Interplay of non-coding RNAs with amino acid and glucose transporters within the solute carrier family in cancer: a review

Abstract

Solute carrier (SLC) transporters play a central role in tumor metabolism by mediating the uptake of amino acids and sugars required for cancer cell growth and survival. Their proper function is crucial for maintaining cellular homeostasis, and their dysregulation contributes to metabolic reprogramming, tumor progression, and therapy resistance. Recent studies have identified non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, as key regulators of SLC transporter expression and function. This review provides a focused and comprehensive overview of the intricate regulatory networks between ncRNAs and amino acid and sugar transporters within the SLC family, highlighting their implications in cancer. We summarize current evidence on direct and indirect regulatory mechanisms, including transcriptional, post-transcriptional, and epigenetic pathways, and discuss how these interactions reshape cancer metabolism. We highlight existing knowledge gaps, such as context-dependent regulation, indirect regulatory networks, and limited mechanistic validation in vivo. Finally, we discuss the therapeutic potential and challenges of targeting ncRNA-SLC networks. A deeper understanding of these interactions may facilitate the development of novel therapeutic approaches aimed at improving cancer treatment outcomes.

Graphical abstract

Introduction

Solute carrier (SLC) proteins are a broad class of transporters and include more than 60 distinct families with diverse structural features, substrate specificities, and transport mechanisms. Members of the SLC family facilitate the transport of a wide range of substrates, including amino acids, sugars, ions, vitamins, metabolites, and drugs, across biological membranes. SLC transporters function through facilitated diffusion or secondary active transport, often coupling substrate movement to ion gradients [1–3]. Other members function as antiporters containing one substrate-binding site operating via an alternating access transport mechanism, while some SLCs have channel-like properties [4]. Moreover, their expression patterns and subcellular localization vary across tissues and organelles, including the endoplasmic reticulum, mitochondria, lysosomes, and peroxisomes [5].

SLCs possess diverse physiological roles, and their dysregulation is associated with different pathological conditions. The brain consumes nearly 20% of energy intake, and SLCs play a crucial role in this process [6]. Furthermore, SLCs are essential regulators of amino acid metabolism in the liver [7]. Since they regulate the influx and efflux of various substances and maintain homeostasis, their dysregulation is often associated with multiple types of disorders, such as metabolic diseases [8, 9], Alzheimer’s disease [10], and cancer [11]. They can also mediate the cellular uptake of drugs, making them one of the most promising targets in cancer therapy [12]. Accumulating evidence has revealed that aberrant expression and function of SLCs contribute to cancer initiation, progression, and metabolic reprogramming. Importantly, downregulation of some SLCs has been reported to be associated with tumor progression, suggesting that these SLCs may function as potential tumor suppressors. Furthermore, a growing body of studies has also revealed the interaction between aberrant expression of SLCs and therapy resistance [13].

Amino acid and glucose transporters within the SLC family are among the most important transporters, as they regulate the uptake of substances critical to energy production in cells. SLCs involved in transporting amino acids such as methionine, tryptophan, and arginine play important roles in tumor immune evasion [14]. For instance, breast cancer cells supply arginine in the tumor microenvironment through high expression of arginine transporters (such as SLC7A2), which drives macrophage polarization and suppresses CD8 + T cell activity. This interaction promotes immune evasion and tumor growth [15]. Among glucose transporters, the GLUT (SLC2A) family plays a major role in cancer metabolism. These transporters have high affinity for glucose and are upregulated by oncogenes such as RAS, MYC, and AKT, as well as by hypoxia through HIF1. This increases glucose uptake and enhances glycolysis, thereby supporting rapid tumor growth and proliferation [16]. These findings confirm the importance of SLC proteins and make them potential targets for therapeutic interventions.

Recent evidence indicates that the aberrant activity of SLC transporters in cancer is not only affected by genetic alterations but is also tightly regulated at the post-transcriptional and epigenetic levels. Understanding the interplay between SLC transporters and non-coding RNAs (ncRNAs) is crucial for elucidating cellular metabolism in diverse aspects of tumor biology, including proliferation, invasion, and therapy response. NcRNAs are RNA transcripts that originate from the non-protein coding part of the genome [17]. MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are the most studied ncRNAs that regulate diverse mechanisms in normal and cancerous cells. In cancer, they regulate all the cancer hallmarks, including proliferation, apoptosis, invasion, epithelial-to-mesenchymal transition (EMT), and therapy resistance [18]. The function of RNA polymerase II initiates miRNA biosynthesis. First, primary miRNAs (pri-miRNAs) are produced and converted into precursor miRNAs (pre-miRNAs) through the action of Drosha/DGCR8. Subsequently, these pre-miRNAs are transported into the cytoplasm by exportin 5, where they undergo maturation in a process facilitated by Dicer [19, 20]. CircRNAs are generated from pre-mRNA transcripts throughout the back-splicing process or lariat-driven circularization. Moreover, RNA Pol II mediates the transcription of lncRNA genes [21]. NcRNAs interact with DNA, RNA, and proteins to regulate several physiological and epigenetic processes, including methylation, acetylation, phosphorylation, ubiquitylation, and SUMOylation. They can also affect the post-transcriptional processes to control RNA stability, translation, and degradation. Additionally, ncRNAs directly or indirectly control cell metabolism and signaling pathways. Their distinct expression patterns also render them useful biomarkers for diagnosis and prognosis [22–24]. The role of these ncRNAs in regulating critical cellular functions positions them as potential targets for cancer therapy [25].

Despite increasing recognition of ncRNA involvement in cancer metabolism, the regulatory interplay between ncRNAs and amino acid and sugar SLC transporters remains incompletely understood. The current review describes the diverse mechanisms through which ncRNAs modulate the activity and expression of SLC transporters, influencing the uptake and distribution of essential nutrients such as amino acids and glucose in cancer. The literature discussed in this review was identified through targeted searches in Google Scholar using combinations of keywords such as “SLC transporters,” “non-coding RNAs,” “miRNA,” “lncRNA,” “circRNA,” and “cancer metabolism”. Studies were selected based on their relevance to ncRNA-mediated regulation of amino acid and sugar SLC transporters in cancer. We summarize direct and indirect regulatory mechanisms, discuss their functional consequences for tumor metabolism and progression, and highlight areas that remain to be studied and research gaps.

Characteristics and function of glucose and amino acid transporters within the SLC family

Cancer cells have increased demands for key nutrients to support their rapid proliferation and survival. To meet these metabolic demands, tumor cells largely depend on SLC transporters. As a result, SLCs play a central role in cancer metabolic reprogramming. Increased glucose uptake through facilitative transporters such as GLUTs and sodium-dependent transporters like SGLTs provides the fuel for glycolysis. Similarly, amino acid transporters, including SLC7A11, are upregulated in cancer to supply essential substrates needed for protein synthesis [26].

The SLC2 family is a group of facilitated glucose transporters. The members of the SLC5 family are sodium-dependent transport proteins that act in three main ways: as Na+/glucose cotransporters, Na+/Cl−/choline cotransporters, or glucose-activated ion channels. The SLC50 family, known as SWEET transporters, has only one member in humans (SLC50A1), which is a glucose uniporter and is involved in glucose efflux [27]. Glucose transporters play diverse roles in cancer. Breast tumors often show high expression of GLUTs and glycolysis-related enzymes, which is linked to disease progression and poor clinical outcomes [28]. In colorectal cancer (CRC) cells, GLUT1 suppression by BAY-876 reduced cell proliferation and viability. This inhibition further led to a shift in metabolism, decreased glycolysis, increased mitochondrial respiration, higher reactive oxygen species (ROS) production, and elevated apoptosis [29]. In esophageal cancer, GLUT1 directly binds to EGFR and inhibits its ubiquitin-mediated degradation, thereby maintaining EGFR signaling and suppressing autophagy-dependent ferroptosis. Through this function, GLUT1 supports cancer stem cell (CSC)-like properties [30]. Although GLUT1 has been studied more extensively than other SLC glucose transporters, this does not imply that the roles of other transporters in cancer cell metabolism are less important. Rather, it highlights the need for further investigation into the functions and regulatory mechanisms of other SLC transporters and their contributions to cancer progression.

Amino acid transporters are commonly classified based on their functional transport systems, such as systems A, N, ASC, L, xc−, and y+, with each designation reflecting substrate specificity [31]. SLC1A5, also known as alanine–serine–cysteine transporter 2 (ASCT2), is a sodium-dependent transporter that mediates the uptake of amino acids such as alanine, serine, cysteine, and glutamine. It functions as an obligate exchanger, meaning that for each Na⁺-coupled amino acid imported into the cell, another Na⁺-coupled amino acid is simultaneously exported in a 1:1 ratio [32, 33].

The SLC7 family is divided into two main subfamilies: the cationic amino acid transporters (CATs) and the L-type amino acid transporters (LATs). LATs function as the light (catalytic) subunits of heteromeric amino acid transporters (HATs) and are linked via a disulfide bond to heavy subunits, either 4F2hc or rBAT. These heavy subunits are glycoproteins that belong to the SLC3 family. Most members of the CAT subfamily have been functionally characterized as facilitated diffusion transporters that mediate both the uptake and efflux of cationic amino acids. In contrast, HATs generally operate as amino acid exchangers with broad substrate specificity. SLC7A5, also known as LAT1, is a transporter responsible for the uptake of large neutral amino acids, including branched-chain amino acids (valine, isoleucine, and leucine) as well as bulky amino acids such as phenylalanine, tyrosine, tryptophan, glutamine, asparagine, and methionine. Functionally, SLC7A5 forms a heterodimer with SLC3A2 (also known as 4F2hc). This complex operates as Na⁺- and pH-independent obligate exchanger. SLC7A11, also known as the catalytic subunit of system xc⁻ (xCT), forms a heterodimer with SLC3A2 and functions as a Na⁺-independent obligate exchanger. This transporter mediates the uptake of extracellular cystine (Cys–S–S–Cys) in exchange for the efflux of intracellular glutamate [34].

