Iron is an essential nutrient, as it is necessary for the maintenance of cellular metabolism and all several important physiological activities, such as oxygen transport, DNA synthesis and ATP production (20). As iron is ubiquitously present, cellular iron homeostasis is a complex and tightly regulated process though the acquisition, utilization, storage and recycling of iron (5). The cellular iron balance is maintained through the redox cycle and iron intake (Fig. 1). The cellular iron redox cycle is primarily dependent on the Fenton reaction (21). In the cellular Fenton reaction, ferrous iron (Fe²⁺) is oxidized to ferric iron (Fe³⁺) during the conversion of H₂O₂ into reactive hydroxyl radicals; conversely, Fe³⁺ is then reduced back to Fe²⁺ through superoxide radicals (22). In of iron intake, transferrin receptor 1 (TfR1) is expressed on the surface of the majority of cells, where it primarily takes up transferrin (TF)-bound iron into cells. The TfR1/TF-(Fe³⁺)₂ complex is endocytosed (23), and Fe³⁺ is released from TF (24), reduced to Fe²⁺ by ferric reductase six-transmembrane epithelial antigen of the prostate 3 (STEAP3), and then transported across the endosomal membrane by divalent metal transporter 1 (DMT1) (25).

The imported cellular iron enters the transient cytosolic labile iron pool, a pool of chelatable and redox-active iron (26), which is utilized by cells for various metabolic processes or stored in ferritin (27). Excess cellular iron is exported out of the cell and transported into circulation by ferroportin 1 (FPN-1), after which it is oxidized by the ferroxidase-ceruloplasmin and binds to serum TF (28). Furthermore, cellular iron balance is also regulated by a network of iron-dependent proteins: The iron-responsive elements (IREs) and iron-regulatory proteins (IRPs). IRPs are cytosolic proteins that regulate the expression of genes involved in iron import (TfR1, DMT1), storage [ferritin (FTH), FTH1 and FTL] and export (FPN-1) by binding IREs (29).

Iron metabolism is an indispensable component of ferroptosis that distinguishes it from other types of RCD. Iron can gain and lose electrons, rendering it capable of contributing to free radical formation. When cellular iron is overloaded, the free radicals accumulate aberrantly, causing increased production of ROS. This effect leads to oxidative stress, which results in ferroptotic cell death (30). However, dysregulation of iron metabolism also serves an active role in carcinogenesis and promotes tumor growth (5,31).

TfR1 is a major regulator of intracellular iron uptake, and researchers found that abnormal accumulation of TfR1 on the cell surface is a specific marker of ferroptosis (32). In hepatocellular carcinoma, TfR1 and FTH1 are upregulated in erastin and sorafenib induced ferroptotic cell death (33), and TfR1 is also upregulated in erastin-induced cell death in myeloid leukemia cell lines (34). Furthermore, in Calu-1 lung cancer cells and HT-1080 fibrosarcoma cells, IRE-binding protein 2 (IREB2) is an essential gene for erastin-induced ferroptosis by regulating TFRC, FTH1 and FTL (1). Furthermore, several studies have suggested that inhibition of DMT1 may prevent iron translocation, leading to lysosomal iron overload, ROS production and ferroptotic cell death in cancer stem cells (35), and sulfasalazine induced ferroptosis is reduced by the inhibitory effect of estrogen receptor on TFRC and DMT1 in breast cancer cells (36). Artemisinin compounds sensitize cancer cells to ferroptosis by regulating IRP/IRE-controlled iron homeostasis (37). Therefore, targeting iron metabolic pathways may offer novel therapeutic options for cancer therapy.

Fatty acid (FA) metabolism provides specific lipid precursors for energy storage, membrane biosynthesis, generation of signaling molecules and lipid oxidation that result in an accumulation of an abundance of lipid ROS (38). Although ferroptosis is induced by multiple stimuli, the accumulation of abundant lipid ROS in cells is the most critical factor causing ferroptotic cell death. In addition to iron-generated ROS production via the Fenton reaction, ROS from lipid oxidation appears to serve a role in ferroptosis (Fig. 1). Therefore, lipid peroxidation is crucial for induction of ferroptosis.

