Negative Regulators of Ferroptosis

In this section, we have attempted to provide an overview of the negative modulators of ferroptotic death.

Acyl-CoA synthetase long chain family, member-4 (ACSL4) is certainly a central pro-ferroptotic regulator. It catalyzes the synthesis of long-chain polyunsaturated CoAs. Moreover, lipoxygenases (ALOXs) act as a trigger for ferroptotic death by catalyzing polyunsaturated fatty acid oxygenation.

Arachidonate 12-lipoxygenase was upregulated in miR-7-5p knockdown cells. miR-7-5p knockdown enhanced ferroptosis signaling and consequently induced cell death (Tomita et al., 2021).

miR-670-3p inhibitors led to significant increase in intracellular accumulation of the iron (Bao et al., 2021). miR-670-3p mimics reduced ferroptosis and promoted the growth and survival rates of glioblastoma cells. ACSL4 inhibition also reduced the levels of ferrous iron in miR-670-3p inhibitor-treated A172 and U87MG cells. ACSL4 silencing led to abrogation of miR-670-3p inhibitor-triggered repressive effects on the growth rate of A172 and U87MG cells. Temozolomide efficacy was noted to be more pronounced in miR-670-3p inhibitors-treated A172 and U87MG cells (Bao et al., 2021).

Ectopically expressed miR-4443 potently reduced the sensitivity of A549-S cells. However, miR-4443 silencing restored cisplatin sensitivity in A549-R cancer cells (Song et al., 2021). miR-4443 promoted cisplatin resistance by the suppression of ferroptosis. Methyltransferase-like 3 (METTL3), a methyltransferase, regulates N6-methyladenosine (m6A) methylation. miR-4443 directly targeted METTL3 and enhanced drug resistance. METTL3 inhibition lowered the sensitivity of A549-S cells, but METTL3 overexpression remarkably restored cisplatin sensitivity in A549-R cells. Ferroptosis suppressor protein 1 (FSP1) is a glutathione-independent suppressor of ferroptosis. Multiple m6A sites were identified in FSP1 mRNA, which indicated that FSP1 expression was controlled by m6A modifications. Reduction in the methylation status of m6A in FSP1 was noticed in A549-S cells transfected with miR-4443 mimics. Contrarily, m6A methylation of FSP1 was reported to be enhanced but FSP1 mRNA levels were reduced in miR-4443 inhibitor-treated A549-R cancer cells. Likewise, miR-4443 overexpression abrogated the inhibitory effects of cisplatin and enhanced tumor size and weight in xenografted mice. Tumor tissues from mice demonstrated higher expression of miR-4443 and FSP1 along with notable reduction in the levels of METTL3 (Song et al., 2021). Collectively, these findings indicated that miR-4443 blocked METTL3-mediated m6A modifications in FSP1 and inhibited ferroptosis (shown in Fig. 1).

• Download figure
• Open in new tab
• Download powerpoint

Fig. 1.

Central role of oncogenic miRNAs in suppression of ferroptosis. miR-130b-3p inhibited DKK1 and miR-137 inhibited SLC1A5. Both miRNAs promoted tumor growth in xenografted mice. miR-7-5p and miR-870-3p targeted ALOX15 and ACSL4, respectively, and blocked ferroptosis. METTL3, a methyltransferase regulates m6A methylation. miR-4443 directly targeted METTL3 and enhanced drug resistance. FSP1 is a glutathione-independent suppressor of ferroptosis. miR-4443 blocked METTL3-mediated m6A modifications in FSP1 and inhibited ferroptosis. Uptake of glutamine is dependent on receptors SLC1A5 and SLC38A1. During glutaminolysis, glutamine is deamidated to glutamate. GOT1 catalyzes the conversion of glutamate to α-KG. miR-9 inhibited GOT1 and suppressed ferroptosis.

miR-130b-3p caused inhibition of erastin and RSL3-mediated ferroptosis in melanoma cells (Liao et al., 2021). miR-130b-3p prevented peroxidation of the lipids and iron overload during ferroptosis. DICKKOPF1 (DKK1) is reportedly involved in the inhibition of taurine-triggered NRF2 cascade in UMR-106 cells. miR-130b-3p negatively regulated and directly targeted DKK1 (shown in Fig. 1). miR-130b-3p overexpression evidently blocked erastin-induced ferroptosis in G-361 and A375 cells; however, these inhibitory effects were antagonized by DKK1 restoration. Overexpression of miR-130b-3p caused rapid increase in the weight and volume of xenografted tumors (Liao et al., 2021).

