with gene exons, adding to the complexity. Although few lncRNA-derived products have been extensively researched, there is a vast range of possible peptides originating from lncRNAs that remain to be investigated [126]. The vital ferroptosis process in cancer cells is solely controlled by lncRNAs, (Fig. 5). An instance of this is the direct regulation of CBS, a potential ferroptosis-manipulating target, by LINC00336. By promoting CBS, LINC00336 facilitates the production of cysteine through trans-sulfuration, thereby inhibiting ferroptosis in lung cancer cells. In addition, LINC00336 amplifies the suppressive effect of the CBS pathway on ferroptosis through its interaction with miR-6852 (Table 1) [127, 128].

Fig. 5

Research has provided a deeper understanding of the significant role played by non-coding RNAs, particularly lncRNAs and circRNAs, in ferroptosis, a form of cell death distinguished by the buildup of lipid peroxidation due to iron. In the context of cancer cells, these particular RNA molecules play a crucial role in controlling ferroptosis processes. This highlights their potential as significant targets for the advancement of groundbreaking treatment methods. An example of this is the lncRNA called LINC00336, which can increase cysteine levels through the CBS pathway, thereby promoting ferroptosis resistance in lung cancer cells. In addition, it downregulates the expression of miRNAs that encourage ferroptosis, such as MIR6852. Based on recent research, another lncRNA called LINC00472 or p53RRA has been discovered to stimulate the activity of the TP53 gene, resulting in heightened levels of ferroptosis in cells affected by lung cancer. These findings demonstrate the immense influence of lncRNAs and circRNAs in the pathways of ferroptosis, implying their potential as valuable targets for the development of novel cancer treatments. PVT1 works together with MIR214 to target TP53 and cause ferroptosis. It does so by reducing the levels of cysteine, which is achieved by suppressing SLC7 A11. Furthermore, LINC00618 involves in sensitizing leukemic cells to ferroptosis. This is achieved by enhancing the levels of ROS and iron accumulation while simultaneously suppressing the expression of SLC7 A11. In the case of ZFAS1, it acts as a competing endogenous RNA (ceRNA) by competing with miR-150 - 5p, thereby reducing the expression of SLC38 A1. This, in turn, regulates glutamine uptake and lipid metabolism, ultimately promoting ferroptosis. LINC01833/RP11–89 also participates in inhibiting ferroptosis in bladder cancer by acting as a ceRNA and soaking up MIR129 - 5p. This leads to the increased expression of PROM2, which facilitates the export of iron through ferritin-containing exosomes. In the case of glioma, CircTTBK2 functions as a circular RNA and governs ferroptosis by acting as a sponge for various miRNAs, most notably MIR761, which targets MFN2. Through its interaction with MIR761, CircTTBK2 boosts the expression of ITGB8, ultimately obstructing the process of ferroptosis in glioma cells. Similarly, Circ_0008367 induces ferroptosis in a manner that relies on autophagy by disrupting ALKBH5's function of promoting autophagy. In contrast, circ_0008035 suppresses ferroptosis in gastric cancer by directly targeting MIR599 and disrupting the regulatory axis of MIR599–EIF4 A1. In addition, CircIL4R and circEPSTI1 can also regulate ferroptosis by influencing the MIR541–3p-GPX4 and MIR375–MIR409–3p-MIR515–5p-SLC7 A11 pathways, respectively. Finally, circSNX12 interacts with MIR224–5p to target FTH1, which regulates iron homeostasis and ferroptosis susceptibility

The lncRNA TPT1–AS1 has been found that promote the growth of tumors in various types of cancer, including OC. However, its impact on ferroptosis and its interactions with other proteins have not been extensively studied [129]. In their study, Cao et al. utilized a comprehensive approach to investigate the functional significance of TPT1–AS1 in OC. They employed a variety of methods such as RT–qPCR, in situ hybridization, and FISH to analyze the expression of TPT1–AS1 in OC tissues and cell lines. In addition, the researchers examined the effects of TPT1–AS1 depletion on OC cell behavior, including proliferation, migration, invasiveness, and cell cycle progression. Using bioinformatics, they also identified and validated the interactions between TPT1–AS1 and other proteins. Furthermore, the researchers investigated the role of TPT1–AS1 in erastin-induced ferroptosis using techniques, such as Iron Assay, MDA assay, and ROS detection. Their results indicated that elevated levels of TPT1–AS1 in OC were associated with a poorer prognosis. Depletion of TPT1–AS1 inhibited cell proliferation, migration, and invasiveness. The team also demonstrated that TPT1–AS1 suppresses erastin-induced ferroptosis, which was further supported by their in vivo experiments showing its oncogenic impact on tumor growth. Moreover, they identified the underlying mechanisms by which TPT1–AS1 regulates the transcription of GPX4 through CREB1 and interacts with RNA-binding protein KHDRBS3 to control CREB1. Overall, this research emphasizes the significance of long non-coding RNAs, RNA-binding proteins, and transcription factors in a complex system of control that plays a crucial role in the advancement of cancer [129].

