Aerobic glycolysis serves as a prominent example of a reprogrammed metabolic pathway in cancer cells. Tumor cells uptake glucose in large quantities, which is converted to pyruvate by enzymes such as hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK). Pyruvate is subsequently converted to lactic acid by lactate dehydrogenase A (LDHA) or transported to the mitochondria, where it is catalyzed by pyruvate dehydrogenase (PDH) to form acetyl-CoA (9).

Glycolysis contributes to drug resistance through multiple mechanism. Glycolysis provides cancer cells with sufficient energy to maintain malignancy (6). 3-bromopyruvate is a glycolysis inhibitor that markedly decreases glycolytic activity by inhibiting the enzyme HK2. This inhibition impairs the energy supply derived from glycolysis, leading to a decrease in ATP and glutathione (GSH) levels in tumor cells, thereby enhancing their sensitivity to chloroethylnitrosoureas, a bifunctional anti-tumor alkylating agent (29). In drug-resistant cancer cells, the PI3K/AKT signaling pathway is activated, which regulates glycolysis (30), causing higher ATP levels than in drug-sensitive cells (31,32). This process provides the necessary energy for ABC transporters to facilitate drug efflux (33). Chondroitin sulfate disrupts mitochondrial electron transport and glycolysis to deplete ATP. This energy depletion impairs P-glycoprotein (P-gp) activity, thereby decreasing doxorubicin efflux (34).

Numerous glycolysis enzymes are associated with cell death. For example, HK2 translocates to mitochondria where it inhibits mitochondrial permeability transition pores to block cytochrome c/Bax release, enhancing tumor cell survival (35). Mitochondrial PKM2 binds BCL2 to suppress reactive oxygen species (ROS)-mediated apoptosis (36). Additionally, fructose-1,6-diphosphate aldolase delays drug-induced apoptosis by decreasing caspase-3 activity through catalytic product accumulation (37). Furthermore, PDH kinase 3 (PDK3) overexpression promotes lycorine hydrochloride resistance in glioblastoma cells via apoptosis inhibition (38). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) activates cyclin-dependent kinases (CDKs), leading to the phosphorylation of p27, a potent inhibitor of G1/S transformation and activator of apoptosis (39). PFKFB3 also regulates angiogenesis through vascular endothelial growth factor (VEGF)-mediated endothelial morphogenesis and Notch signaling suppression (40). The morphology of tumor blood vessels is irregular. This leads to localized nutritional and oxygen deficiency, which in turn promote tumor metastasis (41). Combining anti-angiogenic therapies that target PFKFB3 reverses the abnormal changes in tumor blood vessels, improving the delivery of chemotherapy drugs (41).

The Warburg effect results in the accumulation of lactic acid, which dilates blood vessels and stimulates angiogenesis to enhance local energy supply through an increase in oxygen and nutrients (42). Excessive lactic acid also decreases the pH around tumor cells, creating a pH gradient both inside and outside the cells (43). Weakly basic drugs dissociate in the acidic extracellular environment, hindering their passage through the cell membrane or sequestering them in acidic lysosomal vesicles (43,44), rendering them ineffective. Conversely, weakly acidic drugs enter cells but are often inactivated before reaching their target due to the alkaline intracellular conditions (45). Furthermore, extracellular acidosis promotes drug efflux via P-gp (46), multidrug resistance-related protein 1 (MRP1) (47) and intracellular acidic vesicles (48), further contributing to chemotherapy resistance. Elevated lactate levels serve as agonists for the G protein-coupled receptor GPR81, which is expressed on immune cells. Activation of GPR81 decreases the release of pro-inflammatory cytokines from T cells and may impair the function of natural killer cells, partially through recruitment of monocyte-derived dendritic cells (49). Monocarboxylate transporter-1-mediated lactate transport is essential for maintaining intracellular pH in cancer cells, a process that supports the stem cell properties of pancreatic adenocarcinoma and glioblastoma stem cells (50,51). Additionally, when several key enzymes, such as HK2, PFKFB3 and PKM2, are abnormally elevated, the Wnt/β-catenin, Erk1/2 and YAP/Hippo signaling pathways become activated (52-54). These pathways are recognized as key regulators that promote resistance to anti-cancer drugs.

GLUT is a high-affinity membrane protein responsible for glucose uptake into the cytoplasm. In cancer cells, GLUT1 is often overexpressed, facilitating enhanced glucose uptake to meet the energy demands required for aerobic glycolysis (62). A recent study (65) indicated that elevated GLUT1 expression in endometrial cancer (EC) is associated with increased cell proliferation and invasion and glycolysis. Moreover, GLUT1 overexpression promotes the expression of MMP1, MMP14 and Cyclin D1 in EC cells (66). Dual-luciferase assays confirmed GLUT1 as a direct target of miR-140 and miR-143, which suppress EC cell proliferation and glycolysis by inhibiting GLUT1 expression, thereby enhancing sensitivity to Paclitaxel (PTX) (66). Additionally, circRNA-0002130, secreted in serum exosomes of patients with non-small cell lung cancer (NSCLC), promotes glycolysis and exacerbates resistance to osimertinib. Mechanistically, circRNA-0002130 serves as a sponge for miR-498, which targets GLUT1, thereby indirectly upregulating GLUT1 expression in NSCLC cells (67). Furthermore, miR-1291-5p and miR-218 serve as direct regulators of GLUT1, counteracting cisplatin resistance in pancreatic and bladder cancer cells (68,69).

