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. 2020 Jul 24;11(7):580. doi: 10.1038/s41419-020-02772-8

Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression

Xuefei Zhang 1, Lingling Wang 1, Haixia Li 1, Lei Zhang 1,✉,#, Xiulan Zheng 1,✉,#, Wen Cheng 1,✉,#
PMCID: PMC7381619  PMID: 32709863

Abstract

Cancer progression including proliferation, metastasis, and chemoresistance has become a serious hindrance to cancer therapy. This phenomenon mainly derives from the innate insensitive or acquired resistance of cancer cells to apoptosis. Ferroptosis is a newly discovered mechanism of programmed cell death characterized by peroxidation of the lipid membrane induced by reactive oxygen species. Ferroptosis has been confirmed to eliminate cancer cells in an apoptosis-independent manner, however, the specific regulatory mechanism of ferroptosis is still unknown. The use of ferroptosis for overcoming cancer progression is limited. Noncoding RNAs have been found to play an important roles in cancer. They regulate gene expression to affect biological processes of cancer cells such as proliferation, cell cycle, and cell death. Thus far, the functions of ncRNAs in ferroptosis of cancer cells have been examined, and the specific mechanisms by which noncoding RNAs regulate ferroptosis have been partially discovered. However, there is no summary of ferroptosis associated noncoding RNAs and their functions in different cancer types. In this review, we discuss the roles of ferroptosis-associated noncoding RNAs in detail. Moreover, future work regarding the interaction between noncoding RNAs and ferroptosis is proposed, the possible obstacles are predicted and associated solutions are put forward. This review will deepen our understanding of the relationship between noncoding RNAs and ferroptosis, and provide new insights in targeting noncoding RNAs in ferroptosis associated therapeutic strategies.

Subject terms: Cancer prevention, Cancer therapy

Facts

  • Resistance to apoptosis has become the main obstacle for overcoming cancer progression.

  • Ferroptosis is a type of cell death characterized by excess reactive oxygen species and intracellular iron, and is totally different from apoptosis.

  • NcRNAs serve as important roles in biological processes of cancer.

  • Regulation of ncRNAs to ferroptosis has been partially discovered.

Open Questions

  • Can ferroptosis become the direction around which to design cancer therapy in future?

  • What are the roles of ncRNAs in regulation of ferroptosis?

  • Can ncRNAs become markers to filter cancer patients who are fit for ferroptosis therapy or therapeutic targets of ferroptosis inducers?

Introduction

Cancer progression including proliferation, metastasis and chemoresistance to drugs, has become serious obstacles in cancer therapy1. Although multiple therapeutic manners including operation, targeted therapy, chemotherapy, and radiotherapy have shown satisfactory performance, progression occurs since cancer cells dysregulate apoptosis pathways via various manners2,3. Therefore, new types of cancer therapy or drugs that eliminate cancer cells are urgently needed.

Ferroptosis is a type of programmed cell death discovered in 20124. Unlike apoptosis, ferroptosis is characterized by excess reactive oxygen species (ROS) and intracellular iron5. Superabundant ROS induces peroxidation and disintegration of lipid membrane and cell death6. Regulation of ferroptosis mainly depends on neutral reaction between reduced glutathione (GSH) and ROS7. The exchange of glutamate and cystine is mediated by systemXc−, which is composed of solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2), and offers the substrate cystine for GSH synthesis8,9. Glutathione peroxidase 4 (GPX4) catelyzes interaction between GSH and ROS to reduce intracellular oxidative stress10. Ferroptosis inducers can be divided into two classes based on regulation of neutral reaction to ROS. Class I ferroptosis inducers such as sorafenib, erastin and sulfasalazine, serve as blockers of systemXc− and result in a drop of GSH levels11,12. Class II ferroptosis inducers such as RSL3, FIN56, and ML162, inhibit function of GPX413,14. Numerous studies have confirmed that ferroptosis inducers such as RSL3 and sorafenib eliminates cancer cells15,16. In addition, induction of ferroptosis via erastin and sulfasalazine improved effect of cytarabine and doxorubicin, and overcame cisplatin resistance of head and neck cancer17,18. This suggests that ferroptosis may become a new mechanism around which to design cancer therapy. However, use of ferroptosis in cancer therapy still faces obstacles. First, the specific mechanisms underlying ferroptosis and the interaction between ferroptosis and other processes, such as apoptosis, necrosis, and autophagy are not totally known, so how to control ferroptosis in cancer is in dark. Second, ferroptosis occurs in normal cells. Ferroptosis has been shown to induce the elimination of nerve cells in Parkinson’s disease19. In addition, in acute kidney injury, ferroptosis participated in the death of renal tubular epithelial cells20. Therefore, use of ferroptosis inducers may generate complications. New regulatory factors should be recognized to understand the true appearance of ferroptosis in cancer.

Noncoding RNAs (ncRNAs) are RNAs that account for nearly 98% of transcriptome21. According to length and shapes, ncRNAs are divided into various types including microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), transfer RNAs (tRNAs), and ribosomal RNAs (rRNAs)22,23. NcRNAs participate in regulation of tumorigenesis via various biological processes such as chromatin modification, alternative splicing, competition with endogenous RNAs and interaction with proteins24,25. For example, miR-675-5p promoted the metastasis of colorectal cancer cells via modulation of P5326. Moreover, lncRNA HOTAIR served as an enhancer in epithelial-to-mesenchymal transition of breast cancer cells via competing with BRCA127. In addition, circFOXO3 enhanced progression of prostate cancer through sponging miR-29a-3p28. However, roles of ncRNAs in ferroptosis have not been fully determined.

In this review, we focus on summarizing the ncRNAs which have been found to associate with ferroptosis regulators GSH, iron, nuclear factor (erythroid-derived 2)-like 2 (NRF2) and ROS in cancer5. Moreover, we predict the obstacles that may limit the exploration of ncRNAs in ferroptosis in cancer therapy and offer advice for future studies. We believe that a comprehensive understanding of the interactions between ncRNAs and ferroptosis may benefit clinical therapeutics to cancer

MiRNAs and ferroptosis

MiRNAs exhibit functions by binding to the 3′-untranslated regions of target mRNAs and suppressing their expression29. Some studies have revealed a relationship between miRNAs and ferroptosis. In radioresistant cells, miR-7-5p inhibited ferroptosis via downregulating mitoferrin and thus reducing iron levels30. Furthermore, miR-9 and miR-137 enhanced ferroptosis via reduction of intracellular GSH levels, miR-9 inhibited synthesis of GSH and miR-137 suppressed solute carrier family 1 member 5 (SLC1A5), a component of systemXc−31. Moreover, miR-6852 which was regulated by lncRNA Linc00336, inhibited growth of lung cancer cells via promoting ferroptosis32. In the following sections, we will discuss the interactions between miRNAs and GSH, iron and NRF2 in cancer cells. The information of altered miRNAs in ferroptosis has been listed (Supplementary Table 1).