The findings of the research demonstrated a pronounced connection between the levels of ferroptosis-related genes and the outlook for patients diagnosed with OC [130]. A total of eight lncRNAs, namely, RP5–1028 K7.2, RP11–443B7.3, AC073283.4, TRAM2–AS1, RP11–95H3.1, RP11–486G15.2, AC006129.1, and RP11–958 F21.1, were identified through the use of single-factor Cox and LASSO analysis from a group of selected genes related to ferroptosis. These identified lncRNAs were then utilized to create a risk scoring model, which showed promising accuracy in predicting the prognosis of patients with ovarian cancer. Noticeable variations were observed in the clinical attributes, tumor mutation burden, and infiltration of immune cells among the high-risk and low-risk categories identified by the generated tumor scores. The finding showcases the effectiveness of the risk score in predicting the outcome of immunotherapy and providing valuable information for personalized immunotherapy in individuals with OC. Although additional in-person experiments and investigations are necessary, our analysis shows strong support for the accuracy of the risk signature, which consists of ferroptosis-related lncRNAs, in forecasting the prognosis of OC cases. The findings suggest that the eight lncRNAs that were discovered hold great potential for being utilized in diagnosis and treatment methods for OC. In addition, those with elevated levels of these lncRNAs may see more positive outcomes from traditional chemotherapy or ferroptosis-inducing treatments [130].The research performed by Peng et al. aimed to evaluate the prognostic significance of lncRNAs associated with ferroptosis in ovarian cancer patients, and create a predictive model using these lncRNAs [131]. The RNA sequencing data of ovarian cancer patients and genes related to cell death by iron accumulation were obtained from the Cancer Genome Atlas and FerrDb databases. The information was subsequently partitioned into two separate groups, one for purposes of training and the other for testing, randomly to conduct the analysis. Using Pearson correlation analysis, potential lncRNAs related to cell death by iron accumulation were identified. A predictive model was then developed using the training set, utilizing various methods, such as LASSO, univariate Cox, and multivariate regression analyses. The accuracy of the model was confirmed on both the testing and entire sets, and further assessment was conducted through survival analysis, ROC curves, independent prognostic factor analysis, and correlations with clinical features. Finally, a nomogram was created in the training group to anticipate the likelihood of survival in ovarian cancer patients after 1, 3, and 5 years. The data was then analyzed using principal component analysis to determine the distribution of distinct groups, and gene set enrichment analysis was utilized to identify the specific biological functions influencing the model. Eventually, a total of eleven lncRNAs associated with ferroptosis were pinpointed as pivotal elements in constructing the prognostic model. The subset of individuals classified as high-risk experienced notably inferior results in comparison with the low-risk subset across all training, testing, and full data sets. The efficacy of the risk assessment model can be assessed by the area under the ROC curve, which yielded scores of 0.731, 0.796, and 0.805 at the 1-, 3-, and 5-year survival marks in the training group. In the testing set, the values were 0.704, 0.597, and 0.655, while in the entire set, they were 0.715, 0.691, and 0.736, respectively. In addition, the risk score was found to have a correlation with the patient's age and grade. Furthermore, the danger level was recognized as a self-reliant predictive factor for ovarian cancer. A graph was generated and exhibited a noteworthy C-index value of 0.68. The main element analysis demonstrated distinct differentiation between those at high and low risk, and gene collection enrichment examination indicated a high frequency of cancer-linked pathways in the high-risk group. A prognostic model consisting of eleven lncRNAs linked to ferroptosis was proficient in estimating the long-term consequences for ovarian cancer patients [131].

The primary objective of the research was to create a unique identifier utilizing lncRNA to target ferroptosis, and examine the correlation between this identifier and the future outlook and clinical attributes of patients with ovarian cancer [132]. This study employed a predictive risk evaluation approach using a set of 18 lncRNAs linked to ferroptosis. The high-risk category, identified through the FerRLSig measurement, demonstrated a significantly lower rate of survival in comparison with the low-risk group (P < 0.001). The receiver operating characteristic curve was used to validate the accuracy of the model. In addition, a prognostic nomogram that integrated FerRLSig and clinical factors was created, showing impressive ability to predict prognosis and classify survival risk. An analysis of Gene Set Enrichment indicates that FerRLSig has a significant role in multiple immunomodulatory pathways associated with cancer. A risk model was established, revealing notable variances in immune status and utilization of chemotherapy, immunotherapy, and targeted therapy for the high-risk and low-risk groups. This research provides greater insight into the underlying molecular and signaling mechanisms of ferroptosis in OC, emphasizing the importance of the TME, and offers a predictive model for guiding the treatment of ovarian cancer patients [132].