Disorders associated with the dysfunction of amino acid transporters highlight the diverse physiological roles they play in the human body. For example, mutations in brain amino acid transporters can disrupt neuronal excitability, while defects in renal and intestinal transporters impair systemic amino acid homeostasis, leading to malabsorption and kidney-related disorders. Importantly, when amino acid transporters are essential components of specific metabolic pathways, their dysfunction can compromise the whole pathway function. Moreover, since amino acid uptake is essential for cell growth and proliferation, dysregulation of these transporters is closely linked to tumor development and progression [35]. SLC1A5, SLC7A5, SLC7A11, and SLC38A1 have been reported to be highly expressed in various cancers [36]. Their upregulation often occurs in a tumor type-dependent manner. Notably, these transporters are functionally interconnected, working together to enhance nutrient uptake and metabolic flexibility, thereby supporting tumor growth and contributing to chemoresistance [37].

miRNA regulation of glucose and amino acid transporters

Regulation of glucose transporter SLCs by miRNAs

SLC2A1 (GLUT1)

SLC2A1 (also known as GLUT1) is a direct target of miR-199a-5p, which decreases its expression to exert its tumor suppressor function. For instance, miR-199a-5p can inhibit non-small cell lung cancer (NSCLC) cell proliferation, cell cycle, and migration while inducing apoptosis [38]. Likewise, miR-328 negatively regulates SLC2A1 in colon cancer cells. By inhibiting SLC2A1 function, miR-328 mediates a metabolic shift to suppress tumor progression [39]. In an effort, a novel platform was developed to produce bioengineered miRNA agents. Moreover, a bioengineered miR-328-3p was produced, and its role in nutrient uptake was studied. In highly proliferative osteosarcoma cells, miR-328-3p directly targets and suppresses SLC2A1, which leads to decreased glucose intake and low levels of glycolytic metabolite lactate. Importantly, it has also been documented that co-treatment of miR-328-3p and cisplatin or doxorubicin can synergistically inhibit tumor cell proliferation [40]. Recently, it was found that oncogenic proteins named Human Papillomavirus (HPV)16 E6/E7 decrease the expression level of miR-451 to increase Calcium-binding protein (CAB39) at mRNA and protein levels. The upregulated CAB39 then increases the expression of GLUT1 and its translocation to the plasma membrane through the Phosphoinositide 3-kinase (PI3K)/AKT pathway. Overall, the HPV16/miR-451/CAB39/GLUT1 axis enhances lung cancer progression [41]. Similarly, miR-148a decreases the expression level of GLUT1, which results in suppressed tumor cell proliferation, invasion, and migration in intrahepatic cholangiocarcinoma. Also, miR-148a inhibition was found to increase GLUT1 expression and mediate gemcitabine resistance [42]. In addition, miR-218 negatively regulates glucose metabolism in NSCLC by directly targeting GLUT1 and indirectly targeting Nuclear factor kappaB (NF-κB) signaling [43]. Of note, in another study, the miR-1291 prodrug was applied to pancreatic carcinoma cells. In tumor cells, miR-1291-5p inhibits GLUT1 and argininosuccinate synthase (ASS1), which are involved in glycolysis and arginolysis, respectively. Importantly, the function of miR-1291 ultimately leads to increased sensitivity to arginine deprivation and chemotherapy [44].

In contrast, miR-10b has oncogenic functions and enhances GLUT1 expression, promoting proliferation of oral squamous cell carcinoma (OSCC) cells [45]. Also, it was shown that has-miR-186-3p overexpression is associated with worse overall survival and increased GLUT1 expression in renal cell carcinoma [46]. In addition, it was demonstrated that mitochondrial miR-181a-5p overexpression targets GLUT1, reprogramming glucose metabolism and regulating the electron transport chain in mitochondria, thereby promoting tumor growth and lung metastasis in liver cancer [47]. MiR-155 was found to exert tumor-promoting functions in breast cancer by directly inhibiting phosphoinositide-3-kinase regulatory subunit alpha (PIK3R1)-PDK1/AKT-FOXO3a. As a result, c-Myc, the downstream target of FOXO3a, is increased, resulting in the upregulation of glucose transporters (GLUT1, GLUT3, and GLUT4), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) enzymes. Following the upregulation of these key factors of glucose metabolism, cellular metabolism shifts toward enhanced glycolysis and energy production, supporting rapid cell proliferation and tumor progression [48]. Importantly, the regulatory effects of certain miRNAs, such as miR-155, are highly context-dependent and may vary across different cancer types. Although miR-155 exhibits tumor-promoting activity in several cancers [49], some studies suggest that miR-155 has a tumor-inhibitory function. For instance, miR-155 expression was shown to be reduced in gastric cancer, where increased miR-155 levels may be associated with suppressed tumor cell invasion and metastasis [50]. Similarly, miR-155 mediates tumor suppression in prostate cancer by inhibition of transforming growth factor beta (TGF-β)/SMAD signal pathway [51]. Therefore, the role of microRNAs in regulating SLC transporters can vary depending on the cancer type, particularly for microRNAs with multifunctional roles.

GLUT1 could be targeted by nanoparticles that carry therapeutic agents. For example, in an effort, a novel nanosphere delivery system was developed to carry anti-miR21 using the rolling circle transcription technique. Then, GSH-responsive cationic polymer polyethyleneimine (pOEI) modified with dehydroascorbic acid (DHA) was produced to protect nanospheres from cell enzymes. Next, these polymers were used for contracting nanospheres into nanopompons (Fig. 1) [52]. While delivery systems offer therapeutic potential, they also present notable limitations such as instability, off-target effects, and immune activation. Moreover, effective targeting of ncRNA-SLC regulatory pathways through drug delivery platforms will require more detailed mechanistic studies to support the rational design of such delivery strategies. Collectively, these studies indicate that regulation of GLUT1 by miRNAs is important for metabolic reprogramming in cancer. Tumor-suppressive miRNAs inhibit GLUT1 expression to reduce glycolysis, whereas oncogenic miRNAs enhance GLUT1-dependent glucose uptake directly or indirectly through upstream signaling pathways.

Fig. 1.

The crosstalk among miRNAs and SLC2A1(GLUT1). SLC2A1 enhances tumor progression by increasing glucose import and metabolism. MiRNAs with both tumor suppressor and oncogenic functions could regulate SLC2A1 expression. miRNAs target SLC2A1 directly or indirectly through other signaling pathways

SLC2A3 (GLUT3) and SLC2A5 (GLUT5)

The sine oculis homeobox (SIX) is a transcription factor that promotes cancer progression. In head and neck squamous cell carcinomas (HNSCCs), SIX1 promotes GLUT3 expression, glucose metabolism, and ATP production to enhance tumor cell proliferation. Importantly, it was shown that miR-23a-3p inhibits HNSCC progression through the inhibition of the SIX1/GLUT3 axis [53]. In glioblastoma, miR-3189 induces apoptosis and inhibits proliferation by suppressing GLUT3 expression. However, histone deacetylase 2 (HDAC2) could attenuate miR-3189 function by decreasing its expression, thereby promoting GLUT3 expression and glucose metabolism [54]. In addition, miR-129-5p targets the 3′-UTR of SLC2A3 to block glucose uptake, glucose metabolism, and lactate and ATP production in gastric cancer. Importantly, PI3K/AKT and mitogen-activated protein kinase (MAPK) signaling pathways are involved in this function [55]. Similarly, miR-195-5p directly targets the 3′-UTR region of SLC2A3 in bladder cancer. It was demonstrated that the miR-195-5p/SLC2A3 axis suppresses tumor progression and can be a promising therapeutic target [56]. As an oncogenic miRNA, miR-590-5p directly targets T lymphoma invasion and metastasis 1 (Tiam1) to increase SLC2A3 and promote pancreatic cancer. Tiam1 regulates tumor cell proliferation, EMT, invasive and metastatic capacities, and angiogenesis via regulating SLC2A3 [57].

GLUT5 was shown to be regulated by an AKT/miRNA axis. It was revealed that AKT1 and AKT3 destructively regulate miR-125b-5p. GLUT5 is a downstream target of miR-125b-5p, which is increased by the function of AKT1 and AKT3, and promotes CRC cell migration and drug resistance [58].

SLC5A2 (SGLT2) and SLC35F5

SLC5A2 (SGLT2) is important for tumor progression. It was shown that miR-296-5p mediates the downregulation of SLC5A2 to suppress NSCLC proliferation and cell cycle progression [59].

SLC35F5 is another sugar transporter that is targeted by miR-369-3p. In cisplatin-resistant NSCLC tissues and cells, miR-369-3p overexpression was associated with cisplatin resistance and cancer cell invasiveness. This occurs since miR-369-3p targets the 3’-UTR region of the SLC35F5 gene to suppress its function [60]. A summary of the interactions between miRNAs and SLC2A3, SLC2A5, SLC5A2, and SLC35F5 is shown in Fig. 2.

Fig. 2.

The crosstalk among miRNAs and SLC2A3, SLC2A5, SLC5A2, and SLC35F5. These SLCs promote tumor progression. Oncogenic and tumor suppressor miRNAs exert their function by targeting these SLCs

Regulation of amino acid transporter SLCs by miRNAs

SLC1

In a healthy brain, neurons and astrocytes interact through metabolites, especially glutamine, glutamate, and lactate. A study revealed that extracellular vesicles derived from breast cancer cells that carry miR-199b-5p augment brain metastasis. To inhibit neuron–astrocyte metabolic coupling, miR-199b-5p targets SLC1A2 and SLC38A2 in neurons, resulting in extracellular retention of these metabolites and thereby promoting cancer cell growth. The cancer cells originate from non-brain tissue through this mechanism and induce neural reprogramming to enhance brain metastasis [61].

SLC1A5 (ASCT2) is a glutamine transporter with high expression levels in cancer cells. Inhibition of SLC1A5 by miR-137 decreased glutamine metabolism, thereby suppressing tumorigenesis. Importantly, methyl-CpG-binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) induce methylation of the promoter region of miR-137 to inhibit its transcription and increase SLC1A5 expression [62]. Similarly, miR-122-5p can reversely regulate SLC1A5 in pancreatic cancer, and by inhibiting SLC1A5 function, miR-122-5p can suppress cancer cell growth, while triggering apoptosis [63].

SLC3A2

Recent studies have highlighted the critical role of ncRNAs in regulating ferroptosis through modulation of metabolic and redox-related pathways, including SLC transporters, thereby influencing tumor progression and therapeutic response [64]. Ferroptosis is a type of cell death that happens when iron accumulation leads to lipid peroxidation and consequent damage to cell membranes. A study revealed that miR-142-3p is increased in exosomes derived from hepatitis B virus (HBV)-infected liver cancer cells. miR-142-3p binds to the 3’-UTR region of the SLC3A2 gene to negatively regulate its expression in M1 macrophages. This study revealed that suppression of SLC3A2 by miR-142-3p ultimately induces ferroptosis in these cells. After the induction of ferroptosis, the proliferation of liver cancer cells is decreased, and tumor progression is suppressed [65].