HKs, located in the cytoplasm, are the primary rate-limiting enzymes in glycolysis. HKs catalyzes the phosphorylation of glucose to form glucose-6-phosphate, representing the initial step in the glycolytic pathway (70). HK2, in particular, is overexpressed in numerous types of cancer and is associated with resistance to chemotherapy (34). A study demonstrated that HK2 can enhance cisplatin-induced phosphorylation of ERK1/2, thereby promoting cellular autophagy induced by cisplatin (52). miRNAs can directly target the 3′ untranslated region (UTR) of HK2 to suppress its expression, including miR-708-5p, miR-202, miR-125b-5p and miR-216b-5p (71-74). These miRNAs inhibit glycolysis by downregulating HK2 expression. However, in cancer cells, these miRNAs may be suppressed by upstream lncRNAs, contributing to drug resistance (71-74), along with increased glucose uptake and lactate secretion (74,75). For example, lncRNA-UCA1, functioning as an oncogene in both solid and hematological tumors, is associated with decreased drug sensitivity. Overexpression of UCA1 promotes glycolysis by upregulating HK2, and UCA1 can indirectly regulate HK2 by sponging miR-125a, thereby promoting drug resistance (76). Inhibiting UCA1 enhances the sensitivity of cancer cells to chemotherapy drugs such as PTX and doxorubicin (76,77).

PFK, located in the cytoplasm, is divided into two subtypes: PFK1, which catalyzes the conversion of fructose 6-phosphate to fructose-1,6-bisphosphate, marking the second rate-limiting step in glycolysis, and PFKFB, which converts fructose-6-phosphate to fructose-2,6-bisphosphate (F2,6P2) (70). PFKFB3, the most active isoform of PFKFB, is upregulated in numerous types of cancer in response to activation of hypoxic signals, RAS signaling, estrogen receptor and P53 mutations, driving glycolytic metabolism in tumors (40). PFKFB3 generates F2,6P2, which activates CDKs. This triggers CDK-mediated phosphorylation of p27, leading to its ubiquitination and proteasomal degradation via CDK1, thereby reducing p27 levels (40). PFKFB3 also enhances cancer cell stemness and promotes resistance to numerous chemotherapeutic agents by upregulating the YAP/Hippo signaling pathway in small cell lung carcinoma (53). In CRC, miR-488 has been shown to target and inhibit PFKFB3 expression (78). High levels of PFKFB3 promote the proliferation, invasion and migration of CRC cells, while also contributing to resistance to chemotherapy agents such as 5-FU and oxaliplatin (78). Similarly, the circ-SAMD4A is highly expressed in CRC. SAMD4A can indirectly upregulate PFKFB3 by sponging miR-545-3p, thereby inhibiting apoptosis and decreasing sensitivity to 5-FU in CRC cells through the miR-545-3p/PFKFB3 axis (79).

PKM2 catalyzes the final rate-limiting step of glycolysis in cancer cells, producing pyruvate and ATP (80). The upregulation of PKM2 isoforms in cancer is associated with drug resistance (81). In the cytoplasm, PKM2 facilitates the process of glycolysis. Following post-translational modification, PKM2 is translocated to the nucleus, where it serves as a transcriptional co-activator for STAT3, β-catenin and NF-κB. This activates drug resistance-related genes, which enhance cancer drug resistance (54). TGF-β and STAT3 synergistically promote the expression of PKM2, which upregulates PD-L1 expression in cancer cells, further enhancing cancer immune escape (82). Recent studies (83-86) have revealed that ncRNAs mediate PKM2-associated drug resistance through various mechanisms. For example, miR-122 directly binds the 3′UTR of PKM2, inhibiting its expression and reversing resistance to oxaliplatin, docetaxel and doxorubicin by attenuating glycolysis (87-89). The glycolysis-related lncRNA SNHG3 promotes resistance to enzalutamide in prostate cancer via the miR-139-5p/PKM2 axis (83). In tumor cells, the ratio of PKM1 to PKM2 serves a critical role in regulating both glycolysis and drug resistance. PKM1 and PKM2 are isoforms generated by alternative splicing of PKM pre-mRNA, which is regulated by the PKM gene. In cisplatin-resistant NSCLC cells, the highly expressed lncRNA PCIF1 competes with miR-326, which can directly interact with PKM to downregulate its expression. This decreases the production of PKM2 by influencing PKM splicing. Knockdown of lncRNA PCIF1 restores miR-326 expression, leading to decreased glycolysis and PKM2 levels, which enhances cellular sensitivity to cisplatin (84). Additionally, RNA-binding proteins, such as Heterogeneous Nuclear Ribonucleoprotein A1 (HNRNPA1), Polypyrimidine tract binding protein 1 (PTBP1) and Sam68, serve critical roles in the specific splicing of PKM (90). miR-326 also regulates PKM2 production by inhibiting HNRNPA1, HNRNPA2 and PTBP1 (85). In hepatocellular carcinoma (HCC), miR-374b directly binds to HNRNPA1, reducing selective splicing of PKM into PKM2 and increasing cellular sensitivity to sorafenib (91). In CRC, the lncRNA LINC01852l interacts with the RNA-binding protein SR-like splicing factors5 (SRSF5), which promotes PKM splicing to generate PKM2. Overexpression of LINC01852l leads to upregulated PKM2 levels and increased glycolysis, thereby contributing to resistance to 5-FU (86). Furthermore, in doxorubicin-resistant BC, lncRNA TBX15 is downregulated. TBX15 serves as a sponge for miR-152, which targets Kinesin family member 2C (KIF2C) to inhibit PKM2-mediated glycolysis. KIF2C binds PKM2 and promotes the ubiquitination of PKM2 domain 2, enhancing PKM2 stability. The TBX15/miR-152 axis reverses doxorubicin resistance in BC by targeting KIF2C and blocking cellular glycolysis and autophagy (92). In ovarian cancer (OC), the lncRNA CTSLP8 directly binds to PKM2, forming a dimer. This PKM2-CTSLP8 dimer transcriptionally regulates c-Myc, promoting glycolysis and cisplatin resistance in OC cells (93).