Uptake of glutamine is dependent on receptors SLC1A5 and SLC38A1 (Zhang et al., 2018). During glutaminolysis, glutamine is deamidated to glutamate. Glutamic-oxaloacetic transaminase 1 (GOT1) catalyzes the conversion of glutamate to α-KG. miR-9 considerably reduced erastin- and RSL3-mediated cell death. Whereas, these inhibitory effects were rescued by GOT1 overexpression. miR-9 overexpression led to repression of GOT1 by binding directly to 3′-UTR and suppressed erastin- and RSL3-mediated ferroptotic death (shown in Fig. 1). On the contrary, miRNA-9 suppression greatly enhanced the sensitivity of erastin and RSL3 in melanoma cells (Zhang et al., 2018).

miR-137 has been shown to negatively regulate ferroptosis by direct targeting of SLC1A5 (glutamine transporter) in melanoma cells (Luo et al., 2018). Ectopically expressed miR-137 induced suppression of SLC1A5 and reduced malondialdehyde accumulation and glutamine uptake (shown in Fig. 1). Importantly, antagomir-mediated miR-137 inactivation potently sensitized melanoma cells to erastin- and RSL3-mediated ferroptotic death. Notably, miR-137-overexpressing or miR-137-knockdown A375 cancer cells were xenografted into the subcutaneous spaces of rodent models. miR-137 inhibition induced shrinkage of the size of the tumors. Contrastingly, the size of tumors derived from miR-137-overexpressing cancer cells was reported to be markedly bigger, which clearly indicated that miRNA-137 blocked erastin-mediated ferroptotic cell death in tumor-bearing mice (Luo et al., 2018).

Physcion 8-O-β-glucopyranoside (PG) has been reported to be effective against cancer (Niu et al., 2019). PG promoted ferroptosis in MKN-45 and MGC-803 cells through blockade of miR-103a-3p-mediated inhibitory effects on the expression of glutaminase-2. miR-103a-3p overexpression remarkably abrogated PG-mediated suppressive effects on the invasive and migratory properties of MKN-45 and MGC-803 cancer cells. Intraperitoneal injection of PG hampered the rapid growth of MGC-803 cancer cells in tumor-bearing mice (Niu et al., 2019).

Cancer-associated fibroblasts (CAFs) secreted miRNA-522-suppressed ferroptotic death and promoted acquired chemo-resistant phenotype in gastric cancer cells (shown in Fig. 2) (Zhang et al., 2020). Cancer-associated fibroblasts (CAFs) secrete exosomes which are packed with different non-coding RNAs. Exosomally delivered-miR-522 suppressed ferroptosis in gastric cancer cells. Exosomally-delivered-miR-522 secreted by CAFs suppressed ALOX15 in GC cells (shown in Fig. 2). Heterogeneous nuclear ribonucleoproteins (hnRNP) family has a contributory role in the packaging of non-coding RNAs into exosomes. Overexpression of USP7 or hnRNPA1 in CAFs promoted sophisticated miRNA-522 packaging into exosomes. Yet, knockdown induced relative reduction in exo-miR-522 levels. Paclitaxel or cisplatin enhanced USP7 and hnRNPA1 expression in CAFs. USP7 deubiquitinated hnRNPA1, which resulted in an increase in miR-522 packaging in exosomes. Knocking down of hnRNPA1, USP7, or miRNA-522 in CAFs caused tumor growth impairment and greatly improved cisplatin sensitivity (Zhang et al., 2020).

• Download figure
• Open in new tab
• Download powerpoint

Fig. 2.

CAF-secreted miRNA-522 suppressed ferroptosis. USP7 deubiquitinated hnRNPA1, which lead to an increase in the packaging of miR-522 in exosomes. Exosomally-delivered-miR-522 secreted by CAFs suppressed ALOX15 and downregulated the levels of ferroptosis.