SLC7A5

In retinoblastoma, miR-184 negatively regulates SLC7A5, thereby inhibiting cancer cell proliferation, invasion, and migration. Also, apoptosis increases, leading to enhanced chemosensitivity through reduced phosphorylation of DNA damage repair sensors of the ataxia telangiectasia and Rad3-related (ATR)/ataxia-telangiectasia-mutated (ATM) pathways. Also, miR-184 induces the persistent formation of H2A histone family member X (γH2AX) foci related to the targeting of SLC7A5, which results in persistent DNA damage [66]. As a tumor suppressor, miR-126-3p is downregulated in thyroid cancer. The aberrant expression of miR-126-3p was related to suppressed SLC7A5 expression, thereby inhibiting tumor cell proliferation, migration, lung metastasis, and colony formation [67]. In esophageal squamous cell carcinoma (ESCC), miR-6775-3p upregulation was shown to be accompanied by suppressed tumor cell proliferation, invasion, and liver metastasis. miR-6775-3p directly targets the 3UTR region of MAGE-A to decrease its expression and increase p53 activity. Also, SLC7A5 was shown to be downregulated by miR-6775-3p, which mediates its tumor suppressor functions. Interestingly, this study also found a positive feedback loop between miR-6775-3p and p53 through the MAGE-A family. Indeed, p53 increases the expression of both miR-6775-3p and SLC7A5, but MAGE-A suppresses p53. MiR-6775-3p attenuates MAGE-A to remove the inhibitory effect of MAGE-A on p53 activity and also suppresses SLC7A5 mRNA expression [68]. A summary of the interactions between miRNAs and SLC1A2, SLC3A2, and SLC7A5 is shown in Fig. 3.

Fig. 3.

The crosstalk among miRNAs and SLC1A2, SLC3A2, and SLC7A5. These SLCs are amino acid transporters that act in favor of tumor progression. Tumor suppressor miRNAs that target these SLCs are illustrated in this figure. SLC3A2 increases tumor growth by preventing ferroptosis, and miR-142-3p induces ferroptosis by negatively targeting SLC3A2. In addition, tumor cells could suppress the inhibitory function of miRNAs in their growth. For instance, MeCP2/DNMTs attenuate miR-137 expression by binding to its promoter, thereby enhancing SLC1A5 expression and tumor progression

SLC7A11

Among SLC proteins, SLC7A11 has been extensively investigated [69], and miRNAs primarily target and regulate this SLC. For instance, both mRNA and protein levels of SLC7A11 are suppressed by miR-509–5p in CRC. miR-509–5p inhibits tumor progression by suppressing SLC7A11 and subsequently increases malondialdehyde and iron levels, which results in ferroptosis [70]. Similarly, miR-27a-3p inhibits NSCLC progression by targeting SLC7A11. As a tumor suppressor molecule, miR-27a-3p is downregulated in cancer and exerts its function through decreasing SLC7A11 expression and increasing erastin-induced ferroptosis [71]. In breast cancer, miR-5096 overexpression is associated with ROS, glutathione (GSH), elevated hydroxyl radical levels, and increased lipid peroxidation by targeting SLC7A11. Interestingly, miR-5096 acts synergistically with erastin and promotes lipid peroxidation levels compared to miR-5096 and erastin alone [72, 73]. Another miRNA, miR-139-5p, affects pancreatic carcinoma progression by targeting the SLC7A11/PI3K/AKT pathway. For this purpose, miR-139-5p inhibits SLC7A11, decreasing p-PI3K and p-Akt levels in tumor tissues. As a result, tumor cell proliferation, invasion, and metastasis are suppressed [74].

It bears noting that various compounds affect the miRNA/SLC7A11 axis. For instance, it was demonstrated that lidocaine positively regulates miR-382-5p to suppress SLC7A11 and to enhance ferroptosis-induced cell death in ovarian and breast cancer [75]. In gastric cancer, Levobupivacaine, a local anesthetic with potential anti-cancer ability, increases miR-489-3p expression to reduce the inhibitory effect of SLC7A11 on ferroptosis and repress tumor cell growth [76]. Also, it was found that enhancer of zeste homolog 2 (EZH2) suppresses the ferroptosis process in tongue squamous cell carcinoma by binding to the miR-125b-5p promoter and downregulating its expression. As miR-125b-5p reversely regulates the SLC7A11, the function of EZH2 ultimately results in the upregulation of SLC7A11, ferroptosis inhibition, and tumor progression [77].

SLC36 and SLC38

In gallbladder cancer, it was confirmed that miR-29c-3p is downregulated. This miRNA acts as a tumor inhibitor by reversing EMT and preventing invasiveness and migration by modulating the expression of SLC36A1, also known as proton-coupled amino acid transporter (PAT1) [78].

In primary liver cancer, miR-10b-5p is overexpressed and negatively affects SLC38A2, known as sodium-coupled neutral amino acid transporter 2 (SNAT2), to promote metabolic reprogramming, thereby enhancing the proliferation, malignancy, and invasiveness of cancerous cells [79].

SLC38A4 is a neutral amino acid transporter that acts as a tumor suppressor agent in hepatocellular carcinoma (HCC) by targeting the Wnt/β-catenin/MYC/3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) pathway [80]. Adenosine deaminase acting on double-stranded RNA (ADAR) is a member of the RNA-editing enzyme family, and its expression is dysregulated in liver cancer. Thus, maintaining the normal function of ADARs is crucial for miRNAs involved in oncogenic pathways in hepatocytes [81]. Interestingly, it was shown that adenosine-to-inosine miR-3144-3p editing catalyzed by ADAR1 leads to tumor progression. Excessively editing canonical miR-3144-3p suppresses the translation of SLC38A4 mRNA to enhance hepatocellular carcinogenesis [81]. A summary of the interactions between miRNAs and SLC7A11, SLC36, and SLC38 is shown in the Fig. 4. A list of interactions between other miRNAs and SLCs in cancer is provided in Table 1.

Fig. 4.

The crosstalk between miRNAs and SLC7A11, SLC36, and SLC38. SLC7A11 acts as an oncogenic protein mainly by preventing ferroptosis. Several miRNAs have been found to negatively regulate SLC7A11. Among them, miR-125b-5p expression is suppressed by EZH2 to enhance tumor growth. In contrast, SLC38A4 is a tumor suppressor protein, and oncogenic miR-3144-3p inhibits its expression in cancer cells

Table 1.

The crosstalk among miRNAs and SLCs in cancer

SLC	miRNA	Cancer type	Remarks	Ref.
SLC1A5	miR-137	Melanoma	MiR-137 inhibits SLC1A5 to suppress ferroptosis.	[82]
SLC2A1	miR-148b	Gastric cancer	MiR-148b inhibits glycolysis by targeting SLC2A1.	[83]
	miR-148a	Pancreatic cancer	MiR-148a suppresses tumor pathogenesis by inhibiting GLUT1.	[84]
	miR-1291	Renal cell carcinoma	MiR-129 inhibits tumor cell proliferation, invasiveness, and metastasis by suppressing GLUT1.	[85]
	miR-140-5p	Breast cancer	MiR-140-5p inhibits glycolysis and cancer cell proliferation through inhibiting GLUT1.	[86]
	miR-22	Breast cancer	MiR-22 suppresses tumor cell proliferation, invasion, and distant metastasis capacities by preventing GLUT1 expression.	[87]
	miR-218	Bladder cancer	MiR-218 blocks glucose uptake by targeting GLUT1, thereby increasing sensitivity to cisplatin.	[88]
		OSCC	MiR-218 inhibits tumor cell growth and glucose uptake by targeting GLUT1.	[89]
	miR-143	Colon cancer	MiR-143 inhibits glucose uptake and cancer cell proliferation by targeting GLUT1.	[90]
	miR-378a	Prostate cancer	MiR-378a inhibits glucose metabolism and tumor cell proliferation by suppressing GLUT1.	[91]
	miR-6077	Lung adenocarcinoma	MiR-6077 increases the sensitivity of tumor cells to anlotinib by inhibiting GLUT1.	[92]
	miR-150	Osteosarcoma	miR-150 inhibits tumor cell proliferation, glucose uptake, and lactate secretion by suppressing GLUT1 expression.	[93]
	miR-34a	TNBC	MiR-34a inhibits glucose uptake and tumor cell proliferation by affecting GLUT1 expression.	[94]
	miR-140-5p	Osteosarcoma	MiR-140-5p prevents tumor cell proliferation by suppressing GLUT1 expression.	[95]
	miR-125b	Papillary thyroid carcinoma	MiR-125b suppresses tumor cell proliferation by downregulating GLUT1.	[96]
SLC7A11	miR-148a-3p	CRC	miR-148a-3p inhibits tumor progression by targeting SLC7A11 and activating ferroptosis.	[97]
	miR-375	Gastric cancer	MiR-375 enhances ferroptosis by targeting SLC7A11 to suppress tumor cell stemness.	[98]
	miR-34c-3p	OSCC	MiR-34c-3p enhances Erastin-mediated ferroptosis to suppress tumor cell proliferation through targeting SLC7A11.	[99]
	miR-26b	Breast cancer	MiR-26b Induces apoptosis by repressing SLC7A11.	[100]
	miR-93-5p	Ovarian cancer	MiR-93-5p increases ferroptosis by inhibiting SLC7A11 expression.	[101]

lncRNAs regulation of glucose and amino acid transporters

Regulation of glucose transporter SLCs by lncRNAs

SLC2A1 (GLUT1)

Shi et al. investigated the role of LINC00174 in the progression of glioma. This study revealed that LINC00174 serves as a sponge of miR-152-3p to reduce its expression and subsequently increase SLC2A1 in glioma cells. Overexpression of LINC00174 enhances tumor cell glycolysis, proliferation, invasiveness, and migratory capacities, while its downregulation inhibits tumor volume and growth [102]. Similarly, lncRNA PVT1 is overexpressed in the lung adenocarcinoma cells and promotes progression through increasing SLC2A1 expression. However, miR-378c negatively affects SLC2A1, and lncRNA PVT1 suppresses miR-378c to increase SLC2A1 expression [103]. In HCC, lncRNA SLC2A1-AS1 expression is lower than in normal cells, and its downregulation is accompanied by recurrence-free survival in HCC. In contrast, the upregulation of lncRNA SLC2A1-AS1 attenuated tumor cell proliferation and metastasis. For preventing aerobic glycolysis, lncRNA SLC2A1-AS1 binds to STAT3 to increase FOXM1 and mediate the downregulation of GLUT1 by inhibiting its mRNA transcription. However, the low expression level of lncRNA SLC2A1-AS1 has no suppressor effect on STAT3, and FOXM1 function is decreased, followed by GLUT1’s high expression and function [104]. LncRNA FTO-IT1 originated from the transcript of the Fat mass and obesity-associated protein (FTO) gene and is overexpressed in HCC. LncRNA FTO-IT1 recruits the ILF2/ILF3 protein complex to bind to the 3’UTR region of FTO mRNA to increase its stability and function. FTO decreased the N6-methyladenosine (m⁶A) modification sites on GLUT1, PKM2, and c-Myc mRNAs to suppress their degradation by YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Interestingly, c-Myc positively regulates the expression of the lncRNA FTO-IT1 gene in a reciprocal loop by binding to its promoter under low glucose conditions [105].