LDH, located in the cytoplasm, catalyzes the conversion of pyruvate to lactic acid, the final product of glycolysis. LDHA, a prominent isoform of LDH that is upregulated in cancer, stimulates cellular lactate production, which contributes to the acidic tumor microenvironment and enhances cancer cell resistance to chemotherapy drugs (94). In various cancers, miRNAs such as miR-34a, miR-101-3p and miR-329-3p target and inhibit LDHA, suppressing lactate production and enhancing cancer cell sensitivity to cisplatin. miR-34a and miR-101-3p are sponged by upstream lncRNAs such as SNHG7 and XIST, respectively, leading to their downregulation. Overexpression of these miRNAs can reverse glycolytic metabolism and lactate-mediated cisplatin resistance (95-97). In GC cells, the lncRNA HAGLR sponges miR-338-3p to promote 5-FU resistance by targeting LDHA (98). Similarly, in cervical cancer (CC), knocking down lncRNA-NEAT1 restores miR-34a expression, reversing LDHA-induced 5-FU resistance (99). Besides these ncRNAs that directly bind to and inhibit LDHA expression, Shi et al (100) recently discovered that lncRNA GLTC is overexpressed in thyroid cancer and negatively associated with clinical prognosis. GLTC enhances LDHA succinylation at the K155 site by disrupting the interaction between SIRT5 and LDHA. This modification increases lactate content and the NAD⁺/NADH ratio in papillary thyroid carcinoma cells, promoting resistance to ¹³¹I therapy (100). c-Myc, a transcription factor highly expressed in cancers, is closely linked to the tumor microenvironment, metabolic reprogramming and the activation of various oncogenic signaling pathways (101). c-Myc promotes glycolysis in cancer cells by upregulating key enzymes of glycolytic metabolism. Several ncRNAs have been shown to promote glycolysis and drug resistance by stabilizing c-Myc mRNA. For example, circARHGAP12, through m6A modification, binds c-Myc, promoting doxorubicin resistance. Inhibition of circARHGAP29 decreases its interaction with Insulin-like Growth Factor 2 mRNA-Binding Protein 1 (IGF2BP2), enhancing c-Myc stability and increasing tumor cell sensitivity to docetaxel. Similarly, miR-3679-5p stabilizes c-Myc by inhibiting NEDD4-like E3 ubiquitin protein ligase (NEDD4L). Mechanistically, c-Myc enhances the transcription of LDHA, promoting glycolysis, ATP production and lactate generation in tumor cells, thereby mediating cellular drug resistance (24,102,103).

PDH is an enzyme in the pyruvate dehydrogenase complex (PDC), which catalyzes the irreversible decarboxylation of pyruvate to acetyl-CoA in mitochondria. However, cancer cells exhibit a preference for aerobic glycolysis rather than the mitochondrial oxidation of pyruvate (104). miR-21-5p contributes to cisplatin resistance in OC cells by targeting PDH E1 subunit α1 (PDHA1) (105). Additionally, PDK1 regulates the activity of the PDC by inhibiting PDH (104). The upregulation of PDK1 inhibits the tricarboxylic acid cycle (TCA), leading to enhanced ATP synthesis and decreased production of ROS under cellular hypoxic conditions (106). Previous studies have identified upstream regulators of PDK1, including miR-148a and miR-4290, which suppress cellular glycolysis and promote sensitivity to cisplatin and doxorubicin by inhibiting PDK1 expression (107,108). Overexpression of PDK1 can reverse the effects of these miRNAs, promoting cell proliferation and drug resistance (107,108). PTBP1 is a nuclear regulator of alternative splicing. miR-134 and miR-506-3p directly bind to PTBP1, reducing its expression and inhibiting glucose uptake and lactate production in cells. The inhibition of miR-134 and miR-506-3p induces resistance to doxorubicin and 5-FU, respectively (25,109). PTBP1 can bind to the 3′ UTR of LDHA, enhancing its stability. In aromatase inhibitor (AI)-resistant BC cells, the lncRNA DIO3OS interacts with PTBP1 in the nucleus, promoting BC cell proliferation and glycolysis (110). Phosphoglycerate mutase 1 (PGAM1) is a key enzyme in glycolysis, catalyzing the conversion of 2-phosphoglycerate to 3-phosphoglycerate (111). The m6A-modified circQSOX1 indirectly upregulates PGAM1 expression by sponging miR-326 and miR-330-5p, thereby activating glycolysis in CRC cells. This decreases the response of CRC to anti-CTLA-4 therapy and promotes immune evasion in CRC (112).

Previous studies have highlighted the activation of signaling pathways such as PI3K/AKT, MAPK and EGFR as key drivers of glycolysis in cancer cells through the upregulation of glycolysis-associated genes (113,114). For example, the PI3K/AKT signaling pathway can directly promote the phosphorylation of glycolytic enzymes HK2 and PFKFB. Additionally, PI3K/AKT regulates the expression of the transcription factor MYC, which further enhances the expression of HK2, PFK-1, PDK1, PKM2 and LDHA (115). In FMS-like tyrosine kinase 3 (FLT3)-resistant acute myeloid leukemia (AML) cells, elevated expression of miR-155 activates the PI3K/AKT pathway by directly binding to the 3′UTR of PIK3R1, a PI3K inhibitor. This process enhances glycolysis, which is a key feature of resistance to FLT3 tyrosine kinase inhibitors (116). By contrast, the inhibitory effect of miR-149-3p on AKT1 decreases the expression of HK2, LDHA and GLUT1 in AML cells, thereby enhancing the sensitivity of AML to chemotherapy drugs (117).

EGFR stimulation can enhance the activation of HK2 and PKM2, thereby increasing lactate excretion to support the acidic tumor microenvironment (118). This phenomenon may be associated with the upregulation of HIF-1α and LDHA expression (119). Targeting EGFR has been shown to improve glycolysis-mediated chemotherapy (120-122). Gao et al (120) found that EGFR positively regulates lncRNA FGD5-AS1 expression in CRC. FGD5-AS1 indirectly upregulates HK2 by sponging miR-330-3p, a negative regulator of HK2. The EGFR-targeted inhibitor erlotinib suppresses HK2 expression and glycolysis in CRC, enhancing sensitivity to 5-FU (119). miR-143 can target and inhibit HK2, restoring sensitivity to cisplatin and 5-FU by decreasing HK2-dependent glycolysis. Notably, EGFR negatively regulates miR-143, and its downregulation in drug-resistant cancer cells results in excess HK2 (121,122). Epiregulin (EREG) is an EGFR ligand, which upregulates HK2, GLUT3 and PDK1 by activating EGFR (123). miR-186-3p suppresses the expression of EREG. However, tamoxifen decreases miR-186-3p levels in ER-positive BC cells. The miR-186-3p/EREG axis activates EGFR signaling, promoting glycolysis and mediating tamoxifen resistance in BC cells (124).