In another study, Peng and colleagues investigated eleven ferroptosis-related lncRNAs and their correlation with ovarian cancer patient’s prognosis. They found that these lncRNAs could predict the prognosis of ovarian cancer patients accurately which indicated the possible role of these lncRNAs for using as biomarkers [131].

Ferroptosis and circular RNAs in ovarian cancer in ovarian cancer

Circular RNA molecules, recognized for their distinctive closed circular structure, are produced by back-splicing or lariat-driven mechanisms from pre-messenger RNA molecules [133, 134]. The closed-ring shape of circRNAs ensures their durability against degradation by exonucleases, allowing these non-coding RNA molecules to persist in a sustained fashion [135,136,137]. The robustness of their structure, combined with the presence of numerous binding sites for miRNAs and their significant role in controlling cellular functions, has made circRNAs a focal point in the realm of biological investigations and the study of cancer (Table 1) [138,139,140,141,142,143,144,145,146].

In this particular scenario, it is suggested that circRNAs regulate ferroptosis by acting as sponges for various miRNAs within tumor cells (Fig. 4). One circRNA in particular, known as circTTBK2 or tau tubulin kinase 2, has been linked to glioma growth as it is highly expressed in these cancer cells and is responsible for controlling their ability to multiply, move, and invade other tissues [147]. This circular RNA contributes to regulating cell metabolism by acting as a sponge for miR-1283, miR-520B, miR-217, and miR-761. Of these, miR-761 has the potential to impact the ferroptotic process in HCC through its interaction with MFN2 [148,149,150]. CircTTBK2 specifically targets ITGB8 to inhibit ferroptosis in glioma cells by acting as a sponge for MIR761 [151].

A significant challenge in the treatment of ovarian cancer is the resistance to cisplatin chemotherapy. Yet, recent findings indicate that by reducing the levels of circSnx12, there is a potential to enhance the occurrence of ferroptosis and enhance the efficacy of cisplatin therapy. It has also been noted that circSnx12 hinders ferroptosis in ovarian cancer progression by inhibiting SLC7 A11, through its binding with miR-194 - 5p. To conclude, the involvement of circSnx12 is vital in controlling the processes of ferroptosis and chemoresistance during the treatment of OC [152].

Ferroptosis and ncRNAs: the therapeutic strategies, limitations, and directions of improvement

A connection has been established between ferroptosis and various conditions, including organ fibrosis, neurodegeneration, and ischemia–reperfusion injuries [153,154,155]. Ferroptosis is well-known as a particularly potent mechanism for destroying cancer cells [156, 157]. Cancer cells that have undergone dedifferentiation and have the characteristics of mesenchymal cells are known to be unresponsive to conventional treatments and apoptosis. However, these cells are highly vulnerable to substances that induce ferroptosis, making it a promising approach to overcome treatment resistance.

Numerous methods are being investigated to utilize ferroptosis as a means of treating cancer. One approach involves targeting crucial ferroptosis enzymes found in cancer cells. Via the use of drugs and genetic techniques, scientists have been successful in inhibiting the cystine/glutamate antiporter known as xCT, which is achieved by blocking SLC7 A11and SLC3 A2. This has shown positive outcomes in preclinical models with minimal harmful effects [22, 158, 159]. Moreover, focusing on AIFM2/FSP1 as a therapeutic target shows promise as it is not essential for normal development, indicating a wide range of therapeutic potential [160, 161].

In addition to being a key focus for ferroptosis, GPX4 is essential for the overall health of important organs, such as kidneys and neurons [42, 162, 163]. It is evident that to avoid potential adverse effects, GPX4 inhibitors, including RSL3, must be precisely targeted towards cancer cells. However, indirect ferroptosis-inducing compounds such as erastin may face challenges due to their poor solubility and quick metabolic degradation [164]. A method being investigated to tackle this problem involves enveloping ferroptosis enhancers in safeguarding transportation manners, like nanoparticles.

Ongoing research is focused on utilizing nanoparticles to deliver iron, peroxides, and ncRNAs to target inhibitors of ferroptosis both in vivo and in vitro. NcRNAs have a natural presence in cells and may take advantage of existing metabolic processes. These molecules also have the ability to target multiple genes within interconnected pathways, resulting in a more comprehensive and precise response against cancer. An example of this is the miR-15–miR-16 cluster, which regulates several proteins involved in both cell death and cell cycle regulation [165]. In the future, ncRNA therapeutics are expected to offer a cost-effective alternative for production through chemical synthesis.