In the process of lipid metabolism, arachidonic acid (AA), a fatty acid substrate, is activated by acyl-CoA synthetase long-chain family member 4 (ACSL4) to produce AA-CoA, and then AA-CoA is esterified by lysophosphatidylcholine acyltransferase 3 (LPCAT3) to phosphatidyl-(PE)-AA (39). PE-AA is oxidized to cytotoxic PE-AA-OOH by lipoxygenases (LOXs) that are activated during catalysis of Fe²⁺ (40). Under physiological conditions, glutathione peroxidase 4 (GPX4) reduces cytotoxic PE-AA-OOH to non-cytotoxic PE-AA-OH, which protects cells from oxidative damage. When GPX4 is inactivated or depleted, PE-AA-OOH accumulates in the cell, and this induces ferroptosis (40). Thus, lipid peroxidation accounts for a large proportion of ferroptosis initiation.

ACSL4 is a key enzyme involved in the synthesis of long chain unsaturated fatty acids. ACSL4 was found to sensitize RSL3-induced ferroptosis through altering the cellular lipid composition (8). In hepatocellular carcinoma patients who had complete or partial responses to sorafenib-induced ferroptosis, and had higher ACSL4 expression in the pretreated tumor tissues than those who did not respond, ACSL4 was a predictive biomarker for sensitivity of sorafenib in hepatocellular carcinoma (41). Consistently, ACSL4 suppresses the proliferation of tumor cells through activation of ferroptosis in glioma cells (42). Furthermore, a CRISPR-based genetic screen identified ACSL4 and LPCAT3 as promoting of RSL3- and DPI7-induced ferroptosis, but they did not affect erastin-induced ferroptosis (39). Several studies have supported the conclusion that PUFAs can be oxidized, producing the lipid peroxides that promote the induction of ferroptosis (43). Therefore, targeting the lipid metabolism pathway may also be a novel means of tumor therapy.

GSH, a thiol-containing tripeptide, is a potent antioxidant whose synthesis is limited by the constant import of cysteine and the availability of cystine/cysteine. The system Xc⁻ antiporter is a cystine/glutamate transporter that takes up extracellular cystine in exchange for intracellular glutamate (44). SLC7A11, expressed at the cell surface, is a regulatory light chain component of the system Xc⁻ transporter and is essential for cystine cellular uptake and serves a role in intracellular GSH synthesis (19). Once imported into cells, intracellular cystine is reduced to cysteine, a precursor of GSH used in GSH biosynthesis. GPX4, a central mediator of ferroptosis, which has phospholipid peroxidase activity, catalyzes the reduction of lipid peroxides to lipid alcohols using GSH as an essential co-factor, thus preventing cells from undergoing too much lipid peroxidation (45). Blockade of a member of the system Xc⁻ antiporter, SLC7A11, and inhibition of GPX4 were shown to induce ferroptosis (1). Both interventions impaired cellular antioxidant defenses, thereby facilitating toxic ROS accumulation, suggesting antioxidant pathways as potential regulators of ferroptosis.

Erastin, a RAS-selective lethal compound, triggers ferroptosis by directly inhibiting system Xc⁻ activity to reduce GSH levels in cancer cells (1,2). Similarly, sulfasalazine, a drug used to treat chronic inflammation, also triggers ferroptosis through directly inhibiting SLC7A11 activity (46). Similar to the above two compounds, p53, a well-characterized tumor suppressor, was also shown to sensitize cells to ferroptosis through the repression of SLC7A11 (47,48). Furthermore, the tumor suppressor BRCA1-associated protein 1 suppresses SLC7A11 transcription by decreasing H2Aub, leading to elevated lipid peroxidation and thus, increased ferroptosis (49). kelch-like ECH-associated protein 1 (Keap1) can also suppress the expression of SLC7A11 through degrading the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which is a master transcription factor of the antioxidant response (50). Another molecular mechanism of ferroptosis is the direct suppression of GPX4 by promoting its degradation or the loss of its activity. GPX4 was identified as a target protein of the classical ferroptosis inducer RSL3 (51), which directly binds to GPX4 to inactivate the peroxidase activity of GPX4 and induce ferroptosis (52). Several ferroptosis inducers directly inhibit GPX4 function including DPI7, DPI10, DPI12, DPI13, DPI17, DPI18, DPI19 and ML162 (52,53), and several ferroptosis inducers have an indirect effect on GPX4 function, including SRS13–45 (46), SRS13-60 (46), buthionine (54), sulfoximine (52), DPI2 (52), lanperisone (55), sorafenib (56) and erastin derivatives (52). Taken together, these studies show that the SLC7A11-GSH-GPX4 axis primarily mediates the initiation of ferroptosis, and that GPX4 serves a central role in regulating ferroptosis.