Positive Regulators of Ferroptosis

In this section, we will summarize how different regulators positively modulate ferroptosis.

miR-302a-3p mimics induced iron overload, lipid peroxidation and ferroptosis, thus blocked the growth and colony-forming abilities of non-small cell lung cancer cells (Wei et al., 2021). However, miR-302a-3p inhibitors caused blockade of erastin- or RSL3-mediated ferroptosis as well as tumor suppressive effects. In addition, miR-302a-3p directly targeted 3′ UTR of ferroportin, whereas overexpression of ferroportin significantly reduced miR-302a-3p mimics-mediated ferroptosis and consequent prevention of the cancer progression (Wei et al., 2021).

miR-375 overexpression-mediated downregulation of CD44⁺ sub-population with stemness was attenuated by the overexpression of SLC7A11 (Ni et al., 2021). miR-375 also directly targeted SLC7A11 and induced ferroptosis. The metastasizing potential of miR-375-overexpressing cancer cells was reported to be reduced as evidenced by notable decrease in metastatic nodules. SLC7A11 knockdown suppressed the tumor-initiating ability and metastatic capacity of cancer cells (Ni et al., 2021).

miR-214 overexpression induced an increase in the malondialdehyde and ROS levels, rise in Fe²⁺ concentrations and reduction in glutathione levels in erastin-treated cancer cells (Bai et al., 2020). Activating transcription factor 4 (ATF4) has been shown to inhibit ferroptosis. Furthermore, erastin triggered activation of ATF4 in Hep3B and HepG2 cells. ATF4 upregulation led to prevention of ferroptosis and lipid oxidation induced by erastin and miR‐214. However, pre-miR-214 overexpression reduced the levels of ATF4. Erastin-mediated tumor growth inhibitory effects were reported to be greatly augmented in mice subcutaneously injected with miR‐214-overexpressing Hep3B. Erastin noticeably reduced the growth of Hep3B tumor mass in vivo. Erastin-mediated ferroptosis‐inducing effects were found to be more pronounced upon overexpression of miR‐214 (Bai et al., 2020).

miR-324-3p overexpression led to reversal of cisplatin resistance in cancer cells (Deng et al., 2021). miR-324-3p directly targeted glutathione peroxidase 4 (GPX4), whereas overexpression of GPX4 reversed miR-324-3p-mediated re-sensitization of A549/DDP cancer cells to cisplatin. Additionally, GPX4 inhibitor RSL3 mimicked the effects of miR-324-3p upregulation and re-sensitized cisplatin-resistant cancer cells to chemotherapeutic drugs (Deng et al., 2021).

miR-101-3p directly targeted TBL1-related protein 1 (TBLR1) (Luo et al., 2021a). TBLR1 has been shown to play an oncogenic role. TBLR1 inhibition significantly reduced the activity of the nuclear factor-κB pathway. miR-101-3p mimics induced an increase in reactive oxygen species levels. GPX4 eliminated ROS and reduced oxidative stress. GPX4-mediated elimination of ROS was notably reduced in miR-101-3p mimics-treated cancer cells. Additionally, miR-101-3p mimics caused significant decline in the level of GPX4 and simultaneously increased the expression of PTGS2. Low levels of PTGS2 and high levels of GPX4 were reported in TBLR1/miR-101-3p co-transfected cancer cells. Tail vein injections of nanocarrier containing miR-101-3p mimics induced tumor retrogression in mice transplanted with A549 cancer cells (Luo et al., 2021a).

Positive Regulation of Ferroptosis by Anesthetic Agents

Levobupivacaine is an anesthetic drug and has been shown to trigger ferroptosis (Mao et al., 2021). Levels of lipid ROS and Fe²⁺/iron were enhanced by levobupivacaine in RSL3 and erastin-treated gastric cancer cells. Importantly, levobupivacaine-mediated miRNA-489-3p augmented ferroptotic death in gastric cancer cells. Notably, SLC7A11 belongs to the family of heterodimeric Na⁺-independent anionic amino acid transport system. SLC7A11 is highly specialized for transportation of glutamate and cystine. miR-489-3p directly targeted SLC7A11. MiRNA-489-3p played central role in levobupivacaine-mediated ferroptotic death in gastric cancer cells. Tumor growth was hampered considerably by levobupivacaine in the mice xenografted subcutaneously with SGC7901 cancer cells. Erastin suppressed the growth of SGC7901 cancer cells and enhanced the levels of Fe²⁺, iron, and lipid ROS in the experimental mice. Furthermore, combinatorial treatment with erastin and levobupivacaine further enhanced the effects of erastin (Mao et al., 2021).

Lidocaine is also an anesthetic drug and has been shown to enhance ferroptosis (Sun et al., 2021). Lidocaine promptly enhanced lipid ROS in T47D and SKOV-3 cancer cells. Likewise, levels of GPX4 and SLC7A11 were suppressed in lidocaine-treated SKOV-3 and T47D cancer cells. Colony forming abilities of T47D and SKOV-3 cells were reduced by treatment with miR-382-5p mimics. Depletion of miRNA-382-5p caused blockade of lidocaine-induced ferroptotic death in breast and ovarian cancer cells. Growth rates of SKOV-3 cancer cells were reduced by lidocaine in the nude mice. Levels of miRNA-382-5p were upregulated, but, simultaneously, there was a marked reduction in SLC7A11 levels in the tumor tissues of mice treated with lidocaine (Sun et al., 2021).