MiRNAs and GSH

GSH is a scavengerof ROS and protects lipid membrane33. Under physiological conditions, concentration of reduced GSH is about 10–100-fold more prevalent than the oxidized form. Under oxidative stress, reduced GSH is converted to oxidized form34. Biosynthesis of GSH involves three steps: exchange of glutamic acid and cystine induced by systemXc−; synthesis of 𝛾-glutamylcysteine by glutamic acid and cysteine catalyzed via 𝛾-glutamylcysteine ligase (GCL); and synthesis of GSH via 𝛾-glutamylcysteine and glycine catalyzed by GSH synthetase35. Function of GSH includes detoxification of exogenous or endogenous dangerous compounds catalyzed by GSH-S-transferases (GSTs) and GPXs36. Current knowledge on relation between GSH and cancer are summarized in Table 1, and the schematic diagram of these interactions is shown in Fig. 1a. MiR-18a and miR-218 decreased GSH levels via targeting GCL in hepatocellular carcinoma and bladder cancer37,38. Furthermore, in hepatocellular carcinoma and lung cancer, miR-152 and miR-155 decreased GSH levels via targeting GST39,40. In addition, miR-326 and miR-27a inhibited GSH levels in cancer cells via targeting other factors such as pyruvate kinase m 2 (PKM2), SLC7A11 and zinc finger and BTB domain containing 10 (ZBTB10)41–43. Additionally, downregulation of GSH by miRNAs such as miR-21, miR-24-2, miR-497 and miR‑503 has been observed in different cancer types, however, the specific mechanisms were not explored44–47. These findings indicate that miRNAs repress GSH levels via control of synthesis and consumption. The upregulation of GSH induced by miRNAs has been well-explored. GST was targeted by different miRNAs including miR-124, let-7a-5p, miR-92b-3p, miR-129-5P, miR-144, miR-153-1/2, miR-302c-5p, miR-3664-5p, miR-3714, miR-513a-3p, miR-590-3p/5p, miR-130b, miR-186, and miR-133a/b. These miRNAs bound to the 3′-untranslated regions of GST mRNA and inhibited GST expression, thus blocking GSH consumption and resulting in accumulation of intracellular GSH48–51. It is worth mentioning that miR-133a/b served as effective suppressors of GST in different cancer types, such as bladder cancer, lung cancer, prostate cancer, colorectal cancer, ovarian cancer and head and neck carcinoma. Inhibition of miR-133a/b reversed both increased GSH and insensitivity to drugs51–54. Furthermore, GPX family members are targeted by miRNAs and results in defect of ROS neutralization. In one report, GPX4 was decreased by miR-181a-5p in osteoarthritis55. However, the relationship between GPX4 and miRNAs in cancer is still in dark. Only GPX2 and GPX3 have been found to be modulated by miRNAs such as miR-17, miR-17-3p, miR-196a, and miR-921 in colorectal cancer, prostate cancer, and lung cancer56–59. Overall, regulation of GSH by miRNAs occurs mainly through control of GST and GPX family members. Since GSH has been shown to participate in growth of tumors and chemoresistance to drugs which induce intracellular oxidative stress, miRNAs may regulate ferroptosis and control cancer progression via modulation of GSH.

Table 1.

Summary of GSH associated miRNAs in cancer.

Name Associated cancer type Target Influence to GSH Model of evidence Reference
miR-27a Bladder cancer, colorectal cancer SLC7A11, ZBTB10 Up/Down Cell culture, animal models 42,43
miR-143 Colorectal cancer GPX Up Animal models 199
miR-17 Prostate cancer GPX2 Up Cell culture, animal models 56
miR-17-3p Prostate cancer GPX2 Up Cell culture, animal models 57
miR-196a Lung cancer GPX3 Up Cell culture, animal models 58
miR-921 Lung cancer GPX3 Up Cell culture 59
miR-124 Colorectal cancer GST Up Cell culture, animal models 48
Let-7a-5p Prostate cancer GST Up Cell culture, animal models 49
miR-92b-3p Prostate cancer GST Up Cell culture, animal models 49
miR-129-5P Colorectal cancer cells GST Up Cell culture 50
miR-144 Prostate cancer GST Up Cell culture, animal models 51
miR-153-1/2 Prostate cancer GST Up Cell culture, animal models 51
miR-302c-5p Colorectal cancer GST Up Cell culture 50
miR-3664-5p Colorectal cancer GST Up Cell culture 50
miR-3714 Colorectal cancer GST Up Cell culture 50
miR-513a-3p Colorectal cancer, lung cancer GST Up Cell culture 200
miR-590-3p/5p Prostate cancer GST Up Cell culture, animal models 51
miR-133a/b Bladder cancer, lung cancer, prostate cancer, colorectal cancer, ovarian cancer, head and neck squamous cell carcinoma GST Up Cell culture, animal models 52,53,201
miR-130b Ovarian cancer GST Up Cell culture 202
miR-186 Ovarian cancer GST Up Cell culture 203
miR-34b Prostate cancer MYC Up Cell culture 204
miR-K12-11 Kaposi’s sarcoma xCT Up Cell culture 205
miR-18a Hepatocellular carcinoma GCL Down Cell culture, animal models 37
miR-218 Bladder cancer GCL Down Cell culture 38
miR-21 Lung cancer GSH Down Cell culture 44
miR-24-2 Colorectal cancer GSH Down Clinical samples 45
miR-497 Cervical cancer GSH Down Cell culture 46
miR-503 Hepatocellular carcinoma GSH Down Cell culture 47
miR-152 Hepatocellular carcinoma GST Down Cell culture 39
miR-155 Lung cancer GST Down Cell culture 40
miR-326 Glioma PKM2 Down Cell culture 41
miR-125b Chronic lymphocytic leukemias GSH Unknown Cell culture 206
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Fig. 1. Regulation of ncRNAs to ferroptosis.

Fig. 1

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a Regulation of ncRNAs to GSH metabolism; b Regulation of ncRNAs to iron metabolism; c Regulation of ncRNAs to KEAP1-NRF2 pathway.