The interaction between ncRNAs and the MAPK signal transduction pathways plays a key role in tumor cell proliferation, survival and metabolic reprogramming (125). ERK1/2 serves as the downstream and final effector of the MAPK pathway (125) and promotes glycolysis by facilitating the nuclear translocation of PKM2 or upregulating HIF-1α (126,127). In apatinib-resistant GC cells, both LINC00665 and ERK2 are upregulated. LINC00665 enhances ERK2 expression by sequestering miR-665, which stimulates the expression of GLUT1, LDHB and HK2, thereby promoting glycolysis and inducing apatinib resistance (128).

AMPK has been regarded as a signaling pathway that promotes glycolysis (129). However, some evidence suggests that inhibiting glycolysis through AMPK activation can reverse drug resistance (130,131). Mechanistically, this involves the suppression of AMPK, which activates the mTOR/HIF-α axis (130,131). In CRC, miR-27a inhibits AMPK signaling while enhancing mTOR signaling, a mechanism that allows CRC cells to obtain energy through aerobic glycolysis. This adaptation fosters CRC cell proliferation and contributes to resistance against chemotherapeutic agents such as 5-FU and oxaliplatin (132). The Wnt/β-catenin pathway is associated with the activation of HIF-1α and has also been found to upregulate the expression of PFKFB3 (133). The lncRNA HOTAIRM1 is upregulated in AML and has been linked to resistance to cytarabine (134). Knockdown of HOTAIRM1 can inhibit the Wnt/β-catenin signaling pathway, decrease the expression of its downstream target PFK and suppress glycolysis, which enhances the sensitivity of AML cells to cytarabine (134).

In summary, ncRNAs target key glycolytic enzymes and associated signaling pathways (Fig. 2; Table II). These crucial glycolytic enzymes not only facilitate glycolysis in cancer cells but also activate downstream signaling pathways associated with drug resistance (Fig. 3). While some studies suggest ncRNAs contribute to chemotherapy resistance through glycolysis enhancement (135,136), the precise mechanisms by which downstream targets promote glycolysis remain unclear, with only phenotypical changes in glycolysis observed.

In drug-resistant cancer cells, the uptake and synthesis of FAs are notably enhanced. This leads to the accumulation of cholesterol and lipid droplets within the cells, which decreases ROS levels and promote stemness, thereby contributing to drug resistance (138). Furthermore, FAs and synthesized lipid products regulate the activation of the PI3K/AKT, Wnt/β-catenin and Hippo/YAP signaling pathways, thereby promoting survival and drug resistance in cancer cells (Fig. 4A) (139-141).

As numerous chemotherapeutic agents require cellular entry to target DNA and induce cell death, lipid metabolism also mitigate toxic effects by altering drug uptake in cancer cells (142). Drugs typically enter cells through non-specific lipophilic interactions with the cell membrane. Abnormal lipid metabolism alters the membrane composition, decreasing its permeability to anti-cancer drugs (143). Although the exact changes in membrane composition are not fully understood, the low permeability of certain drugs is associated with poor membrane fluidity (144). Additionally, lipid metabolism affects the expression of transporters on the cell membrane. Free FAs activate the G protein-coupled receptor GPR120, which in turn upregulates ABC transporter expression via the AKT/NF-κB signaling pathway, leading to decreased epirubicin accumulation in BC cells (145). By contrast, long-chain PUFAs decrease multidrug resistance 1 gene (MDR1) expression on the cell membrane, thereby decreasing PTX efflux and enhancing the chemotherapy sensitivity of tumor cells (146). Furthermore, lipid metabolism promotes adipocyte-like transformation in cancer cells, leading to the production of lipid droplets, which act as storage sites for fat-soluble drugs. This results in diminished concentrations of chemotherapeutic agents reaching intracellular targets (147).

Previous studies (141,148-151) have emphasized the effect of ncRNAs on intracellular signaling pathways by modulating active lipid molecules, such as arachidonic acid (AA), phosphatidic acid (PA) and lysophosphatidic acid (LPA), which are produced during phospholipid metabolism. For example, circSNX6 serves as an upstream molecular sponge for miR-1184, mitigating its inhibitory effect on the target gene glycerol phosphocholine phosphodiesterase 1. This interaction leads to increased intracellular LPA levels, thereby promoting resistance to sunitinib in renal cell carcinoma cells (148). The lncRNA ROPM is highly expressed in BC stem cells (BCSCs) and stabilizes Phospholipase A2 group 16 (PLA2G16) mRNA by directly binding to it. Elevated PLA2G16 levels enhance the production of free FAs and AA, thereby driving BCSC stemness and doxorubicin resistance (141). Zhang et al (149) demonstrated that exosomal circRNA-101093 interacts with FA-binding protein 3 (FABP3), augmenting its role in transporting AA and decreasing intracellular AA content. This increase in circRNA-101093 levels enhances FABP3 expression and limits AA incorporation into the plasma membrane, thereby desensitizing cells to ferroptosis (149). FAM3 metabolic regulatory signaling molecule D (FAM3D) effectively inhibits phospholipase D (PLD) activity via interactions with Gαi-coupled G protein-coupled receptors, specifically formyl peptide receptor 1 and 2. The lncRNA DLGAP1-AS2 decreases FAM3D mRNA transcription and extracellular secretion by modulating chromatin accessibility at the histone marker H3K27ac, leading to PLD activation. This promotes PA production and confers cisplatin resistance (150). Moreover, miR-95 targets sphingolipid phosphatase 1, inhibiting the sphingosine-1-phosphate signaling pathway involved in AKT phosphorylation and decreasing the protective effects of AKT signaling on tumor cells (151).