M⁶A modification is dynamically regulated by three classes of modulators, including “writers” (methyltransferases such as METTL3, METTL14, and associated proteins) that install the methyl mark, “erasers” (demethylases including FTO and ALKBH5) that remove it, and “readers” (m⁶A-binding proteins like YTHDF1/2/3, YTHDC1/2, and IGF2BP1/2/3) that recognize m⁶A and mediate downstream functional outcomes [106]. A body of studies indicates that m⁶A modification plays a critical role in the regulation of the expression and function of both ncRNAs and SLCs in cancer. For instance, m⁶A modification of SLC50A1 mRNA by METTL3 has been reported in HCC. Subsequent recognition of this modification by the m⁶A reader IGF2BP2 enhances the stability and translational efficiency of SLC50A1, which is associated with doxorubicin resistance in HCC cells [107]. Another example of the importance of m⁶A modification in cancer is the elevation of lncRNA POU6F2-AS1 expression by KIAA1429. LncRNA POU6F2-AS1 then enhanced CRC cell survival, metastasis, and invasion [108].

LINC00958 is another lncRNA with reported oncogenic roles in gastric cancer. Interestingly, m⁶A methyltransferase KIAA1429 catalyzed m⁶A modification on LINC00958 loci to enhance its stability and expression. Then, LINC00958 binds to GLUT1 mRNA to increase its transcription, promoting aerobic glycolysis and tumor progression [109]. LncRNA SNHG16 also acts as an oncogenic RNA in gastric cancer. LncRNA SNHG16 inhibits miR-506-3p expression to increase polypyrimidine tract binding protein 1 (PTBP1) in cancer cells. PTBP1 then improves glucose metabolism-related enzymes, including GLUT1, HK2, and LDHA. LncRNA SNHG16 and PTBP1 upregulation were reported to elevate 5-fluorouracil resistance in cancer cells [110]. Similarly, lncRNA CCAT1 promotes gastric cancer cell growth, invasion, and metastatic abilities by regulating PTBP1. LncRNA CCAT1 increases the stability of PTBP1 by preventing its degradation through the ubiquitin/proteasome system. The stabilized PTBP1 then facilitates the transition of PKM1 to PKM2, thereby promoting glycolytic reprogramming that supports increased glucose uptake and GLUT1-associated glycolytic activity, ultimately contributing to tumor progression [111].

Vasculogenic mimicry is a new model of tumor microcirculation that contributes to tumor aggressiveness and provides the metabolic demands of cancer cells. It was reported that SOX2 positively regulates vasculogenic mimicry in CRC by targeting lncRNA AC005392.2. SOX2 binds to the promoter of the AC005392.2 gene to decrease H3K27me3 and increase its transcription. Next, AC005392.2 augments GLUT1 SUMOylation and reduces its degradation, leading to enhanced glycolysis and vasculogenic mimicry [112].

In colorectal cancer liver metastasis (CRLM), GLUT1-associated lncRNA (lncRNA GAL) was highly increased compared with CRC tissues. LncRNA GAL enhances CRC cell invasion and migration and augments the ability of the cells to metastasize to the liver. lncRNA GAL interacts with GLUT1 to enhance its stability through GLUT1 SUMOylation and inhibiting ubiquitin-proteasome system-mediated degradation of GLUT1 protein [113]. lncRNA SNHG16 is a known oncogenic lncRNA that regulates different pathways for cancer progression. In prostate cancer, lncRNA SNHG16 augments cancer cell proliferation by positively regulating GLUT1 expression [114].

In endometrial cancer, a high expression level of GLUT1 relates to a worse prognosis in patients. This study showed that GLUT1 overexpression increases tumor cell proliferation, invasion, and glycolysis and enhances paclitaxel resistance. Importantly, lncRNA TMPO-AS1 interacts with miR-140 and miR-143 to increase the expression level of GLUT1 and, subsequently, tumor progression and increased drug resistance [115]. During glucose deprivation, lncRNA NBR2 interacts with AMP-activated protein kinase (AMPK) to regulate its expression. Phenformin, an AMPK activator with anticancer function, increases lncRNA NBR2 expression and enhances therapy resistance, but knocking down the expression of lncRNA NBR2 is associated with high sensitivity of cancer cells to phenformin-mediated cancer cell death. In addition, phenformin increases GLUT1 expression and glucose intake, and this effect is inhibited after lncRNA NBR2 downregulation. Furthermore, GLUT1 suppression increases cancer cell sensitivity to phenformin-induced cell death [116]. The interaction between lncRNAs and SLC2A1 is shown in Fig. 5.

Fig. 5.

The crosstalk among lncRNAs and SLC2A1. SLC2A1 enhances tumor progression by increasing glucose import and metabolism. SLC2A1 is the direct or indirect target of many lncRNAs. M⁶A modification also plays an important role in the function of the lncRNAs/SLC2A1 axis in cancer cells

SLC2A3, SLC2A4, and SLC2A5

LINC01094 is a regulator of SLC2A3 in clear cell renal cell carcinoma (ccRCC) and promotes tumor cell growth, migration, and invasion by preventing the inhibitory effect of miR-184 on SLC2A3 [117]. Similarly, LINC00667 acts as ceRNA for miR-200b-3p to mediate SLC2A3 upregulation in esophageal cancer. LINC00667/miR-200b-3p/SLC2A3 axis ultimately promotes cancer cell proliferation, migration, and invasion [118].

In pancreatic adenocarcinoma, lncRNA SNHG16 acted as a sponge for miR-302b-3p to decrease its expression. SLC2A4 is a downstream target of miR-302b-3p, and lncRNA SNHG16 enhances SLC2A4 expression by attenuating miR-302b-3p function, which then results in increased cancer cell growth, migratory, and invasive function [119].

In the brain, metastatic tissues from lung adenocarcinoma upregulated lnc-REG3G-3-1 attenuates miR-215-3p expression to promote leptin and SLC2A5 expression. Lnc-REG3G-3-1/miR-215-3p axis, leptin, and SLC2A5 target the oncogenic signaling pathways (Vascular endothelial growth factor (VEGF), Notch, and JAK/Stat3) and genes (SRY-Box Transcription Factor 4 (SOX4), Serine/Threonine/Tyrosine Interacting Like 1 (STYXL1), and Flavin Adenine Dinucleotide Synthetase 1 (FLAD1) to promote cancer progression [120]. A summary of interactions between other lncRNAs and GLUT1 in cancer is presented in Table 2.

Table 2.

The crosstalk among lncRNAs and GLUT1 in cancer

Function	LncRNA	NcRNA expression in cancer	Cancer type	Target	Remarks	Ref
Progression	AWPPH	Upregulation	Colon cancer	GLUT1	AWPPH and GLUT1 levels were high in the serum of patients. AWPPH enhanced GLUT1 to increase cancer cell proliferation.	[121]
	Lnc-p23154	Upregulation	OSCC	miR-378a-3p/GLUT1	Lnc-p23154 binds to the miR-378a-3p promoter to suppress its function and increase GLUT1-mediated glycolysis, thereby promoting tumor cell invasion and metastasis.	[122]
	ELF3-AS1	Upregulation	OSCC	GLUT1	The ELF3-AS1/GLUT1 axis increases cancer cell proliferation.	[123]
	LINC01638	Upregulation	HCC	GLUT1	LINC01638/GLUT1 axis increases cancer cell proliferation.	[124]
	HOTAIR	Upregulation	HCC	mTOR/GLUT1	HOTAIR activates mTOR to enhance GLUT1 and glycolysis.	[125]
	MCM3AP-AS1	Upregulation	Papillary thyroid cancer	miR-218/GLUT1	MCM3AP-AS1 inhibits miR-218 to enhance GLUT1 expression and increase cancer cell proliferation.	[126]
	LINC00839	Upregulation	Neuroblastoma	miR-338-3p/GLUT1	LINC00839 inhibits miR-338-3p to increase GLUT1. LINC00839/miR-338-3p/GLUT1 axis develops cancer progression.	[127]
	LINC00346	Upregulation	Breast cancer	miR-148a/b/GLUT1	LINC00346 inhibits miR-148a/b to increase GLUT1, glycolysis, and proliferation.	[128]
Inhibition	GAS6-AS1	Downregulation	LUAD	E2F1/GLUT1	GAS6-AS1 interacts with E2F1 to prevent GLUT1 expression and glucose metabolism reprogramming.	[129]
	GASL1	Downregulation	Prostate carcinoma	GLUT1	GASL1 mediates the reduction of GLUT1 and tumor progression.	[130]
	GATA6‑AS	Downregulation	Mantle cell lymphoma	GLUT1	GATA6‑AS mediates the reduction of GLUT1 and tumor progression.	[131]
	NEF	Downregulation	NSCLC	GLUT1	NEF mediates the reduction of GLUT1 and tumor progression.	[132]
	HAND2‑AS1	Downregulation	Osteosarcoma	GLUT1	HAND2‑AS1 suppresses GLUT1 to reduce cancer cell proliferation.	[133]

Regulation of amino acid transporter SLCs by lncRNAs

SLC1A1

In the Epstein-Barr virus (EBV)-driven natural killer T cell lymphoma, LINC00486 expression is low. LINC00486 exerts a tumor suppressive function by inhibiting tumor cell growth and inducing G0/G1 cell cycle arrest. LINC00486 impairs the interaction of the NF-κB repressing factor (NKRF) and p65 to activate the NF-κB/TNF-α signaling pathway, thereby enhancing the eradication of EBV. In addition, NKRF binds to the promoter region of SLC1A1 to decrease its expression. SLC1A1 uptakes glutamine for cancer progression, and LINC00486 inhibits this function of SLC1A1. Indeed, LINC00486 mediates switching from SLC1A1-mediated glutamine addiction to NF-κB/TNF-α-induced EBV eradication to avoid tumor progression [134].

SLC1A5

LncRNA LINC00857 is an oncogenic RNA that regulates glutamine metabolism in CRC. The transcription factor heat shock factor 1 (HSF1) enriches acetyltransferase P300 to LINC00857 gene loci to promote its transcription. Thereafter, LINC00857 increases the transcription of Annexin A11 (ANXA11) in cooperation with HSF1. ANXA11 then binds to miR-122-5p to prevent the negative effect of miR-122-5p on SLC1A5, thereby enhancing glutamine metabolism and tumor progression [135].

SLC1A5 also plays a critical role in HNSCC progression. Following the inhibition of SLC1A5, cell growth was diminished, and cell cycle arrest on the G0/G1 phase was reported to be induced. Furthermore, decreased tumorigenicity and an increase in the level and function of factors involved in apoptosis, autophagy, and ferroptosis, including cleavage caspase3, LC3B, and intracellular Fe²⁺ were reported. Importantly, immune system function and oxidative stress components were disrupted after SLC1A5 was knocked down. miR-125b-5p is the upstream regulator of SLC1A5, and miR-125b-5p is also regulated by lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1). To exert its effects, NEAT1 sponges miR-125b-5p to increase SLC1A5 function and cancer progression [136].