Though they have advantages, utilizing ferroptosis-based treatments involving ncRNA can have its disadvantages. One of these is that regulating cancer growth through ncRNA-mediated ferroptosis may not be effective in all cases. In addition, the variation in individual ncRNA levels and response to therapy can make predicting outcomes difficult. Achieving a harmonious combination of encouraging ferroptosis to combat tumors and preventing chemoresistance by manipulating ncRNAs warrants additional examination. Thus, a more comprehensive exploration is crucial to fully grasp the potential of utilizing ncRNAs implicated in ferroptosis for the management of cancer.

While ncRNA-based therapeutic strategies offer significant promise for the treatment of ovarian cancer, a major limitation in their clinical translation lies in the development of efficient and targeted delivery systems. Non-coding RNAs, such as miRNAs, siRNAs, and lncRNAs, are inherently unstable in the bloodstream and susceptible to rapid degradation by nucleases. Moreover, their negative charge and large molecular size hinder their cellular uptake [166, 167]. To address these challenges, various delivery mechanisms have been developed, with lipid-based nanoparticles (LNPs) being among the most extensively studied [168, 169]. LNPs can encapsulate ncRNAs, protecting them from enzymatic degradation and facilitating their uptake by tumor cells via endocytosis [169, 170]. These nanoparticles can also be functionalized with targeting ligands, such as folate or antibodies, to enhance their specificity for ovarian cancer cells, which often overexpress certain surface markers [170, 171].

In addition to LNPs, other delivery platforms are being explored, including polymeric nanoparticles, exosomes, and aptamer-conjugated systems [171,172,173]. Exosomes, in particular, show great potential due to their innate biocompatibility and ability to naturally transport RNA molecules between cells [174]. Furthermore, aptamer-guided delivery systems can selectively bind to cancer cell receptors, enabling precise delivery of therapeutic ncRNAs while minimizing off-target effects [175]. The optimization of these delivery strategies is critical for enhancing the therapeutic efficacy and safety profile of ncRNA-based treatments, ultimately paving the way for their integration into personalized medicine approaches for ovarian cancer.

Our understanding of ferroptosis is inadequate as there are several crucial inquiries that remain unresolved. One vital aspect that requires further investigation is the interplay between ferroptosis and other types of controlled cell death, notably TP53-mediated apoptosis. Despite some overlapping mechanisms, a thorough understanding of the precise link between these pathways is essential. Despite iron being deemed a crucial factor in ferroptosis, there could be other non-redox related functions for iron and other metals, like copper, that demand more scrutiny. Furthermore, our understanding of the molecular events that lead to ferroptosis activation is not yet complete, especially in regards to the downstream processes that occur after lipid peroxidation. It is crucial to gain a comprehensive understanding of these events, particularly at the point, where ferroptosis becomes irreversible.

Moreover, the challenge of precisely detecting ferroptosis in viable cells and unaltered tissues presents a major obstacle. NcRNAs, have not been extensively explored in relation to ferroptosis and its connection to cancer. Preliminary studies indicate that alterations in carefully orchestrated non-coding RNA networks frequently inhibit ferroptosis, resulting in increased survival and proliferation of cancer cells. However, further investigation is necessary to comprehensively comprehend this intricate correlation. Despite this, the ability to artificially trigger ferroptosis has immense promise in combatting cancer.

Conclusion

Ferroptosis is a recently identified form of tightly controlled cell death, characterized by lipid peroxidation mediated through iron and oxidative stress. It has emerged as a critical mechanism in various pathological conditions, especially in cancer. This review has examined the role of ferroptosis in female-specific cancers, particularly breast and gynecologic malignancies, and the regulatory influence of non-coding RNAs (ncRNAs) in modulating this process. By exploring the molecular pathways, potential biomarkers, and therapeutic avenues involving ferroptosis and ncRNAs, the analysis underscores the promise of targeting this pathway for more effective and personalized cancer treatment.

However, despite significant progress, several key questions remain unanswered. What are the most reliable and clinically actionable biomarkers for predicting ferroptosis sensitivity in female-specific cancers? How can ferroptosis inducers be optimally combined with existing treatments, such as PARP inhibitors or platinum-based chemotherapies, to overcome drug resistance without inducing toxicity? Furthermore, the intricate regulatory roles of ncRNAs in ferroptosis are only beginning to be understood—comprehensive functional studies and in vivo models are needed to clarify their mechanisms and therapeutic potential. Future research must also focus on developing safe and efficient delivery systems for ferroptosis-targeting agents, as well as understanding tumor heterogeneity and the tumor microenvironment’s influence on ferroptosis susceptibility. Addressing these questions will be critical for translating ferroptosis-based strategies from bench to bedside in the context of female-specific cancers.