Cholesterol serves a pivotal role in cell membrane protein function, receptor transport, proliferation, membrane biogenesis and signal transduction. Increased cholesterol synthesis is associated with poorer survival rates and cancer progression (152). High cholesterol levels are observed in BC cells, where miR-128 and miR-223 regulate cholesterol metabolism by targeting genes such as 3-Hydroxy-3-methylglutaryl-CoA Synthase 1 (HMGCS1), Low-density lipoprotein receptor (LDLR) and ATP-Binding Cassette Transporter A1 (ABCA1), modulating cholesterol biosynthesis, uptake and efflux. Cholesterol accumulation enhances lipid raft formation and membrane rigidity, decreasing membrane permeability and contributing to drug resistance. These miRNAs indirectly influence cell sensitivity to tamoxifen via the regulation of cholesterol (153). Additionally, miR-33a mitigates drug resistance in BC by inhibiting high-density lipoprotein (HDL) expression and preventing HDL-mediated cholesterol extraction (154).

FAs that accumulate in cancer cells are converted into fatty acyl-CoA through the action of acyl-CoA synthetase (ACS). Acyl-CoA is transported to the mitochondrial matrix, where it undergoes β-oxidation to generate acetyl-CoA and ATP (43). Long-term exposure of cancer cells to elevated ROS levels induced by chemotherapy may enhance resistance to further treatment. This phenomenon is due to the activation of several factors, including Nrf2, c-Jun and HIF-1α, which enhance the antioxidant capacity of cancer cells (155). To neutralize ROS, tumor cells produce large amounts of antioxidants such as GSH, which is reduced from its oxidized form via NADPH (156). Elevated ROS levels can promote FAO, enabling cancer cells to generate sufficient NADPH and reduced GSH (157). Increased FAO has been observed in drug-resistant GC and AML (158,159). This increase not only meets the energy demands of tumor cells but also supports their survival in oxidative stress environments (160). Inhibition of FAO reduces NADPH and GSH production in tumor cells while simultaneously increasing ROS production (161). In addition, cancer cells counteract ferroptosis by enhancing FAO and phospholipid synthesis, which elevates the levels of saturated FAs and restores GSH levels, thereby improving resistance to ROS (162).

In sorafenib-resistant HCC cells, the lncRNA LINC01056 is notably downregulated and inversely associated with sorafenib resistance. Mechanistically, LINC01056 binds specifically to peroxisome proliferator-activated receptor α (PPARα), inhibiting its nuclear translocation and transcriptional activity, thus decreasing the expression of FAO-related genes. Overexpression of LINC01056 suppresses PPARα, attenuating FAO in HCC cells and restoring their sensitivity to sorafenib in vitro (163). Previous studies (26,164) have highlighted the key role of mesenchymal stem cells (MSCs) in mediating drug resistance in GC cells. MSCs stimulate the expression of lncRNA MACC1-AS1 in GC through TGF-β secretion. As a sponge for miR-145-5p, MACC1-AS1 enhances the expression of FAO-associated metabolic enzymes such as octamer-binding transcription factor 4 and carnitine palmitoyltransferase 1 (CPT1), thereby promoting FAO in GC cells and contributing to resistance to the 5-FU+leucovorin + oxaliplatin (FOLFOX) regimen (26). Furthermore, exosomes derived from MSCs elevate the expression of lncRNA HCP5 in GC cells, which specifically inhibits miR-3619-5p. By preventing miR-3619-5p from binding PPARG coactivator 1α, HCP5 enhances the transcriptional complex of PPARγ coactivator 1-α/CEBPB, leading to the induction of CPT1 transcription. This process promotes stemness and chemoresistance in GC cancer cells by driving FAO (164).

Ferroptosis is a form of programmed cell death characterized by the accumulation of lipid peroxidation products that serves a key role in cancer occurrence, treatment resistance and tumor suppression (165). Polyunsaturated FAs (PUFAs) are catalyzed by acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferases to produce phospholipids (PLs). Catalyzed by lipoxygenase and P450 oxidoreductase, PL interacts with ROS and iron ions to form PL hydroperoxides (PLOOH). The significant production of PLOOH results in the instability and increased permeability of cell membranes, leading to cell death (166). The occurrence of ferroptosis is influenced by two pathways. The crucial pathway is the inactivation of GSH peroxidase 4 (GPX4). GPX4 serves a pivotal role in the reduction of PLOOH through the utilization of GSH. The other pathway involves inhibition of the cystine/glutamate antiporter system (xCT), mediated by solute carrier family 7A member 11 (SLC7A11). SLC7A11 facilitates the uptake of cysteine, which is key for the synthesis of GSH, a prerequisite for the functional activity of GPX4 (167).

Ferroptosis is induced by anti-tumor drugs that suppress GPX4 or promote lipid peroxidation, as summarized by Li et al (168). For example, the combined treatment of albumin-bound paclitaxel and TMZ enhances ferroptosis in glioblastoma by inhibiting GPX4 expression (169). Sorafenib induces lipid peroxidation in HCC by inhibiting solute carrier family 3A member 2 (SLC3A2) and SLC7A11, thereby suppressing GSH production and GPX4 expression, which upregulates ferroptosis in HCC cells (170). However, in drug-resistant tumor cells, numerous types of lipid metabolic enzyme and endogenous antioxidant mitigate the occurrence of ferroptosis by decreasing lipid peroxidation (171). The SLC7A11-GPX4 system is dysregulated in numerous types of drug-resistant cancer, contributing to resistance against oxaliplatin (172). HER2-positive BC cells activate the β-catenin signaling pathway via fibroblast growth factor receptor 4, leading to an increased synthesis of GSH via the transcription factor 4/SLC7A11 axis (173). Nrf2 is also implicated in cancer drug resistance and ferroptosis. Excessive ROS inactivate Keap1 via oxidation of its cysteine residues, releasing the transcription factor Nrf2 into the nucleus, where it activates the transcription of antioxidant genes, such as GPX4 (174). Furthermore, the activation of Nrf2 induces Metallothionein-1G, which reduces GSH depletion and lipid peroxidation, thereby inhibiting sorafenib-induced ferroptosis (175).