A set of miRNAs that post-transcriptionally regulate gene expression by RNA silencing have been demonstrated to be involved in the regulation of iron and ROS metabolism. The levels of these miRNAs are directly or indirectly correlated with ferroptosis.

As shown in Table II, miRNAs can participate in the ferroptotic process. In A375 and G-361 melanoma cell lines, miR-9 directly suppresses glutamic-oxaloacetic transaminase 1 (GOT1) by binding to its 3′-UTR, which subsequently inhibited erastin- and RSL3-induced ferroptosis (57). In A549 and SPC-A-1 lung cancer cell lines, miR-6852 regulates the expression of cystathionine-β-synthase (CBS), a surrogate marker of ferroptosis, by competing for LINC00336, which increases the intracellular concentrations of iron, lipid ROS and mitochondrial superoxide and decreases the mitochondrial membrane potential (58). Another study showed that miR-137 suppressed erastin- and RSL3-induced ferroptosis through directly targeting the glutamine transporter SLC1A5 in melanoma (58). In the STKM2, MKN45 and OE33 gastric cancer cell lines, miR-4715-3p inhibited AURKA expression by directly targeting its 3′-UTR, leading to downregulation of expression of GPX4. Therefore, depletion of miR-4715-3p promoted ferroptotic cell death by inhibiting GPX4 (60). In MGC-803, MKN-45 and other gastric cancer cell lines, miR-103a-3p directly suppressed glutaminase 2 expression, promoting physcion 8-O-β-glucopyranoside-induced ferroptosis by increasing intracellular Fe²⁺ and ROS levels (61). miR-7-5p expression was shown to be upregulated in clinically relevant radioresistant (CRR) cells, and increased miR-7-5p levels could decrease mitoferrin levels and thus reduce Fe²⁺, causing CRR cells to suppress ferroptosis (62). miR-K12-11 was found to suppress BACH-1 to induce SLC7A11 expression, leading to Kaposi's sarcoma-associated herpesvirus dissemination and persistence in an environment of oxidative stress via inhibition of ferroptosis (63). In endothelial cells, miR-17-92 directly suppressed the expression of ACSL4 by directly targeting A20, protecting endothelial cells from erastin-induced ferroptosis (64). In HepG2 and Hep3B cells, erastin enhanced the activation of transcription factor 4 (ATF4), whereas overexpression of miR-214-3p could sensitized cells to erastin-induced ferroptosis by directly suppressing the expression of ATF4 (65). miR-761 expression is downregulated in glioma, whereas overexpression of miR-761 confers resistance to erastin-induced ferroptosis by directly repressing integrin subunit β8 expression in LN229 and U251 cells (66).

lncRNAs are a class of non-coding RNAs >200 nucleotides in length that function to regulate gene expression by epigenetic, transcriptional and translational modulation. lncRNAs have been implicated in various biological processes. Recent studies have shown dysregulation of several lncRNAs is also involved in the ferroptotic process (Table II).

lncRNA P53RRA is downregulated in lung cancer and acts as a tumor suppressor. In the cytoplasm, P53RRA interacts with G3BP1 to activate the p53 signaling pathway, which in-turn promotes erastin-induced ferroptosis by increasing lipid ROS and altering the iron concentration (67). lncRNA LINC00336 is upregulated in lung cancer and functions as an oncogene. LINC00336 competes with miR-6852 for CBS, inhibiting ferroptosis by decreasing iron concentrations, ROS and mitochondrial superoxide levels, as well as the mitochondrial membrane potential (58). lncRNA GABPB1-AS1 is an antisense lncRNA of GABPB1 that downregulates GABPB1 levels by blocking GABPB1 translation, leading to peroxiredoxin-5 peroxidase suppression and increased lipid ROS concentrations, ultimately promoting erastin-induced ferroptosis (68).

CircRNAs are class of non-coding RNA characterized by a covalently closed loop structure leaving no free ends and have been demonstrated to be involved in tumorigenesis. CircTTBK2 is upregulated in glioma and functions as a master regulator of CPEB4 by sponging miR-217. Knockdown of circTTBK2 promoted erastin-induced ferroptosis accompanied with an increase in the intracellular concentrations of ROS, iron and ferrous iron by competing with miR-217 for CBS in glioma cells (66).