In papillary thyroid cancer, the overexpression of lncRNA ABHD11 antisense RNA 1 (ABHD11-AS1) increases tumor progression via sponging miR-199a-5p. LncRNA ABHD11-AS1 inhibitory effect on miR-199a-5p leads to upregulation of SLC1A5, thereby promoting cancer cell proliferation, migration, and invasion, and inhibiting apoptosis [137]. Interestingly, lncRNA SYTL5-OT4 is involved in vessel co-option in patients with CRLM resistance to antiangiogenic therapies. lncRNA SYTL5-OT4 increases SLC1A5 expression by reducing its autophagic degradation. As a result, SLC1A5 enhances proliferation and EMT in increasing vessel co-option. As a promising therapeutic method, a combination of SLC1A5 inhibitors and antiangiogenic agents overcame vessel co-option-mediated antiangiogenic therapy resistance in patients with CRLM [138].

LncRNA-LET downregulation in ESCC cells and tissues is related to tumor progression. However, its upregulation disrupts tumor cell proliferation, glycolysis, and glutamine decomposition. For this to occur, lncRNA-LET negatively targets miR-106b-5p and miR-93-5p to elevate SOCS4 and decrease SLC1A5 [139].

SLC3A2

LncRNA SNHG1 is highly expressed in multiple types of cancer and possesses oncogenic functions. LncRNA SNHG1 acts in cis and trans with distinct mechanisms to promote cancer progression. By binding to the Mediator complex, lncRNA SNHG1 eases the establishment of enhancer-promoter interaction and promotes SLC3A2 expression in cis. Furthermore, lncRNA SNHG1 binds to Far upstream element-binding protein 1 (FUBP1) and inhibits the binding of FBP-interacting repressor to FUBP1 to enhance MYC expression in trans [140]. MiR-21 is an oncogenic RNA, and its expression is high in cancer cells. In Sorafenib-resistant HCC cells, sorafenib induces nuclear translocation of miR-21 to promote the expression of lncRNA SNHG1, leading to SLC3A2 upregulation and AKT pathway activation. Thereafter, apoptosis and autophagy are reduced , and proliferation is increased. Importantly, lncRNA SNHG1 depletion was shown to enhance sorafenib sensitivity and sorafenib-mediated cell death [141].

SLC7A5

LncRNA PVT1-5 is an oncogenic RNA, and its expression is increased in lung cancer. LncRNA PVT1-5 acted as a sponge for miR-126 to promote SLC7A5 expression, increasing cancer cell proliferation [142]. In CRC, LINC00857 enhances cancer cell viability, proliferation, and migration while preventing apoptosis. For this to occur, LINC00857 interacts with the RNA‑binding protein YTH domain-containing 1 (YTHDC1), leading to increased SLC7A5 mRNA stability [143]. Similarly, lncRNA MINCR is highly expressed in NSCLC tissue and cell lines and promotes SLC7A5 expression. LncRNA MINCR functions as a sponge for miR-126 to increase SLC7A5 expression, resulting in increased NSCLC cell proliferation and migration while suppressing apoptosis [144]. LncRNA OIP5-AS1 mediates the depletion of miR-152-3p expression in endometrial carcinoma to increase its downstream target, SLC7A5. Then, cancer cell proliferation, invasion, EMT, and migration are elevated [145]. The interaction between lncRNAs, SLC7A5 and SLC3A2 is shown in Fig. 6.

Fig. 6.

The crosstalk among lncRNAs, SLC7A5, and SLC3A2. These SLCs enhance tumor progression, and oncogenic lncRNAs target them directly or indirectly through miRNAs

SLC7A11

In the peritoneal dissemination of gastric cancer, the abnormal expression of lncRNA PMAN was elucidated. In these cells, hypoxia-induced HIF-1⍺ increased PMAN transcription. Then, PMAN promotes the cytoplasmic distribution of ELAVL1 to develop the stability of SLC7A11 mRNA. Overexpressed SLC7A11 increases GSH, inhibits ROS and iron accumulation, and impairs mitochondrial dysfunction [146]. LncRNA SNHG15 expression was increased in gastric cancer, and it augments tumor progression via targeting SLC7A11. Importantly, SNHG15 expression is regulated by E2F1 and MYC transcription factors. Reciprocally, SNHG15 functions as a sponge of miR-24-3p to elevate E2F1 and MYC mRNA expression. In addition, SNHG15 competitively binds to HNRNPA1 to promote the stability of SLC7A11 [147].

LncRNA SLC7A11-AS1 is derived from chromosome 4q28.31, which has an SLC7A11 cis-natural antisense transcript. LncRNA SLC7A11-AS1 is downregulated in gastric cancer, and its overexpression disrupts tumor progression. Interestingly, lncRNA SLC7A11-AS1 and SLC7A11 were negatively correlated with each other. LncRNA SLC7A11-AS1 negatively regulates the expression of SLC7A11 and activates ASK1-p38MAPK/JNK signaling to suppress tumor progression [148]. Nonetheless, another study documented that lncRNA SLC7A11-AS1 is an oncogenic factor in HCC. SLC7A11-AS1 binds to the 3′UTR region of SLC7A11 mRNA to promote its stability, thereby enhancing HCC cell growth and resistance to erastin-induced ferroptosis [149].

In cervical cancer, lncRNA FLVCR1-AS1 promotes the proliferative capacity of cancer cells, EMT, migration, and invasion while decreasing apoptosis. miR-23a-5p targets SLC7A11 to inhibit tumor progression, and lncRNA FLVCR1-AS1 inhibits miR-23a-5p expression to enhance SLC7A11 function, leading to tumor progression [150]. LncRNA HEPFAL has low expression in HCC, and when it is abundantly expressed in cancer cells, HEPFAL induces ferroptosis through a reduction in SLC7A11 expression and an increase in ROS and iron levels. LncRNA HEPFAL induces SLC7A11 ubiquitination to reduce its stability and expression. Moreover, HEPFAL sensitizes cancer cells to erastin-mediated ferroptosis by targeting the PI3K/AKT/mTOR signaling pathway [151].

LncRNA DUXAP8 is also overexpressed in HCC and prevents ferroptosis by upregulating SLC7A11. DUXAP8 helps SLC7A11 palmitoylation and hinders its lysosomal degradation to enhance SLC7A11. LncRNA DUXAP8/SLC7A11 enhances HCC progression and mediates sorafenib resistance [152]. LncRNA CASC11 decreases sorafenib-induced ferroptosis through the upregulation of SLC7A11. Moreover, CASC11 increases GSH while reducing the accumulation of ROS [153]. A recent study of liver cancer revealed a high expression level of lncRNA SNHG1. SNHG1 interacts with Staphylococcal Nuclease and Tudor Domain Containing 1 (SND1) to increase SLC7A11 expression and enhance cancer cell proliferation, invasion, sorafenib resistance, and glycolysis. Promisingly, knocking down the expression of SNHG1 sensitized cells to sorafenib [154]. LINC00942 regulates SLC7A11 to enhance cancer cell proliferation, suppress ferroptosis, and convert naive CD4 + T cells to inducible Treg, leading to immunosuppression. Importantly, LINC00942 interacts with IGF2BP3 to raise SLC7A11 mRNA stability in an m⁶A-dependent manner [155].

Intriguingly, LINC00578 blocks SLC7A11 ubiquitination via interacting with Ubiquitin Conjugating Enzyme E2 K (UBE2K) in pancreatic cancer cells. By increasing SLC7A11 expression, LINC00578 prevents ferroptosis, tumor progression, ROS generation, and mitochondrial membrane potential depolarization [156]. LncRNA OIP5-AS1 acts as a competing endogenous RNA for miR-128-3p to inhibit its expression and increase SLC7A11 for ferroptosis inhibition in prostate cancer cells under chronic cadmium exposure [157]. Furthermore, lncRNA prostate cancer-associated transcript 1 (PCAT1) is highly expressed in docetaxel-resistant prostate cancer cell lines and clinical samples. PCAT1 increases SLC7A11 by targeting c-MYC to increase SLC7A11 transcription and by negatively affecting miR-25-3p. Then, overexpressed SLC7A11 inhibits ferroptosis and reduces ferroptosis susceptibility. Importantly, PCAT1 expression could be regulated by transcription factor AP-2 gamma (TFAP2C) [158].

In human acute myeloid leukemia (AML), LINC00618 is increased following treatment with vincristine. LINC00618 induces ferroptosis by inhibiting SLC7A11 expression, ROS, and iron levels and induces apoptosis by promoting BCL2-Associated X (BAX) and caspase-3. Lymphoid-specific helicase (LSH) enhances SLC7A11 transcription by binding to its promoter region, and LINC00618 attenuates LSH for suppressing SLC7A11 [159]. ROR1-AS1 is a CAF-derived lncRNA that affects lung cancer cell progression by inhibiting ferroptosis. For this to occur, exosomal lncRNA ROR1-AS1 interacts with IGF2BP1 to increase the stability and expression of SLC7A11, thereby preventing ferroptosis in cancer cells [160]. In breast cancer, methyltransferase-like 3 (METTL3) mediates methylation of lncRNA DSCAM-AS1 and SLC7A11. Then, DSCAM-AS1 recognized m⁶A sites on the SLC7A11 to increase its mRNA stability. Through this mechanism, lncRNA DSCAM-AS1 was found to reverse erastin-mediated ferroptosis in breast cancer cells [161]. A summary of interactions between other lncRNAs and SLC7A11 is presented in Table 3.

Table 3.