Efficacy of anti-tumor drugs is increased by inducing ferroptosis (Fig. 4B) (176). Erastin, the earliest compound discovered to induce ferroptosis, directly inhibits SLC7A11/xCT, which regulates ferroptosis (177). In CRC, erastin reduces GSH by targeting SLC7A11, thereby enhancing ROS production and chemotherapy sensitivity in CRC cells (178). Additionally, erastin indirectly inhibits GPX4 by upregulating the expression of the hypermethylated in cancer 1 gene, which impairs the resistance of cancer cells to ferroptosis (179). Sulfasalazine and metformin promote ferroptosis by inhibiting SLC7A11, thus suppressing tumor growth and drug resistance (180,181). RAS-selective lethal 3 (RSL3) (182) and A 1,2-dioxolane (183) are ferroptosis inducers that target GPX4. Their mechanism of action involves decreasing the accumulation of ROS in cells by inhibiting the expression of GPX4. A recent study demonstrated that RSL3 does not directly inhibit GPX4; rather, it promotes ferroptosis by inhibiting thioredoxin reductase 1 (TXNRD1) (184). Artemisinin is a drug that induces ferroptosis through various mechanisms. By inhibiting the activity of superoxide dismutase and catalase, artemisinin reduces the clearance of ROS, which leads to the accumulation of lipid peroxide (185). Additionally, it can induce lysosomal degradation of ferritin, increase the levels of cellular free iron, and make cells more susceptible to ferroptosis (186).

The lncRNA PVT1 enhances pleiomorphic adenoma gene 1 (PLAG1) expression at the transcriptional level by targeting miR-195-5p. PLAG1 interacts with GPX4, facilitating its role in stabilizing lipid peroxidation and protecting HCC cells from sorafenib-induced ferroptosis (187). Both miR-128-3p and miR-450b-5p promote ferroptosis and lipid peroxidation by inhibiting the enzymatic activity of GSH and GPX4 (188,189). Additionally, sorafenib upregulates miR-23a-3p expression in HCC via ETS proto-oncogene 1 induction, which targets ACSL4. Sorafenib-mediated overexpression of miR-23a-3p decreases lipid peroxidation and ferroptosis in HCC cells by inhibiting ACSL4, thereby contributing to HCC cell resistance to sorafenib (170). Cancer-associated fibroblasts secrete miR-522 and miR-432-5p to inhibit lipoxygenase15 (ALOX15) and cyclotransferase1 (CHAC1). ALOX15 degrades ROS generated by lipid peroxidation, whereas CHAC1 enhances the production of GSH, thus inducing drug resistance (190,191).

In summary, ncRNAs modulate the sensitivity of tumor cells to drugs by influencing lipid metabolism (Fig. 5; Table III). These mechanisms involve lipid synthesis, FAO and the regulation of ferroptosis. While most of the aforementioned studies have focused on how ncRNAs affect lipid oxidation balance within cancer cells, future investigations should explore how ncRNA-mediated lipid metabolism alters cell membrane components and intracellular lipid droplets to promote drug resistance.

Mitochondria are key in metabolic reprogramming, supporting the catabolism of amino acids, nucleotides and lipids, as well as the production of NADH and NADPH (192). In tumor cells, mitochondrial DNA (mtDNA) mutations or alterations in content lead to mitochondrial dysfunction. For example, the deletion of mtDNA in PC cells results in mitochondrial dysfunction, driving a shift to the Warburg effect and promoting stem cell-like characteristics. This reprogramming helps the cells resist docetaxel treatment (193). In HCC, mtDNA loss contributes to chemotherapy resistance by activating the NRF-2 signaling pathway and upregulating multidrug resistance genes such as MDR1 and MRP1/2 (194). Further evidence from colon cancer cells with mtDNA deletions supports the involvement of MDR1 in resistance mechanisms (195). On the contrary, chemotherapy-induced mitochondrial dysfunction in cancer cells is often accompanied by mutations in mtDNA, which increase ROS production (196).

Resistance to apoptosis is a key mechanism underlying drug resistance in cancer. Under physiological and pathological conditions, cells maintain a balance in redox homeostasis. However, certain chemotherapeutic agents, such as 5-FU, epirubicin and gemcitabine, induce oxidative stress by inhibiting the antioxidant system or mitochondrial function, leading to excessive production of ROS (197). Elevated ROS levels disrupt mitochondrial membrane potential, resulting in the release of cytochrome c and activation of caspases-3, -6 and -7, thereby triggering apoptosis in cancer cells (198). Additionally, tumors often release excess ROS into the microenvironment, which can induce macrophages to adopt a pro-cancer phenotype (199). This phenotype reduces T cell infiltration into tumors and decreases the expression of programmed death-ligand 1 (PD-L1), thereby hindering the effectiveness of anti-PD-L1 immunotherapy (200). The dysregulation of apoptosis is a key factor in cancer resistance to chemotherapy.

Dysregulated ncRNAs within mitochondria modulate the activation of mitochondrial-mediated signaling pathways, promoting tumor growth and drug resistance. miR-125b is associated with increased release of mitochondrial cytochrome c, the induction of apoptotic protease activating factor 1 and the activation of caspase-3 and poly (ADP-ribose) polymerase (201). Furthermore, the overexpression of miR-125b can inhibit the expression of BCL-2 while simultaneously increasing the expression of Bax (201).