MiRNAs and iron

Iron metabolism is another key factor in ferroptosis. Excessive iron increases ROS via Fenton reaction and ROS is neutralized by iron reversely60. Metabolism of iron mainly includes interaction between transferrin (TF) and its receptor (TFR), import of iron via divalent metal transporter 1 (DMT1), storage of iron as ferritin and iron-sulfur cluster (ISC), and export of iron via ferroportin (FPN)61,62. The specific realtion between miRNAs and iron is summarized in Table 2, and the schematic diagram of these interactions are shown in Fig. 1b. In colorectal cancer, targeting of DMT1 by miR-149 and miR-19a led to decreased iron import63. Furthermore, in colorectal cancer and hepatocellular cancer, TFR was targeted by miRNAs including miR-141, miR-145, miR-152, miR-182, miR-200a, miR-22, miR-31, miR-320, miR-758, and miR-19463–65. This inhibition led to disruption of interaction between TF and TFR and the following decreased iron import. Thereinto, miR-194 suppressed the expression of both TFR and FPN in colorectal cancer63. FPN was also targeted by miR-150, miR-17-5p, miR-20a, and miR-492 in hepatocellular carcinoma, multiple myeloma, lung cancer, and prostate cancer, respectively66–68. Furthermore, ferritin which is composed of ferritin heavy chain (FHC) and ferritin light chain (FLC), is controlled by miRNAs69. FHC could be targeted by miR-200b, miR-181a-5p, miR-19b-1-5p, miR-19b-3p, miR-210-3p, miR-362-5p, miR-616-3p, and miR-638 in prostate cancer, resulting in decreased intracellular iron65,70,71. FLC could be targeted by miR-133a in colorectal cancer and breast cancer, and knockdown of miR-133a restored the reduced iron levels inside cancer cells63,72. Among the miRNAs that regulate iron levels, miR-210 serves as an important member. In colorectal cancer cells, miR-210 was activated by hypoxia and then targeted ISCU to alter intracellular iron homeostasis73. Furthermore, transfection of miR-210 decreased the uptake of iron via TFR suppression74. On the contrary, miRNAs can be modulated by iron. MiR-107, miR-125b, and miR-30d were inhibited by iron in hepatocellular carcinoma and ovarian cancer75,76, and miR-146a, miR-150, miR-214-3p and miR-584 were increased by iron in ovarian cancer and neuroblastoma76,77. This phenomenon may derive from the induction of excess ROS by iron and the subsequent regulation of miRNAs transcription. Overall, different miRNAs regulate iron levels in various directions, and the imbalance of iron leads to run-away miRNA expression.

Table 2.

Summary of iron associated miRNAs in cancer.

Name Associated cancer type Target Influence to iron Model of evidence Reference
miR-150 Hepatocellular carcinoma FPN Up Cell culture 76
miR-17-5p Multiple myeloma FPN Up Cell culture, animal models 66
miR-20a Lung cancer FPN Up Cell culture 67
miR-492 Prostate cancer FPN Up Cell culture, animal models 68
miR-194 Colorectal cancer TFR1, FPN1 Up Clinical samples 63
miR-449a Glioma CDGSH iron sulfur domain 2 Down Cell culture, animal models 207
miR-149 Colorectal cancer DMT1 Down Clinical samples 63
miR-19a Colorectal cancer DMT1 Down Clinical samples 63
miR-181a-5p Prostate cancer FHC Down Cell culture, animal models 70
miR-19b-1-5p Prostate cancer FHC Down Cell culture, animal models 70
miR-19b-3p Prostate cancer FHC Down Cell culture, animal models 70
miR-210-3p Prostate cancer FHC Down Cell culture, animal models 70
miR-362-5p Prostate cancer FHC Down Cell culture, animal models 70
miR-616-3p Prostate cancer FHC Down Cell culture, animal models 70
miR-638 Prostate cancer FHC Down Cell culture, animal models 70
miR-200b Hepatocellular carcinoma, breast cancer Ferritin Down Cell culture 65,71
miR-133a Colorectal cancer, breast cancer FLC Down Cell culture 63,72
miR-29 Lung cancer Iron-responsive element binding protein 2 Down Clinical samples 208
miR-210 Renal cancer, head and neck paragangliomas, breast cancer, colorectal cancer, and oropharyngeal squamous cell carcinomas ISCU, TFR1 Down Cell culture, animal models 73,74,209–211
miR-126 Malignant mesothelioma Mitochondria-destabilizing stress signals Down Cell culture, animal models 212
miR-7-5p Ovarian cancer, colorectal cancer Mitoferrin Down Cell culture 30
miR-122 Hepatocellular cancer Nocturnin Down Cell culture, animal models 213
miR-34a Lung cancer P53 Down Cell culture, animal models 214
miR-141 Colorectal cancer TFR1 Down Clinical samples 63
miR-145 Colorectal cancer TFR1 Down Clinical samples 63
miR-152 Hepatocellular carcinoma TFR1 Down Cell culture, animal models 64
miR-182 Colorectal cancer TFR1 Down Clinical samples 63
miR-200a Hepatocellular carcinoma TFR1 Down Cell culture 65
miR-22 Hepatocellular cancer TFR1 Down Cell culture 65
miR-31 Colorectal cancer TFR1 Down Clinical samples 63
miR-320 Hepatocellular cancer TFR1 Down Cell culture 65
miR-758 Colorectal cancer TFR1 Down Clinical samples 63
miR-107 Hepatocellular carcinoma – Inhibited by iron Cell culture, animal models 75
miR-125b Ovarian cancer – Inhibited by iron Cell culture 76
miR-30d Hepatocellular carcinoma – Inhibited by iron Cell culture, animal models 75
miR-146a Ovarian cancer – Induced by iron Cell culture 76
miR-150 Ovarian cancer – Induced by iron Cell culture 76
miR-214-3p Neuroblastoma – Induced by iron Cell culture 77
miR-584 Neuroblastoma – Induced by iron Cell culture 77
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MiRNAs and NRF2

NRF2 serves as a transcriptional factor and activates downstream antioxidant factors. The expression of NRF2 mainly depends on Kelch-like ECh-Associated Protein 1 (KEAP1), which assembles Cullin3 to form the Cullin-E3 ligase complex and then degrades NRF2 protein via the ubiquitin-proteasome route78. Inhibition of NRF2 has been confirmed to enhance ferroptosis79. The specific information regarding interaction between miRNAs and NRF2 is listed in Table 3, and the schematic diagram is shown in Fig. 1c. In esophageal cancer, miR-129, miR-142, miR-144-3p, miR-450, miR-507, and miR-634 targeted the 3′-untranslated region of NRF2 mRNA and decreased NRF2 expression, resulting in an increase of ROS80–85. Among these miRNAs, miR-144-3p played an important role in the regulation of NRF2. Targeting NRF2 by miR-144-3p inhibited tumor progression in melanoma and acute myeloid leukemia86, and increased the sensitivity of lung cancer cells to cisplatin87, indicating the role of miR‑144‑3p in oxidative homeostasis. Other miRNAs that targeted NRF2 include miR-144, miR-153, miR-200c, and miR-212-3p, although their effects have not been explored82,88–90. Moreover, miRNAs regulate NRF2 via targeting KEAP1. In hepatocellular carcinoma, ovarian cancer, leukemia, and neuroblastoma cells, KEAP1 was targeted by miR-141, miR-23a, miR-432, miR-7, and miR-200a88,91–95. Thereinto, miR-200a served as an active role. In esophageal squamous cell carcinoma, methylseleninic acid activated KEAP1/NRF2 pathway via upregulating miR-200a, the latter inhibited KEAP1 expression and induced expression of NRF296. In breast cancer and pancreatic adenocarcinoma, miR-200a suppression reverted expression of KEAP1 and then inhibited NRF2 and promoted the anchorage-independent cell growth in vitro97. In turn, NRF2 enhances miRNAs expression via binding to the antioxidative response element box. In myelocytic leukemia, miR-125b driven by NRF2 promoted leukemic cells survival. Inhibition of miR-125b enhanced responsiveness of leukemic cells towards chemotherapy98. However, in oral squamous cell carcinoma, repression of miR-125b by peroxiredoxin like 2A (PRXL2A) protected cancer cells from drug-induced oxidative stress in an NRF2-depedent manner99, indicating the mutual regulation between miR-125b and NRF2. In addition, expression of miR-29B1, miR-129-3p, and miR-380-3p was induced by NRF2 in acute myelocytic leukemia, hepatocellular carcinoma, and neuroblastoma98,100,101. Conversely, miR-181c, miR-378, miR-122, miR-17-5p, miR-1, and miR-206 were repressed by NRF2 in various cancer types66,102–107. Thereinto, inhibition of miR-1 and miR-206 was mediated by SOD1 induced by NRF2 but not the role of NRF2 as a transcriptional factor. In summary, miRNAs regulate NRF2 pathway through targeting KEAP1 and NRF2 mRNAs. Conversely, NRF2 controls miRNAs via transcription or downstream factor SOD1.