The crosstalk among lncRNAs and SLC7A11

Function	LncRNA	NcRNA expression in cancer	Cancer type	Target(s)	Remarks	Ref.
Progression	SLC16A1-AS1	Upregulation	Renal cancer	miR-143-3p/SLC7A11	SLC16A1-AS1 inhibits miR-143-3p to increase SLC7A11. The SLC16A1-AS1/SLC7A11 axis enhances cancer cell viability, growth, and migration.	[162]
	T-UCR Uc.339	Upregulation	LUAD	miR-339/SLC7A11	T-UCR Uc.339 sponges miR-339 to increase SLC7A11 and promote tumor progression by regulating ferroptosis.	[163]
	NRAV	Upregulation	HCC	miR-375-3p/SLC7A11	NRAV weakens the repressive effect of miR-375-3p to increase SLC7A11 expression and reduce ferroptosis.	[164]
	BBOX1-AS1	Upregulation	ESCC	miR-513a-3p/SLC7A11	BBOX1-AS1 inhibits miR-513a-3p to increase SLC7A11 expression and enhance tumor progression by blocking ferroptosis.	[165]
	PTPRG-AS1	Upregulation	TNBC	miR-376c-3p/SLC7A11	PTPRG-AS1 inhibits miR-376c-3p to elevate SLC7A11 expression and enhance tumor progression by preventing ferroptosis. POU2F2 enhances PTPRG-AS1 transcription.	[166]
	PART1	Upregulation	HCC	miR-490-3p/SLC7A11	PART1 serves as a ceRNA for miR-490-3p to upregulate SLC7A11. PART1/miR-490-3p/SLC7A11 axis promotes tumor growth while attenuating apoptosis and erastin-mediated ferroptosis.	[167]
	XIST	Upregulation	LUAD	SLC7A11/GPX4	XIST/SLC7A11/GPX4 axis enhanced cell proliferation and inhibited ferroptosis.	[168]
	PELATON (LINC01272)	Upregulation	Glioblastoma	Mutant P53/SLC7A11	PELATON inhibits ferroptosis by mutant P53, mediating the ROS ferroptosis pathway and promoting SLC7A11.	[169]
	ITGB2-AS1	Upregulation	NSCLC	SLC7A11/GPX4	ITGB2-AS1 repressed p53-mediated ferroptosis by targeting SLC7A11. ITGB2-AS1 promotes cisplatin resistance by targeting the FOSL2/NAMPT pathway.	[170]
	LINC00942	Upregulation	HCC	IGF2BP3/SLC7A11	LINC00942 prevents ferroptosis by targeting the IGF2BP3/SLC7A11 axis.	[155]
	MEG8	Upregulation	Human hemangioma	SLC7A11/GPX4 miR-497-5p/NOTCH2	MEG8 promotes the expression of SLC7A11 to suppress ferroptosis. MEG8 decreased the miR-497-5p expression to increase NOTCH2 expression.	[171]
	ORC1	Upregulation	LUAD	SLC7A11	ORC1 increases SLC7A11 expression to reduce gefitinib-induced ferroptosis.	[172]
Inhibition	As-SLC7A11	Downregulation	Epithelial ovarian cancer	SLC7A11	As-SLC7A11 inhibits SLC7A11 expression and tumor cell migration.	[173]

SLC38A1 and SLC38A2

SLC38A1, also known as sodium-coupled neutral amino acid transporter 1 (SNAT1), is highly expressed in lung cancer, and its expression could be regulated by lncRNA opioid growth factor receptor pseudogene 1 (OGFRP1). MiR-299-3p inhibits SLC38A1 to prevent tumor progression, but lncRNA OGFRP1 reverses this effect and mediates SLC38A1 overexpression via inhibiting miR-299-3p. lncRNA OGFRP1 upregulation augments cancer cell proliferation, while its knockdown suppresses tumor progression and induces ferroptosis via promoting lipid peroxidation and iron accumulation in lung cancer cells [174]. LncRNA NEAT1 is also an upstream regulator of SLC38A1. NEAT1 acts as a sponge for miR-138 to increase SLC38A1 expression, thereby promoting CRC cell growth and invasion and inhibiting cell apoptosis and autophagy processes [175]. In addition, LINC01559 competitively interacts with miR-511 to decrease its negative effect on SLC38A1, thereby increasing the expression level of SLC38A1 in HCC cells. LINC01559/miR-511/SLC38A1 axis then resulted in high cell viability, invasion, and migration [176]. LINC01614, an exosomal lncRNA derived from cancer-associated fibroblasts (CAFs), regulates glutamine uptake and metabolism in lung adenocarcinoma (LUAD) cells by targeting SLC38A2. LINC01614 interacts with ANXA2 and p65 to activate NF-κB, leading to the upregulation of SLC38A2 and SLC7A5. Furthermore, tumor-derived proinflammatory cytokines affect CAFs to further express LINC01614 in a reciprocal loop [177]. A summary of the crosstalk between lncRNAs, SLC38A1 and SLC38A2 in cancer is provided in Fig. 7.

Fig. 7.

The crosstalk among lncRNAs, SLC38A1, and SLC38A2. These SLCs’ function in cancer cells increases tumor cell growth. The inhibitory function of miRNAs on these SLCs could be attenuated by lncRNAs. Exosomal lncRNAs derived from cells in TME also accelerate tumor cell growth. For instance, CAFs-derived exosomes carry LINC01614, which targets SLC38A2 to enhance tumor progression

circRNAs regulation of glucose and amino acid transporters

Regulation of glucose transporter SLCs by circRNAs

SLC2A1 (GLUT1)

ZNF609 is a circRNA with an oncogenic function in glioma. Its overexpression enhanced glioma cell proliferation, viability, EMT, invasion, and migration. The suppression of ZNF609 augments E-cadherin levels and decreases vimentin in cancer cells, inhibiting EMT. Moreover, ZNF609 regulates glucose metabolism by sponging miR-378b to increase SLC2A1 expression, elevating glucose uptake, lactate, and ATP production [178]. CircHECTD1 also acts as an oncogene in glioblastoma. CircHECTD1 functions as ceRNA to inhibit miR-320-5p expression, resulting in SLC2A1 overexpression. This axis ultimately increases tumor cell proliferation and migration [179]. Likewise, circ_0001955 negatively regulates miR-1299 expression to augment GLUT1 expression in breast cancer, leading to increased glucose uptake and consumption, and lactate and ATP production. Circ_0001955/miR-1299/GLUT1 axis ultimately enhances cancer cell proliferation, migration, invasion, and angiogenesis [180]. Similarly, Circ_0058063 supports glucose uptake and tumor cell proliferation by upregulating GLUT1 expression in ESCC cells [181]. Furthermore, circRNA_100290 promotes OSCC cell proliferation and glycolysis by targeting GLUT1. circRNA_100290 relieves the inhibitory effect of miR-378a on GLUT1, thereby enhancing glucose metabolism and tumor progression [182]. In addition, circARHGAP10 is carried by exosomes extracted from the sera of NSCLC patients. In a pathway different from what was mentioned in the previous study, circARHGAP10 serves as a sponge of miR-638 to increase Family With Sequence Similarity 83 Member F (FAM83F) expression, and FAM83F then attenuates the inhibitory effect of miR-638 on GLUT1 [183].

Importantly, hsa_circ_0002130 was highly expressed in the sera of NSCLC patients, and it improves tumor progression. hsa_circ_0002130 sponges miR-498 to enhance GLUT1, HK2, and LDHA expression in osimertinib-resistant cancer cells, followed by glycolysis and tumor progression [184]. Interestingly, Cui et al. reported that m⁶A-modified circFOXK2 (hsa_circ_0000816), originating from the FOXK2 gene, has oncogenic functions in OSCC. In addition, circFOXK2 interacts with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to enhance the GLUT1 mRNA stability. CircFOXK2/GLUT1 axis function then leads to increased glycolysis, tumor progression, and malignant phenotypes of OSCC cells [185]. In breast cancer, circRBM33 decreases miR-542-3p expression to increase GLUT1 and hypoxia-mediated glycolysis while decreasing apoptosis. Indeed, miR-542-3p inhibits HIF-1α to block glycolysis, and HIF-1α upregulation reverses the negative regulatory effect of miR-542-3p on glycolysis and tumor progression [186]. The crosstalk between other oncogenic circRNAs and GLUT1 is listed in Table 4.

Table 4.

The crosstalk among oncogenic circRNAs and GLUT1

CircRNA	NcRNA expression in cancer	Cancer type	Target(s)	Remarks	Ref.
CircTUBGCP5	Upregulation	Liver cancer	miR-144-3p/ACSL4	CircTUBGCP5 suppresses miR-144-3p to increase ACSL4 and GLUT1. CircTUBGCP5 promotes tumor cell proliferation and glycolysis by targeting both GLUT1 and c-MYC.	[190]
Circ_0000376	Upregulation	NSCLC	miR-1182/NOVA2	Circ_0000376 reduced miR-1182 expression to increase NOVA2, and NOVA2 prevents the inhibitory effect of miR-1182 on GLUT1-mediated glycolysis.	[191]
CircPUM1	Upregulation	NSCLC	miR-590-5p/METTL3	CircPUM1 mediates the sequestration of miR-590-5p to increase METTL3. miR-590-5p inhibits circPUM1 function by suppressing METTL3. miR-590-5p inhibits GLUT1-mediated glycolysis.	[192]
Circ_0000376	Upregulation	Gastric cancer	miR-145-5p/GLUT1	Circ_0000376 inhibits miR-145-5p to augment GLUT1 expression and promote glycolysis. Bupivacaine prevents circ_0000376-mediated tumor progression and glycolysis.	[193]
CircHIF1A	Upregulation	Metastatic CRC	miR-361-5p/HIF1A/GLUT1	CircHIF1A suppresses miR-361-5p to upregulate HIF1A, and then HIF1A increases GLUT1 expression. CircHIF1A induces cetuximab resistance by promoting HIF1α-mediated glycometabolism.	[194]
Circ_0047921	Upregulation	Lung cancer	miR-1287-5p/GLUT1	Circ_0047921 mediates miR-1287-5p downregulation to increase GLUT1, thereby enhancing tumor cell proliferation, migration, and invasion.	[195]
CircC6orf132	Upregulation	Gastric cancer	miR-873-5p/PRKAA1/GLUT1	CircC6orf132 blocks the inhibitory effect of miR-873-5p on PRKAA1, and then PRKAA1 increases GLUT1. CircC6orf132 promotes hypoxia-induced cancer cell proliferation, migration, and invasion.	[196]
CircYIPF6	Upregulation	Glioma	miR-760/PTBP1	CircYIPF6 decreases Bax and increases Bcl-2 and GLUT1 by sponging miR-760. PTBP1 is suppressed by miR-76, and circYIPF6 promotes its expression.	[197]
Hsa_circ_0,019,054	Upregulation	Intrahepatic cholangiocarcinoma	miR-340–5 p/HIF1A	Hsa_circ_0,019,054 sponges miR-340–5 p to increase HIF1A and GLUT1-mediated glycolysis and tumor progression.	[198]

In addition to these circRNAs, there are others with tumor suppressor function. For instance, circRNA ITCH inhibits GLUT1 expression and glucose uptake in melanoma to suppress tumor cell proliferation [187]. Circ_0004913 also diminishes tumor progression by targeting GLUT1 in HCC. Circ_0004913 acts as a molecular sponge for miR-184, thereby reducing miR-184 availability. MiR-184 directly targets HAMP, a gene encoding hepcidin. By sequestering miR-184, circ_0004913 restores HAMP expression, and the circ_0004913/miR-184/HAMP axis modulates the JAK2/STAT3/AKT signaling pathway, further contributing to the suppression of tumor proliferation, metastasis, and glycolysis. Notably, circ_0004913 overexpression is associated with reduced expression of glycolysis-related proteins, including GLUT1, HK2, and LDHA, highlighting its role in metabolic reprogramming [188]. CircRNF13 expression is low in nasopharyngeal carcinoma, and increasing its level in cancer cells is associated with tumor suppression. CircRNF13 binds to the 3′-UTR of the SUMO2 gene to increase its mRNA stability. SUMO2 then mediates the degradation of GLUT1 through its SUMOylation and ubiquitination. In nasopharyngeal cancer cells, GLUT1-induced glycolysis leads to the activation of the AMPK/mTOR pathway and enhances tumor cell proliferation and metastasis. Promisingly, circRNF13/SUMO2 reduces glycolysis-mediated tumor progression by inhibition of GLUT1 [189].