Chemotherapy agents, including cisplatin, doxorubicin and PTX, are known pro-oxidants that induce cell death through mitochondrial dysfunction and increased ROS production (202). This has intensified interest in the role of ncRNAs in modulating ROS generation within mitochondria (203,204). Sorafenib, for example, induces mitochondrial dysfunction and ROS production via the C-Jun/p53-upregulated modulator of apoptosis signaling pathway, while miR-518d-5p impedes this process by targeting and inhibiting C-Jun, resulting in sorafenib resistance (205). Mitochondrial miRNA (mitomiRNA)-2329 is significantly upregulated in cisplatin-resistant cells. It inhibits the activity of mitochondrial complexes I, III and IV, leading to elevated mitochondrial ROS and decreased ATP production. Additionally, mitomiR-2329 partially regulates mtDNA transcription in an Argonaute2 (AGO2)-dependent manner, promoting glycolysis and lactate production (206). Similarly, the lncRNA SAMMSON increases ROS production in BC cells by inhibiting mitochondrial complex I (207). These findings underscore the key role of ncRNAs targeting mitochondrial complexes in regulating mitochondrial function. Furthermore, Hillman et al (208) demonstrated that miR-150, miR-328 and miR-616 target membrane complement regulatory factors CD46, CD55 and CD59, thereby rendering mitochondria resistant to complement lysis and enhancing cellular tolerance to complement-dependent cytotoxicity. miR-98 regulates mitochondrial fusion and fission by directly targeting Longevity Assurance Homologue 2, promoting mitochondrial fission and increasing mitochondrial membrane potential, which contributes to resistance to cisplatin and doxorubicin (209). Notably, mitomiR-5787 inhibits oxidative stress and glycolysis in mitochondria by binding mitochondrial cytochrome c oxidase subunit 3 (MT-CO3), restoring cisplatin sensitivity (205). Conversely, the binding of mitomiR-5787 to MT-CO3 does not suppress MT-CO3 expression but enhances its translation. This may be due to the absence of the RNA-induced silencing complex (RISC)-associated factor GW182, which is responsible for mRNA cleavage, within mitochondria (210).

ncRNAs serve a key role in mitigating intracellular ROS and oxidative stress by promoting the production of GSH. For example, in prostate cancer, miR-34b/c facilitates the generation of GSH and Bcl-2 via the c-Myc/γ-glutamyl-cysteine synthetase axis, which decreases the cytotoxic effects of oxidative stress and enhances cellular tolerance to ROS (211). lncRNA H19 is overexpressed in cisplatin-resistant high-grade serous ovarian cancer (HGSC), and its overexpression enhances cisplatin resistance. H19 upregulates Nrf2 expression, promoting the transcription of GSH-associated proteins such as Glutathione reductase (GSR), Glutamate-cysteine ligase catalytic subunit (GCLC) and Glutamate-cysteine ligase modifier subunit (GCLM), which increases intracellular GSH accumulation (212). Conversely, miR-27a targets GSH-associated genes such as cystathionine gamma-lyase, xCT and Nrf2, reducing cellular resistance to ROS and increasing sensitivity to chemotherapy (213). Moreover, Nrf2 is regulated by its upstream regulatory factor SKP1-Cul1-Rbx1 (SCF^β−TRCP). SLC7A11-AS1 blocks SCF^β−TRCP-mediated Nrf2 ubiquitination, resulting in low intracellular ROS levels (214).

In conclusion, ncRNAs regulate mitochondrial complexes, apoptosis-related proteins and other factors, playing a key role in mediating mitochondrial dysfunction in cancer cells. Targeting ncRNAs can modify the ROS/GSH balance within mitochondria, diminishing the tolerance of cancer cells to drug-induced ROS (Fig. 6, Table IV).

Glutamine (Gln), a non-essential amino acid, serves a key role in cancer initiation and progression. Cancer cells depend on glutamine for its involvement in the TCA, as well as for the biosynthesis of nucleotides, GSH and other non-essential amino acids, thus providing essential nutrients for cancer drug resistance (10). Numerous studies (215-220) have demonstrated that ncRNAs regulate GSH metabolism in cancer cells primarily by targeting glutaminase (GLS), a mitochondrial enzyme responsible for catalyzing the deamidation of glutamine (Fig. 7; Table V). GLS is a key player in cancer drug resistance, tumor growth and metastasis (221). In cancers such as HCC and NSCLC, numerous miRNAs have been identified as tumor suppressors that inhibit glutamine metabolism by targeting the 3′UTR of GLS (215-218). Overexpression of these miRNAs, which suppress GLS, enhances cancer cell sensitivity to drugs and promotes apoptosis (214). lncRNAs, such as PVT1 and FEZF1-AS1, restore GLS expression by serving as sponges for miR-181a-5p and miR-32-5p, respectively, which target GLS, thereby promoting cell resistance to cisplatin (219,220). These findings highlight the key role of the ncRNA network in regulating GLS expression and contributing to cellular drug resistance. Additionally, in imatinib-resistant chronic myelogenous leukemia cells, lncRNA PXN-AS1 indirectly upregulates glutamine synthetase by modulating miR-653, promoting glutamine synthesis. Increased glutamine activates the mTOR signaling pathway, leading to elevated expression of CDK4, Cyclin D and CDK6 in the nucleus, thus promoting cell proliferation and cell cycle dysregulation (222).

NSCLC is characterized by a strong dependence on aerobic glycolysis, with elevated expression of glycolytic enzymes such as GLUT1 and PKM2, which promote rapid proliferation and confer resistance to targeted therapy, such as Osimertinib (64,84). In NSCLC, circRNA-0002130 has been shown to promote glycolysis and osimertinib resistance by serving as a sponge for miR-498, leading to the upregulation of GLUT1 and enhanced glucose uptake (64). Similarly, miR-326 directly targets HNRNPA1, a key regulator of PKM splicing, to suppress PKM2 expression and reverse cisplatin resistance (84). Additionally, lncRNA PCIF1 competitively binds miR-326, promoting PKM2 expression and glycolysis, thereby enhancing cisplatin resistance (84). Other ncRNAs, such as miR-200a-3p, target GLS to suppress glutamine metabolism. Concurrently inhibiting miR-200a-3p may represent an effective strategy to prevent the compensatory increase of glutamine in cancer cells (214). Therapeutic strategies targeting these axes, such as silencing circRNA-0002130 or restoring miR-326, may sensitize NSCLC cells to chemotherapy.