Table 3.

Summary of NRF2 associated miRNAs in cancer.

Name Associated cancer type Target Influence to NRF2 Model of evidence Reference
miR-141 Hepatocellular carcinoma, ovarian cancer KEAP1 Up Cell culture 88,91–93
miR-23a Leukemic KEAP1 Up Cell culture, animal models 94
miR-432 Esophageal cancer KEAP1 Up Cell culture 92,95
miR-7 Neuroblastoma cells KEAP1 Up Cell culture 92
miR-200a Breast cancer, esophageal cancer, hepatocellular carcinoma, and pancreatic adenocarcinomas KEAP1, Up Cell culture, animal models 81,92,96,97,215,216
miR-155 Lung cancer NRF2 Up Cell culture 217
miR-101 Hepatocellular carcinoma, prostate cancer NRF2, SOD1 Up/Down Cell culture, animal models 88,105,218
miR-1 Lung cancer, prostate cancer NRF2, SOD1 Up/Inhibited by NRF2 Cell culture, animal models 105,107
miR-206 Lung cancer, prostate cancer NRF2, SOD1 Up/Inhibited by NRF2 Cell culture, animal models 105–107
miR-148b Endometrial cancer ERMP1 Down Cell culture 219
miR-129 Esophageal cancer NRF2 Down Cell culture, animal models 80
miR-129-5a Esophageal cancer NRF2 Down Cell culture, animal models 80,81
miR-129-5p Esophageal cancer NRF2 Down Cell culture, animal models 80
miR-142 Esophageal cancer NRF2 Down Cell culture 82
miR-144 Hepatocellular carcinoma, leukemia, hepatocellular carcinoma, neuroblastoma NRF2 Down Cell culture 88,89
miR-144-3p Melanoma, lung cancer, and acute myeloid leukemia NRF2 Down Cell culture 86,87,220,221
miR-153 Neuroblastoma, breast cancer, and oral squamous cell carcinoma NRF2 Down Cell culture 82,90
miR-200c Lung cancer NRF2 Down Cell culture, animal models 222
miR-212-3p Melanoma NRF2 Down Cell culture 86
miR-23b-3p Melanoma NRF2 Down Cell culture 86
miR-27 Neuroblastoma NRF2 Down Cell culture, animal models 223
miR-28 Breast cancer, esophageal cancer NRF2 Down Cell culture 81,224
miR-340 Hepatocellular carcinoma, esophageal cancer NRF2 Down Cell culture 85,88,92
miR-34a Breast cancer, colon cancer, ovarian cancer, and lung cancer NRF2 Down Cell culture 225,226
miR-450 Esophageal cancer NRF2 Down Cell culture 83
miR-450a Esophageal cancer NRF2 Down Cell culture, animal models 80,81
miR-495 Nonsmall-cell lung cancer NRF2 Down Cell culture 227
miR-507 Esophageal cancer NRF2 Down Cell culture, animal models 80,81,84
miR-634 Esophageal cancer NRF2 Down Cell culture, animal models 80,81,85
miR-93 Pancreatic adenocarcinomas, breast cancer NRF2 Down Cell culture, animal models 97,221
miR-93-5p Melanoma NRF2 Down Clinical samples 86
miR-125b Acute myelocytic leukemia, oral squamous cell carcinoma, and renal cancer NRF2 Down/Induced by NRF2 Cell culture, animal models 98,99,228
miR-181c Colorectal cancer – Inhibited by NRF2 Cell culture, animal models 102
miR-378 Mucoepidermoid carcinoma – Inhibited by NRF2 Cell culture, animal models 103
miR-122 Hepatocellular carcinoma – Inhibited by NRF2 Cell culture 104
miR-17-5p Multiple myeloma – Inhibited by NRF2 Cell culture, animal models 66
miR-29B1 Acute myelocytic leukemia – Induced by NRF2 Cell culture 98
miR-129-3p Hepatocellular carcinoma – Induced by NRF2 Cell culture, animal models 100
miR-380-3p Neuroblastoma – Induced by NRF2 Cell culture, animal models 101
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MiRNAs and ROS

In addition to factors above, miRNAs regulate ROS via other mechanisms. The information of miRNAs that are related to ROS in cancer is listed in Table 4. MiRNAs can positively regulate ROS levels. For example, miR-21 whose expression increased with tumor grade, has been identified to enhance ROS level in lung cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, and prostate cancer108–113. Mechanically, miR-21 targeted STAT3, proline oxidase (POX), and programmed cell death 4 (PDCD4) to induce oxidative stress114–116. Moreover, miR-146a has attracted much attention. In ovarian cancer, miR-146a repressed SOD2 expression and inhibited proliferation of cancer cells and enhanced chemosensitivity to drugs117. In lung cancer, suppression of miR-146a restored catalase and inhibited ROS induction, and protected cancer cells from cisplatin-induced cytotoxicity118. In addition, overexpression of miR-124, miR-526b, and miR-655 led to excess ROS via thioredoxin reductase 1 in breast cancer119,120. Furthermore, the antioxidant enzyme SOD1 was downregulated by stable expression of miR-143 or miR-145 in colorectal cancer121. This indicates that miRNAs enhance intracellular ROS via different manners. On the other hand, in lung cancer, miR-99 suppressed the invasion and migration of cancer cells via targeting NOX4-mediated ROS production122. Additionally, miR-520 and miR-373 reduced ROS via targeting NF-κB and TGF-β signaling pathways and repressed growth and lymph node metastasis of breast cancer123. Other miRNAs such as let-7, miR-137, miR-193b, miR‑199, and miR-26a, have been found to decrease ROS level in cancer cells via diverse targets such as heme oxygenase-1, C-MYC, and triglyceride124–128, indicating that miRNAs inhibit ROS level. Conversely, miR-133a, miR-150-3p, miR-1915-3p, miR-206, miR-34, miR-638, and miR-182 were activated by oxidative stress and then played a role in the subsequent biological processes129–133. Moreover, miR-125, miR-145-5p, miR-17-5p, miR-199, and miR-17-92, were decreased by excess intracellular ROS134–137. Among them, miR-125b plays a dual role in oxidative homeostasis. As discussed above, miR-125b serves as a regulator of NRF2. In addition, miR-125b could be inhibited by ROS via a DNMT1-dependent DNA methylation in ovarian cancer140. Moreover, although miR-21 has been discussed as the enhancer of ROS in breast cancer, DNA damage induced by ROS led to activation of miR-21 via NF-κB, indicating the interaction between miRNAs and ROS138. In total, we can infer that altered levels of GSH, iron, and NRF2 are not the only methods by which miRNAs regulate ROS and vice versa in, miRNAs and ROS can also regulate each other in various pathways.