In the upcoming sections, we will comprehensively analyze and discuss how long non-coding RNAs and circular RNAs regulate ferroptosis.

Role of Long Non-Coding RNAs in the Regulation of Ferroptosis

OIP5-AS1 expression was found to be significantly elevated in PC3 and DU145 cells chronically exposed with cadmium. OIP5-AS1 acted as a sponge of miR-128-3p and potentiated the expression of SLC7A11. Tumor growth was found to be enhanced in mice xenografted with cadmium-exposed prostate cancer cells (Zhang et al., 2021).

Vincristine stimulated the expression of LINC00618 and induced ferroptosis and apoptosis. Levels of lymphoid-specific helicase (LSH) and SLC7A11 were found to be reduced in LINC00618-overexpressing K562 and MV4-11 cells. LSH transcriptionally upregulated SLC7A11 and inhibited ferroptosis (Wang et al., 2021c).

GABPB1-AS1 reduced the levels of GABPB1. Interactions between GABPB1 mRNA and eIF4A were found to be significantly enhanced in GABPB1-AS1-depleted cells. GABPB1 transcriptionally upregulated peroxiredoxin 5 (PRDX5) (shown in Fig. 3). Repression of PRDX5 led to accumulation of ROS and consequent induction of ferroptosis (Qi et al., 2019).

• Download figure
• Open in new tab
• Download powerpoint

Fig. 3.

(A) GABPB1-AS1 reduced the levels of GABPB1. eIF4A interacted with GABPB1 mRNA and stabilized it. GABPB1 transcriptionally upregulated PRDX5. PRDX5 blocked induction of ferroptosis. (B) P53RRA-G3BP1 interactions led to displacement of p53 from a G3BP1 complex which resulted in greater nuclear accumulation of p53. (C) P53-mediated downregulation of ELAVL1 is blocked by LSH. LINC00336 interacted with ELAVL1 through its RRM interaction domain and inhibited ferroptosis. ELAVL1 increased the stability of LINC00336.

P53RRA, an lncRNA, promoted the nuclear accumulation of p53. P53RRA interacted with G3BP1 through the RRM interaction domain (shown in Fig. 3). P53RRA-G3BP1 interactions led to displacement of p53 from a G3BP1 complex which resulted in greater nuclear accumulation of p53 (Mao et al., 2018).

p53 was recruited to the promoter region of ELAVL1, but LSH blocked p53-mediated transcriptional downregulation of ELAVL1 in PC9 cells (Wang et al., 2019). LINC00336 interacted with ELAVL1 through its RRM interaction domain and inhibited ferroptosis. Moreover, ELAVL1 increased post-transcriptional stability of LINC00336 (shown in Fig. 3). LINC00336 overexpression potently resisted erastin-induced ferroptosis in A549 or SPC-A-1 cells. LINC00336 efficiently blocked MIR6852-mediated targeting of cystathionine-β-synthase. Injections of LINC00336-expressing-A549 and LINC00336-expressing-SPC-A-1 cells in experimental mice clearly indicated that LINC00336 overexpression led to significant formation of tumor mass, whereas, expectedly, tumor growth was significantly reduced in experimental models injected with LINC00336-silenced PC9 cells (Wang et al., 2019).

RP11-89 promoted proliferation, migration, and carcinogenesis via miR-129-5p/PROM2 axis. RP11-89 markedly antagonized miR-129-5p-mediated targeting of PROM2 (Luo et al., 2021b).

TMEM161B-AS1 sequestered hsa-miR-27a-3p away and relieved inhibitory effects of hsa-miR-27a-3p on FANCD2 and CD44. TMEM161B-AS1 silencing or hsa-miR-27a-3p overexpression inhibited the growth of tumors in nude mice (Chen et al., 2021b).