Iron metabolism (Table III), lipid metabolism (Table IV) and antioxidant metabolism (Table V) are basic functions in the ferroptotic process, and they serve a vital role in ferroptosis. The primary modulators of iron, lipid and antioxidant metabolism-related genes are also involved in regulating the process of ferroptosis and act as ferroptotic markers. Therefore, these metabolism-related ncRNAs may also be involved in regulating the process of ferroptosis.

Previous studies have demonstrated that cellular iron overload causes ferroptosis. TfR1 is a critical transporter involved in iron uptake and a specific ferroptosis marker, which imports Tf-iron from the extracellular environment into cells, contributing to the cellular iron pool required for ferroptosis (32). miR-320 (69), miR-107 (70), miR-148a (71), miR-7-5p/miR-141-3p (72), miR-152 (73) and miR-210 (74) are all involved in suppression of TfR1 by directly targeting TfR1. Therefore, it has been reasonably shown that these miRNAs can suppress ferroptosis by targeting TfR1.

FTH1, a major intracellular iron storage protein, is an iron regulators involved in iron storage. Expression levels of FTH1 are regulated by oncogenic RAS signaling, which controls the cellular iron pool and ferroptosis sensitivity in tumor cells (51). FTH1 is regulated by NRF2 in ferroptosis, knockdown of FTH1 enhances erastin or sorafenib-induced ferroptosis sensitivity in hepatocellular carcinoma, suggesting that reduced iron storage may contribute to cellular iron overload causing ferroptosis and that FTH1 may serve as a specific marker of ferroptosis marker as well (54). miR-200b is involved in the repression of FTH1 by directly targeting FTH1, which transforms H₂O₂ and O₂ into the reactive •OH radical, thus inducing tumor cell death (75). Oncogenic miR-638 and miR-362 have been identified as targets of FTH1 transcript or multiple FTH1 pseudogenes by an unbiased screen in prostate cancer (76). lncRNA H19 is the pre-miRNA template of miR-675, and knockdown of FTH1 upregulates H19 expression and thus its cognate miR-675, and H19/miR-675 activation primarily contributes to altered iron metabolism induced by FTH1 silencing (77). Therefore, it has been reasonably confirmed that these miRNAs may suppress ferroptosis by targeting TfR1. Together, these studies have shown that these ncRNAs may be involved in regulating the process of ferroptosis through iron storage.

IREB2 is an intra-cellular iron metabolism RNA-binding protein which regulates the translation and the stability of iron homeostasis related genes. Knock down of IREB2 suppresses erastin-induced ferroptosis by amino acid/cystine deprivation (1). miR-29 regulates IREB2 directly, thus affecting both energy production and redox status of the cell (78). Furthermore, miR-29a-related genetic variants alter the expression of IREB2 and may modify the risk of lung cancer together with dietary iron intake (79). Oncogenic miR-935 is elevated in renal cell carcinoma, and miR-935 directly suppresses the transcription of IREB2 by binding to the 3′-UTRs of IREB2 (80). Therefore, these miRNAs may suppress ferroptosis by targeting IREB2.

DMT1 is a widely expressed key iron transporter located within the plasma membrane and membranes of lysosomes and endosomes, which enables the uptake of Fe²⁺ to the cytosol following iron endocytosis. DMT1 inhibitors were selected as a target in cancer stem cells by blocking lysosomal iron translocation, which leads to lysosomal iron accumulation, and thus production of ROS and induction of ferroptotic cell death (35). DMT1 is also involved in sulfasalazine-induced ferroptosis via activation of iron metabolism in breast cancer cells (36). miR-Let-7d binds to the 3′-UTR of DMT1-IRE decreasing its expression at both the mRNA and protein levels in K562 and HEL cells (81). miR-16 family members miR-16, miR-195, miR-497 and miR-15b have been shown to suppress intestinal DMT1 expression by targeting DMT1 3′-UTR in HCT116 cells (82). These miRNAs may be involved in ferroptosis by targeting DMT1.