Table 4.

Summary of ROS associated miRNAs in cancer.

Name Associated cancer type Target Influence to ROS Model of evidence Reference
miR-124 Non-small cell lung cancer TXNRD1 Up Cell culture 120
miR-125a Osteosarcoma Estrogen-related receptor alpha Up Cell culture 229
miR-128a Medulloblastoma BMI-1 Up Cell culture 230
miR-139-5p Breast cancer Unknown Up Cell culture, animal models 231
miR-143 Colorectal cancer SOD1 Up Cell culture 121
miR-146a Lung cancer, ovarian Cancer Catalase, SOD2 Up Cell culture, animal models 117,118
miR-146b-5p Leukemic Unknown Up Cell culture 232
miR-15 Colorectal cancer, cancer stem cells C-MYC Up Cell culture, animal models 233
miR-155 Glioma, pancreatic cancer MAPK13, MAPK14, and Foxo3a Up Cell culture, animal models 234,235
miR-15a-3p Lung cancer P53 Up Cell culture 236
miR-16 Colorectal cancer, cancer stem cells C-MYC Up Cell culture, animal models 233
miR-186 Colorectal cancer CKII Up Cell culture 237
miR-193a-3p Glioma γH2AX Up Cell culture 238
miR-210 Cancer stem cells, glioma P53 Up Cell culture, animal models 239
miR-212 Colorectal cancer MnSOD Up Clinical samples 240
miR-216b Colorectal cancer CKII Up Cell culture 237
miR-22 Hepatocellular carcinoma SIRT-1 Up Cell culture 241
miR-223 Breast cancer HAX-1 Up Cell culture 242
miR-23b-3p Acute myeloid leukemia PrxIII Up Cell culture 243
miR-25-5p Colorectal cancer SOX10 Up Cell culture 244
miR-26a-5p Acute myeloid leukemia PrxIII Up Cell culture 243
miR-26b Small cell lung cancer Myeloid cell leukemia 1 protein Up Cell culture, animal models 245
miR-30 Gastric cancer P53 Up Cell culture 246
miR-337-3p Colorectal cancer CKII Up Cell culture 237
miR-34c Nonsmall cell lung cancer HMGB1 Up Cell culture 247
miR-371-3p Lung cancer PRDX6 Up Cell culture, animal models 248
miR-422a Gastric cancer PDK2 Up Cell culture, animal models 249
miR-4485 Breast cancer Mitochondrial protein Up Cell culture, animal models 133
miR-4673 Lung cancer 8-Oxoguanine-DNA Glycosylase-1 Up Cell culture 250
miR-504 Lung cancer P53 Up Cell culture 251
miR-506 Lung cancer P53, NF-κB Up Cell culture, animal models 252
miR-509 Breast cancer P53 Up Cell culture 253
miR-526b Breast cancer Thioredoxin Reductase 1 Up Cell culture 119
miR-551b Lung cancer MUC1 Up Cell culture 254
miR-655 Breast cancer Thioredoxin Reductase 1 Up Cell culture 119
miR-661 Colorectal cancer Hexose-6-phosphate dehydrogenase, pyruvate kinase M2 Up Cell culture 255
miR-760 Colorectal cancer CKII Up Cell culture 237
miR-92 Hepatocellular carcinoma Unknown Up Clinical samples 256
miR-128 Glioma, hepatocellular carcinoma PKM2 Up/Down Cell culture 257
miR-145 Colorectal cancer, hepatocellular carcinoma SOD1, PKM2 Up/Down Cell culture 121,258
miR-211 Myeloma, oral carcinoma PRKAA1, TCF12 Up/Down Cell culture, animal models 259,260
miR-222 Hepatocellular carcinoma, breast cancer NF-κB, TGF-β Up/Down Cell culture, animal models 261,262
miR-23a/b Myeloma, renal cancer C-MYC, POX Up/Down Cell culture, animal models 263,264
miR-29 Ovarian cancer, lung cancer, and lymphoma C-MYC, SIRT1 Up/Down Cell culture, animal models 265,266
miR-34a Gastric cancer, glioma NOX2 Up/Down Cell culture 267
Let-7 Hepatocellular carcinoma, prostate cancer, and pancreatic cancer Heme oxygenase-1, P53 Up/Down Cell culture, animal models 123,268
miR-33a Glioma, hepatocellular carcinoma SIRT6 Up/Down Cell culture, animal models 269
miR-221 Hepatocellular carcinoma, breast cancer NF-κB, TGF-β, and DICER Up/Down/Induced by ROS Cell culture, animal models 261,262,270
miR-21 Lung cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, and prostate cancer SOD, MAPK, SOD2, Glucose, NFκB, STAT3, POX, and PDCD4 Up/Down/Induced by ROS Cell culture, animal models 108,112,114,271
miR-17-92 Gastric cancer, lung cancer C-MYC, P53, and NFκB Up/Down/Inhibited by ROS Cell culture 137,272,273
miR-181 Hepatocellular carcinoma, uterine leiomyoma Unknown Up/Induced by ROS Cell culture 132,274
miR-200 Breast cancer, cancer stem cells, hepatocellular carcinoma, and lung cancer P53, PRDX2, GAPB/NRF2, SESN1 Up/Induced by ROS Cell culture, animal models 222,275–277
miR-34 Cancer stem cells, bladder cancer, lung cancer C-MYC, P53 Up/Induced by ROS Cell culture 278,279
miR-182 Uterine leiomyoma, lung cancer PDK4 Up/Induced by ROS Cell culture, animal models 132,133
miR-199 Gastric cancer, ovarian cancer DNMT1 Up/Inhibited by ROS Cell culture 134
miR-20a Breast cancer, pancreatic cancer BECN1, ATG16L1, and SQSTM1 Up/Inhibited by ROS Cell culture, animal models 136,280
miR-125b Hepatocellular carcinoma, ovarian cancer, and breast cancer Hexokinase 2, DNMT1, and HAX-1 Up/Inhibited by ROS Cell culture, animal models 228,281
miR-1246 Breast cancer NF-κB, TGF-β Down Cell culture 124
miR-137 Ovarian cancer C-MYC Down Cell culture, animal models 125
miR-193b Liposarcoma Antioxidant methionine sulfoxide reductase A Down Cell culture, animal models 127
miR-199a-3p Testicular cancer Transcription factor specificity protein 1 Down Cell culture 126
miR-26a Hepatocellular carcinoma Triglyceride, totalcholesterol, malondialdehyde Down Cell culture 128
miR-30c-2-3p Breast cancer NF-κB, TGF-β Down Cell culture 282
miR-346 Ovarian cancer GSK3B Down Cell culture 283
miR-373 Breast cancer NF-κB, TGF-β Down Cell culture, animal models 123
miR-520 Breast cancer NF-κB, TGF-β Down Cell culture, animal models 123
miR-7 Nonsmall cell lung cancer MAFG Down Cell culture 284
miR-885-5p Hepatocellular carcinoma TIGAR Down Cell culture 285
miR-99a Lung cancer NOX4 Down Cell culture, animal models 122
miR-133a Rhabdomyosarcoma 9 Induced by ROS Cell culture, animal models 129
miR-150-3p Hepatocellular carcinoma – Induced by ROS Cell culture 130
miR-1915-3p Hepatocellular Carcinoma – Induced by ROS Cell culture 130
miR-206 Rhabdomyosarcoma – Induced by ROS Cell culture, animal models 131
miR-34a-3p Hepatocellular carcinoma – Induced by ROS Cell culture, animal models 129
miR-34a-5p Hepatocellular carcinoma – Induced by ROS Cell culture 130
miR-638 Hepatocellular carcinoma – Induced by ROS Cell culture 130
miR-125 Gastric cancer – Inhibited by ROS Cell culture 134
miR-145-5p Gastric cancer – Inhibited by ROS Cell culture, animal models 135
miR-17-5p Pancreatic cancer – Inhibited by ROS Cell culture, animal models 136
miR-27a Pancreatic cancer, colorectal cancer – Inhibited by ROS Cell culture, animal models 286
miR-328 Gastric cancer – Inhibited by ROS Cell culture, animal models 287
miR-329 Breast cancer – Inhibited by ROS Cell culture, animal models 288
miR-362-3p Breast cancer – Inhibited by ROS Cell culture, animal models 288
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LncRNAs and ferroptosis