Role of Circular RNAs in the Regulation of Ferroptosis

CircPVT1 has been reported to be frequently overexpressed in 5-fluorouracil-resistant esophageal squamous cell carcinoma cells (Yao et al., 2021). Knockdown of circPVT1 sensitized esophageal squamous cell carcinomacells to 5-fluorouracil. CircPVT1 acted as a sponge of miRNA-30a-5p and potentiated the expression of Frizzled3. It was noted that increase in 5-fluorouracil drug-sensitivity by circPVT1 knockdown was reversed by miR-30a-5p inhibitors. In addition, evident increase in 5-FU drug sensitivity by miR-30a-5p mimics was reversed upon overexpression of Frizzled3. Moreover, circPVT1 knockdown enhanced ferroptosis via suppression of phosphorylated-β-catenin, glutathione peroxidase-4 and SLC7A11, whereas inhibition of miR-30a-5p or Frizzled3 overexpression reserved ferroptosis by inducing an increase in the levels of phosphorylated-β-catenin, glutathione peroxidase-4 and SLC7A11 (Yao et al., 2021).

Circ_0000745 knockdown efficiently inhibited the progression of cell cycle as well as glycolysis and induced ferroptosis and apoptosis (Yang et al., 2022). Circ_0000745 has the ability to serve as a sponge for miRNA-494-3p in acute lymphoblastic leukemia cells. Knockdown of miR-494-3p partially abolished circ_0000745 silencing-mediated tumor-suppressive effects in ALL cells. Essentially, neuroepithelial cell transforming 1 (NET1) was directly targeted by miR-494-3p. Furthermore, miR-494-3p overexpression-mediated ferroptosis induction in acute lymphoblastic leukemia cells was partially reversed because of NET1 overexpression (Yang et al., 2022).

CircFOXP1-silenced lung cancer cells demonstrated marked reduction in the migratory and invasive properties (Wang et al., 2021b). Importantly, vimentin expression was reduced, but E-cadherin levels were noted to be enhanced in circFOXP1-knockdown cancer cells. Moreover, erastin or RSL3 effectively repressed the viability of lung cancer cells but circFOXP1 overexpression rescued the phenotype. Levels of iron, malondialdehyde, and lipid reactive oxygen species were found to be enhanced upon circFOXP1 silencing in both erastin and RSL3-stimulated lung cancer cells. Significantly, CircFOXP1 potentiated the expression of SLC7A11 by the blockade of miR-520a-5p-mediated targeting of SLC7A11 in lung cancer cells. Use of either miR-520a-5p inhibitors or SLC7A11 overexpression reversed circFOXP1 silencing-mediated ferroptosis in lung cancer cells (Wang et al., 2021b).

Silencing of circGFRA1 drastically reduced the proliferation potential of HER-2-positive breast cancer cells (Bazhabayi et al., 2021). Intra-tumorally injected si-circGFRA1 led to notable reduction in tumor mass in mice subcutaneously administered with breast cancer cells. Suppression of circGFRA1 remarkably suppressed number of pulmonary metastatic lesions in tumor-bearing mice (shown in Fig. 4). CircGFRA1 antagonized miR-1228-mediated targeting of apoptosis inducing factor mitochondria associated-2 (AIFM2). Generally, AIFM2 is considered as a ferroptosis suppressor and CircGFRA1 silencing led to significant reduction in the levels of AIFM2. CircGFRA1-silenced cancer cells demonstrated notably decrease in the levels of GPX4. Importantly, the decrease in the GSH/GSSG ratio resulted in the deactivation of GPX4, which further enhanced the accumulation of toxic lipid reactive oxygen species and ferroptosis induction (Bazhabayi et al., 2021).

• Download figure
• Open in new tab
• Download powerpoint

Fig. 4.

Oncogenic circular RNAs negatively regulated ferroptosis. Moreover, oncogenic circRNAs led to tumor growth and pulmonary metastasis in tumor-bearing mice.

CircFNDC3B enhanced SLC7A11 expression by interfering with miR-520d-5p-mediated targeting of SLC7A11 (Yang et al., 2021). However, miR-520d-5p induced ferroptosis of OSCC cells by downregulation of SLC7A11. Notably, there was a marked reduction in the tumor growth in mice injected subcutaneously with circFNDC3B-silenced CAL27 cells (Yang et al., 2021).

circDTL silencing led to the release of mitochondrially located proteins cytochrome c and SMAC/DIABLO into the cytosol (Shanshan et al., 2021). circDTL interfered with miR-1287-5p-mediated targeting of GPX4. The increase in cell death and release of mitochondrial proteins caused by circDTL knockdown were also impaired upon GPX4 overexpression. Tumor growth rates were found to be reduced in mice xenografted with circDTL-silenced non-small cell lung cancer cells (Shanshan et al., 2021).