ACSL is expressed on the mitochondrial outer membrane and endoplasmic reticulum, where they catalyze fatty acids to form acyl-CoAs, which are lipid metabolic intermediates that facilitate fatty acid metabolism and membrane modifications (83). According to genome-wide recessive genetic screening, ACSL4 has been identified as an essential pro-ferroptotic gene and as a critical determinant of ferroptosis sensitivity by shaping cellular lipid composition (8). Another study also showed that ACSL4 is a biomarker and contributor of ferroptosis via ACSL4-mediated production of 5-hydroxyeicosatetraenoic acid (5-HETE) (84). miR-34a-5p/miR-204-5p (85), miR-141 (86), miR-3595 (87), miR-34a/c (88,89), miR-548p (90), miR-205 (91), miR-224-5p (92) and miR-19b-3p/miR-17-5p/miR-130a-3p/miR-150-5p/miR-7a-5p/miR-144-3p/miR-16-5p (93) can suppress the transcription of ACSL4. These miRNAs may inhibit ferroptosis by targeting ACSL4. In addition, a recent study reported that lncRNA NEAT1 promotes the transcription of ACSL4 by competing with miR-34a-5p and miR-204-5p, which may suppress ferroptosis (85).

LOXs are a family of iron-containing enzymes, including six LOX genes in humans; LOX5, LOX12, LOX12B, LOX15, LOX15B and LOXE3 (94). These genes can catalyze dioxygenation of PUFAs to produce fatty acid hydroperoxides in a stereospecific manner (94). Oxidation of PUFAs by LOXs had been implicated in erastin-induced ferroptosis (94). LOX15-driven enzymatic generation of lipid peroxidation is a hallmark of ferroptotic signals (95). In the miR-17 family, miR-18a and miR-203 bind to four sites of the 3′-UTR in 15-LOX1, and miR-17, miR-20a, miR-20b, miR-106a, miR-106b, miR-93 and miR-590-3p bind to four sites of the 3′-UTR of 15-LOX2 (96). Oncogenic miR-219-2 (97) directly targets the 3′-UTR of 15-LOX, whereas miR-674-5p (98), miR-216a-3p (99) and miR-19a-3p/miR-125b-5p (100) regulate 5-LOX through directly targeting the 3′-UTR of 5-LOX.

GPX4, unlike other members of the GPX family, serve a unique role in physiology; they catalyze the reduction of lipid peroxides in a complex cellular membrane environment. Overexpression or knockdown of GPX4 modulates the lethality of ferroptosis inducers, indicating that GPX4 is an essential regulator of ferroptotic cell death (52). miR-181a-5p decreases the expression of GPX4 by targeting SBP2 or SECISBP2 and reduces the ability to counter oxidation, which may promote ferroptosis (101,102).

Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting step catalytic enzyme in mono-unsaturated fatty acid (MUFA) synthesis that serves a central role in FA metabolism by converting the saturated fatty acids palmitate and stearate to the MUFAs palmitoleate (PMA) and oleate. SCD1, as an inhibitor of ferroptosis, serves an important role in the negative regulation of ferroptosis through the products of MUFAs (103). miR-27a (104), miR-212-5p (105), miR-103 (106), miR-192* (107), miR-378 (108), miR-4668 (109), miR-600 (110) and let-7c (111) significantly suppress the relative expression of SCD1 by directly binding to its 3′-UTR. Moreover, lncRNA uc.372 promotes the transcription of SCD1 by competing with miR-4668 (109).

Citrate synthases (CSs) are implicated in the regulation of mitochondrial fatty acid metabolism, which supply a specific lipid precursor necessary for ferroptotic cell death (1). Silencing CS suppresses erastin-induced ferroptosis (1). miR-122 suppresses the expression of mRNAs and proteins related to CS (112), whereas miR-19 only regulates the expression of proteins related to CS (113). Therefore, these ncRNAs have been implicated in promoting ferroptosis by targeting lipid metabolism-related genes.