LncRNAs mainly serve as regulators of transcription factors in nucleus or as sponges of miRNAs in cytoplasm139. Linc00336 was promoted by lymphoid-specific helicase in lung cancer and inhibited ferroptosis via sponging miR-685232. Furthermore, in breast cancer and lung cancer, lncRNA P53rra bound to Ras GTPase-activating protein-(SH3domain)-Binding Protein 1 (G3BP1) and displaced P53 from a G3BP1 complex, resulting in retention of P53 in nucleus and downregulation of SLC7A11140. In addition, ferroptosis inducer erastin upregulated lncRNA GA binding protein transcription factor subunit beta 1 (GABPB1) antisense RNA 1 (Gabpb1-AS1), which suppressed GABPB1 and led to downregulation of peroxiredoxin-5 peroxidase and suppression of cellular antioxidant capacity in hepatocellular carcinoma141. Interaction between lncRNAs and ferroptosis has been listed (Supplementary Table 1), and the relationship between lncRNAs and ferroptosis associated factors is summarized in Table 5. The schematic diagram of these interactions is shown in Fig. 1.

Table 5.

Summary of GSH, iron, NRF2, and ROS associated lncRNAs in cancer.

Control point Name Associated cancer type Target Influence to control point Model of evidence Reference
GSH Linc01419 Esophageal squamous cell carcinoma GST Up Clinical samples 144
Neat1 Hepatocellular carcinoma GST Up Cell culture 143
H19 Ovarian cancer GCLC, GCLM, GST Up/Down Cell culture, animal models 145
Xist Colorectal cancer GST Down Cell culture, animal models 48
Ror Breast cancer GST Down Cell culture, animal models 142
Iron Pvt1 Hepatocellular carcinoma miR-150/HIG2 Up Cell culture, animal models 146
H19 Myeloid leukemia miR-675 Inhibited by iron Cell culture 147
NRF2 Aatbc Bladder cancer NRF2 Down Cell culture, animal models 148
Kral Hepatocellular carcinoma KEAP1 Down Cell culture 91
Malat1 Multiple myeloma KEAP1 Down Cell culture, animal models 149
H19 Ovarian cancer NRF2 Down Cell culture, animal models 145
Scal1 Lung cancer – Induced by NRF2 Cell culture 92
Loc344887 Gallbladder cancer – Induced by NRF2 Cell culture 150
ROS Meg3 Lung cancer P53 Up Cell culture 154
Uca1 Bladder cancer miR-16 Down Cell culture 151
Gas5 Melanoma G6PD Down Cell culture 153
H19 Hepatocellular carcinoma MAPK/ERK signaling pathway Down Cell culture 152
Miat Neuroblastoma, glioblastoma MAPK7, FUT8, and MCL1 Unknown Cell culture 289–295
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LncRNAs and ferroptosis associated factors

Since there are only a few studies about lncRNAs and ferroptosis factors, we will discuss them together. Regulation of GSH by lncRNAs in cancer mainly depends on GST and GCL46. In breast cancer, knockdown of lncRNA Ror led to reduced multidrug resistance-associated P-glycoprotein and GST expression, resulting in restored sensitivity of breast cancer cells to tamoxifen142. Similarly, in colorectal cancer, knockdown of lncRNA Xist inhibited doxorubicin resistance via suppressing GST and increasing GSH48. Furthermore, in hepatocellular carcinoma cells, silencing lncRNA Neat1 inhibited IL-6-induced STAT3 phosphorylation which contributed to the increase of GST143. In addition, lncRNA Linc01419 bound to the promoter region of GSTP1 and recruited DNA methyltransferase, increasing promoter methylation and decreasing GST expression in esophageal squamous cell carcinoma144. Moreover, knockdown of lncRNA H19 resulted in recovery of cisplatin sensitivity via reduction of GCL and GST145. In total, regulation of GSH by lncRNAs mainly depends on GST and GCL. Moreover, in hepatocellular carcinoma, silencing of lncRNA Pvt1 inhibited TFR expression and obstructed iron uptake via miR-150146. Furthermore, silencing of FHC in leukemia cells induced production of ROS and altered downstream genes via increasing H19 and miR-657 expression147. This means that lncRNAs are associated with iron metabolism in cancer cells. Moreover, in bladder cancer, suppression of NRF2 by lncRNA associated transcript in bladder cancer (Aatbc) resulted in apoptosis148. In multiple myeloma, metastasis associated lung adenocarcinoma transcript 1 (Malat1) which has been proved to play a role in various cancers, inhibited NRF2 via activation of their negative regulator KEAP1149. Furthermore, overexpression of Keap1 regulation-associated lncRNA (Kral) inhibited NRF2 via increasing KEAP1 expression, and reversed the resistance of hepatocellular carcinoma cells to 5-fluorouracil91. Therefore, lncRNAs regulate NRF2 expression via direct and indirect manners. On the contrary, NRF2 participates in regulation of lncRNAs. In gallbladder cancer, downregulation of lncRNA loc344887 suppressed cell proliferation and decreased migration and invasion. Further studies found that loc344887 was upregulated after ectopic expression of NRF2150. In a recent study, NRF2 activated smoke and cancer-associated lncRNA 1 (Scal1) and induced oxidative stress protection. Knockdown of NRF2 suppressed Scal1 and alleviated the proliferation of lung cancer cells92. In sum, lncRNAs can regulate NRF2 by directly controlling expression or modulating KEAP1 indirectly, and NRF2 can regulate lncRNAs expression reversely.