SLC2A3 (GLUT3), SLC5A1, and SLC5A7

In NSCLC cells, the overexpression of circMYLK is associated with poor prognosis, malignant phenotypes, and worse clinicopathological characteristics. CircMYLK promotes cancer cell proliferation, migration, and invasion by positively regulating GLUT3. For this purpose, circMYLK acts as a sponge for miR-195-5p to counteract miR-195-5p-mediated GLUT3 suppression [199].

Circ_0003028 is highly expressed in NSCLC, and its expression is linked to tumor progression. Circ_0003028 negatively affects miR-1305 and miR-1322 to enhance SLC5A1 expression, thereby improving cancer cell proliferation and glycolytic capacity [200].

CircFBXW4 regulates CRC progression by targeting SLC5A7. Thus, circFBXW4 acts as ceRNA for miR-338-5p and prevents suppression of its downstream target SLC5A7 [201].

Regulation of amino acid transporter SLCs by miRNAs

SLC1A5

Circ-LDLRAD3 increased SLC1A5 expression by sponging miR-137 in NSCLC, thereby enhancing cancer cell proliferation and invasion [202]. Circular RNA 3-oxoacid CoA-transferase 1 (circ-OXCT1) is also upregulated in lung cancer and promotes tumor cell growth by targeting SLC1A5. For this purpose, circ-OXCT1 binds to miR-516b-5p to inhibit its negative effect on SLC1A5, followed by increased cancer proliferation, migration, and invasion, and decreased apoptosis [203]. Similarly, circRNA septin 9 (circSEPT9) exerts an oncogenic function in breast cancer by augmenting SLC1A5 expression. CircSEPT9 mediates the upregulation of SLC1A5 by sponging miR-149-5p, thereby increasing glutamine uptake and cell proliferation [204]. Circ-SFMBT2 sponges miR-107 to trigger SLC1A5 expression in esophageal cancer. By activating SLC1A5, circ-SFMBT2 promotes glutamine metabolism to enhance cancer cell proliferation and invasion [205]. Circ_0000808 expression in NSCLC is related to cancer cell proliferation, migration, and invasion. For this purpose, miR-1827 is downregulated, and it is sequestrated by circ_0000808, leading to the elevation of its downstream target, SLC1A5 [206]. Similarly, circ_0025033 sponges hsa_miR-370-3p to increase SLC1A5 expression in ovarian cancer. This activation ultimately leads to cancer cell proliferation, invasion, and angiogenesis [207]. In esophageal cancer, circ_0001273 mediates miR-622 downregulation to increase SLC1A5 expression. Activated SLC1A5 can then increase cancer cell proliferation, migration, EMT, and glutamine metabolism [208]. Circ_0062558 also elevated TNBC cell proliferation, migration, invasion, and glutamine metabolism. Circ_0062558 inhibits miR-876-3p to disrupt its negative regulatory effect on SLC1A5 [209]. In ovarian cancer, circ_0072995 attenuates the repressive effect of miR-122-5p on SLC1A5 to enhance tumor progression. In addition, cancer cell proliferation, migration, and invasion are enhanced following SLC1A5 activation [210]. Circ_0000518 functioned as a sponge for miR-330-3p to upregulate SLC1A5 expression in NSCLC, thereby enhancing cancer cell proliferation, invasion, and glutamine metabolism [211]. Circ_0000463 expression is also increased in NSCLC and exerts oncogenic function. It improves cancer cell proliferation, migration, and invasion by inhibiting miR-924 function and increasing SLC1A5 expression [212].

SLC7A5

Circ-FAM158A sponges miR-138–5p to modulate SLC7A5 expression in retinoblastoma. Circ-FAM158A augments cancer cell proliferation and metastasis while inhibiting apoptosis [213]. CircARID1A served as a scaffold to enable the interaction between IGF2BP3 and SLC7A5 mRNA to increase SLC7A5 stability in gastric cancer. CircARID1A binds to IGF2BP3 and SLC7A5 to form a ternary complex that promotes the proliferation of gastric cancer by regulating the AKT/mTOR pathway [214]. CircFAM192A is also overexpressed in gastric cancer. FTO increased the stability of circFAM192A and prevented its degradation by removing the m⁶A modification sites on circFAM192A. The stabilized circFAM192A binds to SLC7A5 to increase leucine uptake, mTOR activation, and cancer cell proliferation. In the absence of FTO, YTHDF2, which is an m⁶A reader, detects the m⁶A sites and mediates circFAM192A degradation, followed by tumor suppression [215]. The crosstalk between circRNAs, SLC1A5 and SLC7A5 in cancer is shown in Fig. 8.

Fig. 8.

The crosstalk among circRNAs, SLC1A5, and SLC7A5

SLC7A11

CircST6GALNAC6 is a molecule with a tumor suppressor function in bladder cancer, and its expression is depleted in cancer cells. CircST6GALNAC6 binds to the N-terminus region of the small heat shock protein 1 (HSPB1) to inhibit the erastin-induced phosphorylation of HSPB1 at its Ser-15 site, leading to HSPB1 suppression. CircST6GALNAC6 induces ferroptosis by inhibiting HSPB1, activating the p38/MAPK signaling pathway, and inhibiting the function of SLC7A11 transporter and GPX4 enzyme [216]. CircTMEM87A and SLC7A11 are upregulated in gastric cancer, whereas miR-1276 is decreased. A study has shown that circTMEM87A acts as a sponge for miR-1276 to increase SLC7A11 expression. The circTMEM87A/miR-1276/SLC7A11 axis enhances cancer cell proliferation and migration while inhibiting apoptosis and ferroptosis [217]. In addition, circPDE3B sponged miR-516b-5p to upregulate the expression level of cystathionine β-synthase, a negative regulator of ferroptosis. Moreover, circPDE3B interacts with Heterogeneous nuclear ribonucleoprotein K (HNRNPK) to enhance the stability of SLC7A11. Through these mechanisms, circPDE3B suppresses miR-516b-5p-mediated ferroptosis in ESCC, leading to cancer progression [218].

The overexpression of circFAT1 also improves tumor progression by targeting SLC7A11. CircFAT1 positively regulates the expression level of SLC7A11 by acting as a sponge for miR-375, thereby inhibiting ferroptosis. In addition, the circFAT1/miR-375/SLC7A11 axis ultimately promotes cancer cell proliferation, invasion, and colony formation of malignant melanoma cells [219]. In glioma, circCDK14 increases malignancy, tumor cell proliferation, migration, and invasion via targeting the miR-3938/PDGFRA axis. For this purpose, circCDK14 sponged miR-3938 to upregulate PDGFRA gene expression. CircCDK14 also attenuates the sensitivity of glioma cells to erastin-induced ferroptosis by increasing SLC7A11 and GPX4 through the miR-3938/PDGFRA axis. Moreover, circCDK14 increases Zinc finger E-box-binding homeobox 1 (ZEB1) and Vimentin while decreasing E-cadherin expression to enhance EMT [220]. Exosomes carrying circUPF2 were found to enhance sorafenib resistance in HCC cells. CircUPF2 acts as a scaffold that enhances the formation of a ternary complex with IGF2BP2 and SLC7A11 mRNA, stabilizing its transcripts. Increased SLC7A11 expression then reduces sensitivity to ferroptosis, a form of regulated cell death important for sorafenib effectiveness [221].

Interestingly, dexmedetomidine, which is an anesthetic, exerted a tumor suppressor function by blocking the inhibitory effect of circ0008035 on ferroptosis-induced cell death in gastric cancer. Circ0008035 sponges miR-302a to increase the expression of E2F2 and then the elevation of SLC7A11 and GPX4 expression. Dexmedetomidine negatively regulates circ0008035 to decrease E2F2, SLC7A11, and GPX4 and increase ferroptosis [222]. The interactions between other oncogenic circRNAs and SLC7A11 are listed in Table 5.

Table 5.

The crosstalk between oncogenic circRNAs and SLC7A11

CircRNA	NcRNA expression in cancer	Cancer type	Target(s)	Remarks	Ref.
CircSTIL	Upregulation	CRC	miR-431/SLC7A11	CircSTIL sponges miR-431 to increase SLC7A11 and reduce ferroptosis.	[223]
CircEPSTI1	Upregulation	Cervical cancer	miR-375, miR-409-3P and miR-515-5p/SLC7A11	CircEPSTI1 is a miRNA sponge of miR-375, miR-409-3P, and miR-515-5p to enhance SLC7A11 expression. CircEPSTI1 inhibits ferroptosis and increases cancer cell proliferation.	[224]
CircEIF6	Upregulation	Pancreatic cancer	miR-557/SLC7A11/PI3K/AKT	CircEIF6 serves as a sponge of miR-557 to increase SLC7A11 expression and PI3K/AKT signaling pathway.	[225]
Circ_0067934	Upregulation	Thyroid cancer	miR-545-3p/SLC7A11	Circ_0067934 prevents the inhibitory effect of miR-545-3p on SLC7A11 expression.	[226]
CircPVT1	Upregulation	OSCC	miR-143-3p/SLC7A11/MAPK	CircPVT1 enhances cancer growth by sponging miR-143-3p, increasing SLC7A11, and activating the MAPK signaling pathway.	[227]
CircRPPH1	Upregulation	Gastric cancer	miR-375/SLC7A11	CircRPPH1 promotes stemness and suppresses ferroptosis by targeting the miR-375/SLC7A11 axis.	[228]
Circ-BGN	Upregulation	Breast cancer	OTUB1/SLC7A11	Circ-BGN enhances OTUB1 expression to reduces SLC7A11 degradation, thereby inhibiting ferroptosis and mediating trastuzumab resistance.	[229]
Circ_0000140	Upregulation	OSCC	miR-527/SLC7A11	Circ_0000140 prevents ferroptosis-induced cell death by targeting the miR-527/SLC7A11 axis.	[230]
CircP4HB	Upregulation	LUAD	miR-1184/SLC7A11	CircP4HB inhibits ferroptosis-induced cell death by targeting the miR-1184/SLC7A11 axis.	[231]
CircPDSS1 (hsa_circ_0017998)	Upregulation	NSCLC	miR-137/SLC7A11/GPX4/GCLC	CircPDSS1 suppresses ferroptosis-induced cell death by blocking the negative effect of miR-137 on SLC7A11 expression.	[232]
CircCOL5A1	Upregulation	CRC	miR-1287-5p/SLC7A11	CircCOL5A1 overexpression is associated with TNM stage, lymph node metastasis, distant metastasis, and tumor differentiation. CircCOL5A1 targets the miR-1287-5p/SLC7A11 axis to enhance cell proliferation and invasion while reducing ferroptosis.	[233]
CircKIF4A (hsa_circ_0007255)	Upregulation	Osteosarcoma	miR-515-5p/SLC7A11	CircKIF4A enhances tumor cell growth and metastasis by upregulating SLC7A11 through inhibiting miR-515-5p.	[234]
CircFNDC3B	Upregulation	OSCC	miR-520d-5p/SLC7A11/GPX4	CircFNDC3B counteracts the negative effect of miR-520d-5p on SLC7A11 expression to inhibit ferroptosis.	[235]
Circ-CDK8	Upregulation	OSCC	miR-615-5p/SLC7A11	Circ-CDK8 mediates the downregulation of miR-615-5p to increase SLC7A11 and impair erastin-induced ferroptosis.	[236]
CircCDR1as	Upregulation	OSCC	miR-876-5p/SLC7A11	The upregulation of circCDR1as enhances autophagy, cancer cell cycle progression, and metastatic capacity by inhibiting miR-876-5p and increasing SLC7A11.	[237]
Circ_0120175	Upregulation	Laryngeal squamous cell carcinoma	miR-330-3p/SLC7A11	Circ_0120175 overexpression is accompanied by advanced tumor staging, lymph node metastasis, and low overall survival. Circ_0120175 targets the miR-330-3p/SLC7A11 axis to enhance cancer progression.	[238]
Hsa_circ_0018189	Upregulation	NSCLC	miR-656-3p/SLC7A11	Hsa_circ_0018189 improves cancer cell growth and glutamine metabolism by attenuating miR-656-3p and increasing SLC7A11 expression.	[239]