Nrf2 is a pivotal inhibitor of ferroptosis due to its ability to inhibit cellular iron uptake, limit ROS production, and upregulate SLC7A11 expression by regulating the Nrf2-targeted genes FTH1, HO-1 and NQO1. Certain miRNAs can directly or indirectly suppress the transcription of Nrf2 or Nrf2 signaling to promote ferroptosis. For example, miR-675 (114), miR-181 (115), miR-302b-3p (116), miR-141 (117,118), miR-1225 (119), miR-25 (120), miR-128-3p (121), miR-19b (122), miR-125b (123) and miR-494 (124) restrain Nrf2 signaling by targeting Nrf2-related genes. In contrast, miR-365 (125), miR-495 (126), miR-136 (127), miR-34a (128), miR-340-5p (129), miR-125b (130), miR-101-3p (131,132), miR-155 (133), miR-380-3p (134), miR-144 (135–137), miR-153 (138), miR-28/miR-708 (139), miR-129-3p (140), miR-27b (141), miR-140-5p (142), miR-93 (143) and miR-365-1/miR-193b/miR-29-b1 (144) have been shown to decrease Nrf2 levels through directly binding to the 3′-UTR of Nrf2. Additionally, certain miRNAs activate Nrf2 signaling via a variety of mechanisms, ultimately resulting in inhibition of ferroptosis. For example, miR-152-3p (145), miR-101 (146), miR-455 (147), miR-601 (148), miR-7 (149), miR-200a (150), miR-873-5p (151), miR-24-3p (152), miR-34b (153), miR-223 (154), miR-146b-5p (155) and miR-98-5p (156) activate Nrf2 signaling by targeting Nrf2-related genes. It is thus hypothesized that these miRNAs can regulate ferroptosis by targeting Nrf2, but this has not yet been demonstrated.

Emerging evidence has indicated that lncRNAs Blnc1 (157), MALAT1 (158–162), Nrf2-lncRNA (163), AK094457 (164), Linc01213 (165), lncRNA74.1 (166), ODRUL (167), SNHG14 (168), UCA1 (126), LUCAT1 (169), TUG1 (170–172), Loc344887 (173), H19 (174), Mhrt (175), MIAT (176), MRAK052686 (177), AATBC (178), HOTAIR (179), NRAL (129), H19 (114), Sox2OT (180), MT1DP (125), MEG3 (127,128,181) and KRAL (117) may activate Nrf2 signaling by targeting Nrf2-related genes. Furthermore, circRNA-4099 may activate Nrf2 signaling by targeting miR-706, which augments H₂O₂-induced cell damage in the L0₂ cells (182). Notably, these ncRNAs are involved in regulating ferroptosis and may be a potential target for cancer therapy.

SLC7A11, the subunit of cystine-glutamate antiporter, is a crucial mediator in the process of ferroptosis. Studies have shown that miR-27a (183), miR-375 (184) and miR-26b (185) directly suppress the transcription of SLC7A11 by binding to its 3′-UTR. Therefore, these miRNAs have been implicated in promoting ferroptosis by directly targeting SLC7A11. Furthermore, lncRNAs SLC7A11-AS1 (186) and AS-SLC7A11 (187), the antisense lncRNAs of SLC7A11, suppress the transcription of SLC7A11. Therefore, these two SLC7A11-antisense lncRNAs have been hypothesized to suppress ferroptosis by downregulating SLC7A11 levels.

Keap1 is a member of the BTB-kelch protein family, which are primarily located in the perinuclear region of the cytoplasm (188). Keap1 represses Nrf2 transcriptional activity, a transcriptional target of Keap1. Overexpression of Keap1 enhanced erastin- and RSL3-induced ferroptosis, while knockdown conferred resistance to ferroptosis (189). Studies have shown that overexpression of miR-7 (149), miR-873-5p (151), miR-24-3p (152), miR-34b (153), miR-223 (154), miR-26b (190), miR-941 (191), miR-200a (192,193), miRNA-421 (194), miR-626 (195), miR-1225 (119), miR-141 (118) and miR-432 (196) suppressed Keap1 3′-UTR expression and downregulated its mRNA and protein expression. Notably, lncRNA MALAT1 could epigenetically downregulate Keap1 expression (161). lncRNA KRAL functions as a ceRNA by effectively binding to miR-141 and then restoring Keap1 expression (117). These studies suggest that Keap1 related-ncRNAs are involved in the process of ferroptosis.

GOT1 is essential for cell sustaining proliferation and maintenance of redox homeostasis. Reduced GOT1 suppresses erastin-induced ferroptosis by amino acid/cystine deprivation (197). According to previous studies, both in pancreatic cancer and melanoma, miR-9-5p inhibited the expression of GOT1 by directly binding to its 3′-UTR, ultimately resulting in decreased proliferation, glutamine metabolism and redox homeostasis, which suppresses the process of ferroptosis (57,198).

Collectively, the modulators of ferroptotic markers are their related ncRNAs, which serve critical roles in the regulation of ferroptosis. As discussed above, ncRNAs possess tumor suppressor or oncogenic roles in the process of ferroptosis during the course of tumorigenesis and progression. Thus, targeting ncRNAs may be a viable strategy in the development of novel cancer treatments.