Other than the factors above, lncRNAs regulate ROS levels via various mechanisms. In bladder cancer, lncRNA urothelial cancer associated 1 (Uca1) decreased ROS level via targeting miR-16 which led to decreased GSH synthetase151. Furthermore, in hepatocellular carcinoma, downregulation of H19 increased ROS via MAPK/ERK signaling pathway and reversed chemotherapy resistance152. Moreover, knockdown of lncRNA growth arrest specific 5 (Gas5) in melanoma enhanced intracellular ROS via increased superoxide anion and NADPH oxidase 4 (NOX4)-oxidized GSH153. In lung cancer cells, the intracellular oxidative stress induced by paclitaxel was attenuated by knockdown of maternally expressed 3 (Meg3), and Meg3 overexpression induced cell death and increased sensitivity to paclitaxel in an ROS-dependent manner154. In total, lncRNAs influence ROS metabolism via control of GSH, iron, NRF2 and other factors, and these factors can regulate lncRNAs expression reversely.

Other ncRNAs and ferroptosis

CircRNAs, tRNAs, rRNAs, piRNAs, snRNAs, and snoRNAs are also contained in family of noncoding RNAs21. However, studies on the relations between these ncRNAs and ferroptosis are few. The interactions have been listed (Supplementary Table 2). The schematic diagram of these interactions is shown in Fig. 1.

CircRNAs

CircRNAs are covalently closed, single-stranded RNA molecules derive from exons via alternative mRNA splicing22. Several studies have uncovered function of circRNAs in ferroptosis. In glioma, circ-TTBK2 enhanced cell proliferation and invasion and inhibited ferroptosis via sponging miR-761 and subsequent ITGB8 activation, knockdown of circ-TTBK2 promoted erastin-induced ferroptosis155. Furthermore, circ0008035 inhibited ferroptosis in gastric cancer via miR-599/EIF4A1 axis. Knockdown of circ0008035 enhanced anticancer effect of erastin and RSL3 via increased iron accumulation and lipid peroxidation156. According to ferroptosis associated factors, in gastric cancer, circPVT1 promoted multidrug resistance by enhancing P-gp and GSTP. MRNA levels of P-gp and GSTP were obviously repressed after downregulation of circ-PVT1 in paclitaxel-resistant gastric cancer cells157. Moreover, high-throughout microarray-based circRNA profiling revealed that 526 circRNAs were dysregulated in cervical cancer cells, and bioinformatic analyses indicated that these circRNAs participated mainly in GSH metabolism158. However, associated miRNAs and downstream factors were not screened. Thus, further studies on the modulation of ferroptosis by circRNAs are needed.

TRNAs

TRNAs serve as adapter molecules between mRNAs and proteins. The interaction between tRNAs and ferroptosis includes two possible manners. First, tRNAs are required in the synthesis of ferroptosis associated factors such as SLC7A11, GPX4, and IREB2, thus the mutation of tRNAs may alter the expression of these factors and then influence ferroptosis217. Second, tRNAs have multiple interaction partners including aminoacyl-tRNA-synthetases, mRNAs, ribosomes and translation factors159. Among them, cysteinyl-tRNA synthetase plays a role in ferroptosis. In fibrosarcoma, rhabdomyosarcoma and pancreatic carcinoma, loss of cysteinyl-tRNA synthetase suppressed erastin-induced ferroptosis via increasing intracellular GSH and transsulfuration, and inhibition of the transsulfuration pathway resensitized cells to erastin160. Interestingly, tRNAs mutation may control ferroptosis in an opposite manner. Selenocysteine which is formed from serine at the respective tRNA, is a component of GPXs. However, in hepatoma, colorectal cancer and breast cancer, the mutation of tRNA led to decline of selenoprotein expression except GPX4 and GPX1, and weak ferroptosis alteration161–163. This indicates that tRNAs modulate GSH levels mainly via synthesis but not metabolism. In addition, tRNAs influence ROS levels via various manners. Lung cancer mouse model with deletion of selenocysteine-tRNA gene exhibited ROS accumulation and increased susceptibility to lymph nodules metastasis164. Additionally, Queuine-modified tRNAs promoted cellular antioxidant defense via catalase, SOD, GPX, and GSH reductase and inhibited lymphoma165. In total, tRNAs decrease GSH synthesis and increase ferroptosis without modulating GPX4, while on the other hand, tRNAs enhance the antioxidant defense system and then inhibit ferroptosis.

RRNAs

RRNAs constitute the structural and functional core of ribosomes166. Some reports have provided clues for role of rRNAs in ferroptosis. In cervical cancer, NRF2 was found to contain a highly conserved 18S rRNA binding site on 5′ untranslated region that is required for internal initiation. Deletion of this site remarkably enhanced translation, indicating that the 18S rRNA regulates NRF2 expression167. In another study, hepatoma cells treated with ethidium bromide exhibited a 70% decrease in the 16S/18S rRNA ratio and enhanced NRF2 expression168. However, whether NRF2 and 18S rRNA are mutually regulated remains unclear. Regarding ROS, nuclear mitotic apparatus protein (NuMA) is involved in cellular events such as DNA damage response, apoptosis, and P53-mediated growth arrest. In breast cancer cells, NuMA bound to 18S and 28S rRNAs and localized to rDNA promoter regions. Downregulation of NuMA expression triggered nucleolar oxidative stress and decreased pre-rRNA synthesis169. Furthermore, in leukemia HL-60 cells treated with iron chelator deferoxamine, rRNA synthesis in nucleoli was inhibited170. In conclusion, interaction between rRNAs and ferroptosis has not been completely uncovered. Role of ribosomes as the place in which proteins related to ferroptosis are synthesized may provide clues for further studies.