SLC38A1 and SLC38A2

CircRUNX1 is upregulated in CRC and enhances tumor cell colony formation, migration, invasion, and glutaminolysis by targeting the miR-485-5p/SLC38A1 axis [240]. Circ_0003602 is also an upstream regulator of SLC38A1 and augments its expression in CRC cells. However, miR-149-5p suppresses SLC38A1 to reduce cancer progression. miR-149-5p downregulation by Circ_0003602 increases the level of SLC38A1, accompanied by cancer cell viability, migration, invasion, angiogenesis, and glutaminolysis [241]. In contrast, circTADA2A (hsa_circ_0043278) is significantly downregulated in melanoma, and it reverses tumor cell proliferation, migration, and invasion. CircTADA2A binds to CNBP to block the interaction of CNBP and SLC38A1, limiting SLC38A1 transcription [242]. Hsa_circRNA_001859 is downregulated in pancreatic cancer and acts as a tumor suppressor factor by inhibiting EMT. For this purpose, hsa_circRNA_001859 attenuates miR-21-5p expression to increase SLC38A2. MiR-21-5p directly binds to SLC38A2 to reduce its level in cancer cells. However, hsa_circRNA_001859 disrupts this effect to suppress cancer progression [243](Fig. 9).

Fig. 9.

The crosstalk among circRNAs and SLC7A11, SLC38A1, and SLC38A2. CircRNAs affect SLCs’ function mainly by targeting their upstream regulator miRNAs. CircRNAs may have oncogenic or tumor suppressor functions. Has-circRNA-001859 suppresses tumor progression by targeting the miR-21-5p/SLC38A2 axis

Conclusion and perspectives

The complex interplay between SLC transporters and ncRNAs plays an important role in regulating glucose and amino acid transport by cells, influencing cancer cell metabolism, proliferation, and therapy resistance. This review highlights the mechanisms by which miRNAs, lncRNAs, and circRNAs regulate the expression and function of amino acid and glucose transporters within the SLC family.

SLC transporters are involved in various physiological processes. For example, SLCs that transport amino acids are vital for protein synthesis. Glucose transporters, another subgroup of SLC proteins, facilitate the uptake of glucose into cells, which is essential for energy production. Dysregulation of SLC transporters is associated with different diseases, including cancer, underscoring their importance in health and disease. SLC proteins exhibit tissue-specific expression patterns and mechanisms of action. Thus, understanding the intricate regulation of SLC transporters, including their regulation by ncRNAs, can provide critical insights into therapeutic interventions targeting diseases associated with the dysfunction of these transporters.

From a translational research perspective, the deeper exploration of ncRNA-SLC regulatory networks could pave the way for novel therapeutic strategies. For instance, restoring tumor-suppressive ncRNAs or silencing oncogenic ncRNAs could selectively modulate SLC transporter activity, disrupting cancer metabolism and enhancing drug sensitivity. In particular, targeting these regulatory networks may offer new therapeutic strategies, including the use of miRNA mimics and ncRNA-based inhibitors to disrupt cancer metabolic pathways [244]. Recent advances in RNA-based therapeutics, including antisense oligonucleotides (ASOs) [245] and small interfering RNAs (siRNAs) [246] have shown promise in selectively targeting SLC transporters in preclinical disease models. These methods could also be applied to study ncRNA-SLC regulatory networks in cancer.

Targeting ncRNAs in combination with metabolic inhibitors or chemotherapeutic agents could be another approach. Moreover, many ncRNA-SLC interactions influence ferroptosis [247–249], and exploring ferroptosis-inducing therapies by targeting oncogenic ncRNAs that regulate SLC7A11 could offer promising anticancer strategies.

Despite the new avenues that opened in cancer research by studying ncRNAs-SLC interactions, several limitations remain in this field that can be addressed in future studies. First, ncRNAs operate within highly complex regulatory networks, interacting with multiple targets and pathways simultaneously. Many ncRNAs exhibit context-dependent roles, acting as tumor suppressors or oncogenes. These complicate the identification of specific ncRNA-SLC interactions that could be broadly targeted for therapy. Second, despite the large number of in vitro studies on ncRNA-SLC interactions, in vivo validation remains unexplored. The predominance of correlative evidence, together with the lack of in vivo and mechanistic studies, represents a major limitation of current research in this area. The lack of well-established animal models for studying these interactions also poses a significant limitation. Third, it is often challenging to determine whether an ncRNA directly regulates an SLC transporter or if the effect is indirect through upstream signaling cascades. Clinical studies aimed at validating these targets and exploring their efficacy are essential for addressing research gaps.

While this review focuses on the role of ncRNAs in regulating SLC transporters in cancer, these regulatory interactions have significant implications for other diseases and biological processes. Given the essential role of SLC proteins in cellular homeostasis and metabolic balance, ncRNA-mediated modulation of SLCs could influence a wide range of physiological and pathological conditions.

Abbreviations

ABHD11-AS1

ABHD11 antisense RNA 1

ACSL4

Acyl-CoA synthetase long chain family member 4

ADAR

Adenosine deaminase acting on double-stranded RNA

AML

Acute myeloid leukemia

AMPK

AMP-activated protein kinase

ANXA11

Annexin A11

ASOs

antisense oligonucleotides

ASS1

Argininosuccinate synthase

ATM

Ataxia-telangiectasia-mutated proteins

ATR

Ataxia telangiectasia and Rad3-related

BAX

BCL2-Associated X

CAB39

Calcium-binding protein

CAFs

Cancer-associated fibroblasts

ccRCC

Clear cell renal cell carcinoma

circ-OXCT1

Circular RNA 3-oxoacid CoA-transferase 1

circRNAs

Circular RNAs

circSEPT9

CircRNA septin 9

CRC

Colorectal cancer

CRLM

Colorectal cancer liver metastasis

CSC

Cancer stem cell

DHA

Dehydroascorbic acid

DNMTs

DNA methyltransferases

EBV

Epstein-Barr virus

EMT

Epithelial-to-mesenchymal transition

ESCC

Esophageal squamous cell carcinoma

EZH2

Enhancer of zeste homolog 2

FAM83F

Family with sequence similarity 83 member F

FLAD1

Flavin adenine dinucleotide synthetase 1

FTO

Fat mass and obesity-associated protein

FUBP1

Far upstream element-binding protein 1

GLUT

Glucose transporter

GSH

Glutathione

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

HDAC2

Histone deacetylase 2

HK2

Hexokinase 2

HMGCS2

3-hydroxy-3-methylglutaryl-CoA synthase 2

HNRNPK

Heterogeneous nuclear ribonucleoprotein K

HNSCC

Head and neck squamous cell carcinomas

HPV

Human Papillomavirus

HSF1

Heat shock factor 1

HSPB1

N-terminus region of the small heat shock protein 1

IGF2BP3

Insulin-like growth factor 2 mRNA-binding protein 3

LDHA

Lactate dehydrogenase A

lncRNA GAL

GLUT1-associated lncRNA

LncRNAs

long non-coding RNAs

LSH

Lymphoid-specific helicase

LUAD

Lung adenocarcinoma

m⁶A

N6-methyladenosine

MAPK

Mitogen-activated protein kinase

MeCP2

Methyl-CpG-binding protein 2

METTL3

Methyltransferase-like 3

miRNAs

microRNAs

ncRNAs

non-coding RNAs

NEAT1

Nuclear Enriched Abundant Transcript 1

NF-κB

Nuclear factor kappaB

NKRF

NF-κB repressing factor

NSCLC

Non-small cell lung cancer

OGFRP1

Opioid growth factor receptor pseudogene 1

OSCC

Oral squamous cell carcinoma

OTUB1

OTU Deubiquitinase, Ubiquitin Aldehyde Binding 1

PCAT1

Prostate cancer-associated transcript 1

PI3K

Phosphoinositide 3-kinase

PIK3R1

Phosphoinositide-3-kinase regulatory subunit alpha

PKM2

Pyruvate kinase M2

pOEI

Polyethyleneimine

PTBP1

Polypyrimidine tract binding protein 1

ROS

Reactive oxygen species

siRNAs

small interfering RNAs

SIX

Sine oculis homeobox

SLC

Solute carrier

SND1

Staphylococcal Nuclease And Tudor Domain Containing 1

SOX4

SRY-Box Transcription Factor 4

STYXL1

Serine/Threonine/Tyrosine Interacting Like 1

TFAP2C

Transcription factor AP-2 gamma

TGF-β

Transforming growth factor beta

Tiam1

T lymphoma invasion and metastasis 1

TNBC

Triple-negative breast cancer

UBE2K

Ubiquitin Conjugating Enzyme E2 K

VEGF

Vascular endothelial growth factor

YTHDC1

RNA‑binding protein YTH domain-containing 1

YTHDF2

YTH N6-methyladenosine RNA binding protein 2

ZEB1

Zinc finger E-box-binding homeobox 1

γH2AX

H2A histone family member X

Author contributions

KH: Writing – review & editing, Writing – original draft, Investigation, Conceptualization, Supervision. NF, HA, MA, AAIF: Writing – original draft, Investigation, Visualization. RJR: Writing – original draft. WCC, LL: Investigation, Writing – review & editing. SS: Visualization, Writing – review & editing, Supervision. LL, GS: Supervision, Writing – review & editing.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.