circ_0067934 knockdown induced apoptotic death of thyroid cancer cells and repressed proliferation of thyroid cancer cells (Wang et al., 2021a). SLC7A11 is a negative regulator of ferroptosis. Circ_0067934 potentiated the expression of SLC7A11 by sequestering miR-545-3p in thyroid cancer cells. SLC7A11 overexpression or miR-545-3p inhibition led to reversal of circ_0067934 silencing-mediated suppression of thyroid cancer cell proliferation. Tumor growth was significantly reduced in mice subcutaneously injected with circ_0067934-silenced-FTC-133 cancer cells (Wang et al., 2021a).

circKIF4A fueled the malignancy of papillary thyroid tumor by sponging miR-1231 and upregulation of GPX4 (Chen et al., 2021c). Intra-tumoral injections of si-circKIF4A induced regression of the tumors in mice subcutaneously injected with KAT-5 and TPC-1 cancer cells. Silencing of circKIF4A also reduced pulmonary metastasis in mice injected with cancer cells through tail veins (Chen et al., 2021c) (shown in Fig. 4).

Circ0097009 acts as a competing endogenous RNA to regulate the expression of SLC7A11 by sponging miR-1261 (Lyu et al., 2021). Intra-tumoral injections of si-circ0097009 considerably inhibited tumor growth in mice xenografted with HepG2 cells. Pulmonary metastasis was also noted to be drastically reduced in mice intravenously injected with circ0097009-silenced-HepG2 cells into the tail veins (Lyu et al., 2021) (shown in Fig. 4).

circEPSTI1 antagonized miRNA-375, miRNA-409-3p and miRNA-515-5p-mediated targeting of SLC7A11. Injections of si-crEPSTI1 led to evident shrinkage of tumor xenografts in mice inoculated with HeLa cells (Wu et al., 2021).

SLC7A11 (xCT) was frequently overexpressed at the cytoplasmic membranes and SLC7A11-induced metabolic reprogramming fueled the progression of lung cancer (Ji et al., 2018). Mice injected with circP4HB-overexpressing cells demonstrated an evident increase in growth rates of the tumors. Levels of circP4HB and SLC7A11 were increased in the tumor xenografts in mice injected with circP4HB-overexpressing cells (Pan et al., 2022).

circ-BGN, an oncogenic circular RNA is frequently overexpressed in trastuzumab resistant-breast cancer cells (Wang et al., 2022). OTUB1 is a deubiquitinating enzyme, and it de-ubiquitinates SLC7A11. Importantly, circ-BGN interacted with OTUB1 and rapidly enhanced OTUB1-driven de-ubiquitination of SLC7A11. An orthotopically implanted tumor model clearly revealed that erastin and circ-BGN inhibition considerably impaired tumor growth by trastuzumab-resistant breast cancer cells (Wang et al., 2022).

circCDK14 sponged miR-3938 and upregulated PDGFRA in glioma cells (Chen et al., 2022). Levels of PDGFRA, p-PDGFRα, SLC7A11, and GPX4 were reported to be profoundly enhanced in circCDK14 overexpressing-U87 cells. However, expectedly, PDGFRA, p-PDGFRα, Vimentin, ZEB1, SLC7A11 were noted to be drastically suppressed in circCDK14-knockdown tumors (Chen et al., 2022).

Concluding Remarks

Ferroptosis activators can cause bone marrow injuries (Song et al., 2016) which is certainly a related toxicity of cytotoxic therapies. Minimizing the off-target effects or toxicity of drugs promoting ferroptotic death remains an overarching goal in clinical and molecular oncology. Keeping in view the limitations that one key cannot unlock every lock, it is imperative to decode context-specific regulatory mechanisms that drive cell type-specific or tissue-specific ferroptotic process in various cancers. Excitingly, discovery of non-coding RNAs and phenomenal advancements in characterization of non-coding RNAs have paradigmatically shifted our conceptual knowledge about regulation of ferroptosis in different cancers. Series of seminal research-works provided detailed insights about momentous contributory roles of miRNAs, lncRNAs and circRNAs in the regulation of ferroptosis. Consequently, researchers identified oncogenic and tumor suppressor non-coding RNAs which contextually regulated ferroptotic death. With growing evidence of instrumental role of non-coding RNAs in regulation of ferroptosis, scientists also analyzed pharmacologically valuable non-coding RNAs for cancer inhibition/prevention. Pharmacological targeting of RNAs has emerged as an advantageous strategy for the treatment of different diseases (Yu et al., 2020). These challenges will require well designed sophisticated preclinical models and innovative technology.