PiRNAs, snRNAs, and snoRNAs

PiRNAs are the class of small ncRNA molecules distinct from miRNAs in that they are larger, lack sequence conservation, and are more complex171. PiRNAs are involved in tumorigenesis of variety cancers172. However, studies on piRNAs and ferroptosis are few. In prostate cancer, piR-31470 formed a complex with piwi-like RNA-mediated gene silencing 4 (PIWIL4). This complex recruited DNMT1, DNA methyltransferase 3 alpha, and methyl-CpG binding domain protein 2 to initiate and maintain the hypermethylation and inactivation of GSTP1. Overexpression of piR-31470 inhibited GSTP1 expression and increased vulnerability to oxidative stress and DNA damage in human prostate epithelial RWPE1 cells, resulting in tumorigenesis173. However, the GSTP1 inactivation may inhibit tumor growth via induction of ferroptosis once the tumors are formed. Clearly, further studies are needed to explore the roles of piRNAs in different stages of cancer. SnoRNAs are a class of small RNA molecules that mediate modifications of rRNAs, tRNAs, and snRNAs. The snoRNA ACA11 was overexpressed in multiple myeloma cells, increasing ROS and resulting in protein production and cell proliferation174. There are currently no reports on ferroptosis and snRNAs which mediate post-transcriptional splicing in gene expression. In cervical cancer and osteosarcoma, assembly chaperones and core proteins devoted to snRNA maturation contributed to recruiting trimethylguanosine synthase 1 to selenoprotein mRNAs including GPX1 for cap hypermethylation175. Future studies should focus on the possible regulation of snRNAs towards GPX families. In sum, further studies are needed to explore functions of circRNAs, tRNA, rRNAs, piRNAs, snoRNAs and snRNAs in ferroptosis. Furthermore, the network of factors modulating ferroptosis remains to be established. As ferroptosis is a process of dynamic equilibrium, any alteration of the associated factors may intersect with others. For example, GSH maintains the cytosolic labile iron pool via formation of iron-GSH complexes176. In addition, GSH regulates iron trafficking, and inhibition of GSH synthesis leads to diminished iron efflux following nitric oxide exposure177. Moreover, iron is exported via multidrug resistant protein 1 (MRP1), a known transporter of GSH conjugates178. GSH depletion, MRP1 inhibition or MRP1 knock-out leads to decreased iron release upon nitric oxide treatment179. Conversely, the secondary increase in ROS induced by iron stimulates GSH production, indicating that iron and GSH are interconnected46. Moreover, targets of NRF2 play a critical role in mediating iron/heme metabolism. Both FTL and FTH, the key iron storage protein, as well as FPN, which is responsible for cellular iron efflux, are controlled by NRF2180,181. In addition, a number of integral GSH synthesis and metabolism related enzymes including both the catalytic and modulatory subunits of GCLC, GCLM, GSS, and SLC7A11, are under the control of NRF2182–184. In total, regulation of ferroptosis are linked together, modulation of GSH, iron and NRF2 by ncRNAs may result in further change of each other, and finally alter ferroptosis process.

Clinical application potential of ncRNA-associated ferroptosis

Targeting ncRNAs in cancer has yielded some promising results, however, application of ferroptosis via an ncRNA-dependent manner in clinic is facing obstacles. Inadequate understanding of specific mechanisms results in the limited use of ncRNA modifiers in ferroptosis. Furthermore, cell death occurs in a variety of ways, and numerous ncRNAs may be simultaneously regulated, thus how to ensure that the alteration of associated ncRNAs leads to ferroptosis is another problem. Moreover, ncRNAs act in various ways that may intersect with ferroptosis. For example, ferroptosis inducer miR-210 and H19 could modulate autophagy via targeting BECN1, ATG7, SIRT1, and HIF-1α185–188. In addition, miR-146a could regulat ROS modulator catalase and SOD2 which repressed mitochondrial function189,190. Alteration of autophagy or mitochondrial function resulted in multiple pathologic changes such as neuroinflammation, neurodegeneration, vessel remodeling and myocardial fibrosis, thus how to overcome these possible complications should be considered191–194. In addition, some pathways such as the KEAP1-NRF2 axis, is inhibited by multiple miRNAs and lncRNAs and promotes ferroptosis. Nevertheless, the repression of KEAP1-NRF2 results in the defect in cleaning of ROS and leads to susceptibility to DNA damage and tumorigenesis195,196. To solve these problems, future studies should address the following points. First, more ncRNAs should be identified. A ferroptosis-associated ncRNA screening platform should be established to identify the spectrum of ferroptosis associated ncRNAs and those specific to certain cancers. Second, more intensive studies using complex molecular biological experiments, such as chromosome immunoprecipitation, RNA immunoprecipitation, RNA pull-down, luciferase assays, and RNA truncation should be performed to explore the precise roles of ncRNAs in ferroptosis. Third, in order to translate fundamental experimental results into clinic, functions of ncRNAs in ferroptosis should be tested in animal models. Transgenic mouse models should be established to verify the function of ncRNAs more clearly. Fourth, in order to ensure whether ferroptosis is modulated by ncRNAs, accurate detection of ROS and iron levels, and observation of mitochondrial morphology in tumor tissues are needed. Furthermore, primary culture of tumor cells from patients should be performed to explore whether the proliferation of cancer cells is enhanced by Fer-1, which is the specific inhibitor of ferroptosis. The involvement of ncRNAs in ferroptosis in cancer can be verified in knockdown or overexpression studies. Finally, since ferroptosis occurs in not only tumors but also normal tissues, and as above, ferroptosis regulation by ncRNAs may activate other biological processes and even increase the susceptibility to tumorigenesis. Thus, both ferroptosis-related ncRNAs and associated markers of cell death, senescence, and remodeling should be assessed in patients who are suitable for ferroptosis-associated therapy. In addition, adverse events, dose-limiting toxicities and therapeutic effects should be carefully monitored through rigorous detection of organ functions, imaging of vital organs and tumors, and hematological changes during the application of ferroptosis inducers in clinic. After all, as cancer is a developmental process, the collaboration between multidisciplinary teams should be made to obtain rational therapy regimens to enhance therapeutic effect and alleviate complications.

Conclusions and perspectives

Cancer cells may be intrinsically insensitive or evolve and develop resistance to apoptosis, resulting in cancer progression197. Under the development of molecular biological technologies, identification of new targets or methods to eliminate cancer cells has attracted substantial attention. Ferroptosis is a recently recognized form of programmed cell death that relies on excess intracellular ROS and consequent lipid peroxidation198. Ferroptosis has been successfully applied to limit tumor growth and overcome the resistance of cancer cells to apoptosis, indicating that it may be useful as a new therapeutic approach3. Nevertheless, the application of ferroptosis inducers in cancer therapy is limited, mainly because the specific mechanisms underlying ferroptosis remain unexplored.

NcRNAs have been proved to regulate gene expression by various manners. Numerous ncRNAs have been found to regulate behaviors of cancer cells. In recent years, researchers have examined some ferroptosis-associated ncRNAs in cancer cells. Nevertheless, the specific regulatory mechanisms have not been explored. Therefore, wider and deeper studies to explore the function of ncRNAs in ferroptosis are needed. In this review, the landscape of ncRNAs associated with ferroptosis in cancer thus far is summarized. In addition, possible obstacles during application of ncRNA-associated ferroptosis in clinic are put forward and associated solutions are suggested. However, the information summarized in this review is not sufficient to support the application of ferroptosis inducers in cancer, more ncRNAs should be identified and deeper researches should be performed. In conclusion, ncRNAs may become markers to filter cancer patients who are fit for ferroptosis therapy and become therapeutic targets of ferroptosis inducers.

Supplementary information

Supplementary Table 1 (32.4KB, docx)
Supplementary Table 2 (53KB, docx)

Acknowledgements

The authors thank the personnel at Harbin Medical University Cancer Hospital for their generous help. This study was financially supported by the National Natural Science Foundation of China (grant numbers LH2019H099), Youth Project of Haiyan Foundation of Harbin Medical University Cancer Hospital (grant numbers JJQN2018-15).

Conflict of interest

The authors declare that they have no conflict of interest.

Footnotes

Edited by G. Calin

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Lei Zhang, Xiulan Zheng, Wen Cheng

Contributor Information

Lei Zhang, Email: tianwang.3000@163.com.

Xiulan Zheng, Email: zhengxiulan@hrbmu.edu.cn.

Wen Cheng, Email: chengwenhmu@126.com.

Supplementary information

Supplementary Information accompanies this paper at (10.1038/s41419-020-02772-8).

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