CRC cells also exhibit enhanced glycolysis, which supports stemness and drug resistance (78). In CRC, circ-SAMD4A drives glycolysis and 5-FU resistance by sponging miR-545-3p, leading to the upregulation of PFKFB3 and enhanced glycolytic flux (78). miR-488 also directly targets PFKFB3 (77). Furthermore, lncRNA LINC01852 promotes PKM2 splicing via SRSF5, enhancing glycolysis and 5-FU resistance (86). miR-143 inhibits HK2, reversing 5-FU resistance by suppressing glycolysis (122). Inhibiting glycolysis-related ncRNAs, such as circ-SAMD4A or miR-143, may disrupt energy supply and stemness, thereby overcoming chemoresistance.

HCC cells exploit abnormal lipid metabolism and resistance to ferroptosis, a key mechanism of sorafenib-induced cell death (170,187). In HCC, miR-23a-3p is upregulated by sorafenib and suppresses ACSL4, a key enzyme in lipid peroxidation, thereby inhibiting ferroptosis (170). lncRNA PVT1 promotes PLAG1 expression by sponging miR-195-5p, enhancing GPX4 activity (187), while miR-128-3p directly inhibits GPX4, promoting ferroptosis and overcoming sorafenib resistance (188). Additionally, LINC01056 inhibits PPARα, suppressing FAO and restoring sorafenib sensitivity (163). Other ncRNAs, such as miR-374b, target HNRNPA1 to reduce PKM2 expression and sensitize HCC cells to sorafenib (91). Restoring lipid peroxidation, for example by inhibiting miR-23a-3p or PVT1, may enhance sorafenib efficacy in patients with HCC.

BC, particularly ER⁺ subtypes, relies on glycolysis and cholesterol metabolism to sustain tumor growth and evade endocrine therapies such as tamoxifen (59,154). In BC, lncRNA HISLA stabilizes HIF-1α, promoting glycolysis and resistance to chemotherapy-induced apoptosis (59). Additionally, miR-186-3p suppresses EREG to inhibit glycolysis and reverse tamoxifen resistance (123). Moreover, lncRNA DIO3OS interacts with PTBP1 to stabilize LDHA mRNA, enhancing glycolysis and aromatase inhibitor resistance (110). Another key regulator, miR-128, targets ABCA1, a cholesterol efflux transporter, leading to cholesterol accumulation and tamoxifen resistance, while miR-33a inhibits HDL-mediated cholesterol efflux, contributing to drug resistance (153,154). Targeting HISLA or restoring miR-128 expression may disrupt metabolic adaptations and restore sensitivity to endocrine therapy.

OC cells exhibit enhanced glycolysis and antioxidant capacity, which contribute to cisplatin resistance (93,210). In OC, lncRNA CTSLP8 binds to PKM2, forming a dimer that transcriptionally activates c-Myc, driving glycolysis and cisplatin resistance (93). Another key player, lncRNA H19, upregulates Nrf2, enhancing GSH synthesis and oxidative stress resistance (210). Additionally, miR-21-5p targets PDHA1, suppressing mitochondrial metabolism and promoting cisplatin resistance (105). Targeting CTSLP8 or H19 may disrupt glycolysis and redox balance, sensitizing OC cells to platinum-based therapy.

Early detection, diagnosis and treatment are critical for improving cancer prognosis. However, many patients with cancer experience disease progression due to drug resistance, which delays treatment opportunities. ncRNAs, particularly circulating miRNAs, are found in bodily fluids such as blood, urine and saliva and exhibit high stability when stored under appropriate conditions (223). These ncRNAs are specifically expressed in cancer cells and enter bodily fluids after binding proteins or being encapsulated by exosomes, making them potential biomarkers for cancer (Fig. 8) (224). Numerous studies have demonstrated that ncRNAs can predict patient responses to treatment (67,93,225). For example, the upregulation of circ-0002130 in serum exosomes from patients with osimertinib-resistant NSCLC can predict sensitivity to osimertinib (67). In OC, patients with high CTSLP8 expression have notably reduced overall survival (93). Liu et al (225) used changes in the levels of eight lncRNAs to predict the response of patients with HGSC to platinum-based chemotherapy.

Additionally, ncRNAs reflect the association between drug resistance and metabolic changes in cancer cells (226). AIs, the first-line endocrine therapy for postmenopausal patients with ER⁺ BC, have resistance closely linked to glycolysis (225). High baseline expression of miR-155 is associated with increased glycolysis and poor response to AI treatment (227). Changes in the expression of lncRNAs associated with cholesterol and sphingolipids predict the prognosis of HCC and pancreatic cancer and assess their sensitivity to immunotherapy (228,229). A study used 11 lncRNAs associated with FA metabolism to construct a risk prediction model for skin melanoma, aimed at predicting melanoma sensitivity to immunotherapy (230). Ongoing research efforts are being made to establish ncRNAs as biomarkers of tumor drug resistance (231-233). For example, a clinical trial involving 144 patients with BC found that lncRNA MEG3 is associated with the response and toxicity of PTX and cisplatin chemotherapy (231).

The regulation of metabolism in combination with anti-tumor therapy is a promising strategy to overcome tumor drug resistance (234). Numerous studies have demonstrated that blocking key metabolic pathways in cancer cells contributes to the eradication of recurrent or drug-resistant cancer cells (234,235). However, non-cancerous and immune cells exhibit metabolic fragility; targeting the intrinsic metabolism of cancer cells can also affect these essential cells, leading to severe adverse reactions (12). The advantage of targeting ncRNAs to regulate metabolism is the specific abnormal expression of these ncRNAs in cancer cells. This specificity allows more targeted ncRNA-based therapy. miRNAs promoting glycolysis are notably elevated in drug-resistant cancer cells. When anti-miR drugs are delivered to these cells, specific miRNAs are notably inhibited (236). Although these miRNAs are inhibited in normal cells as well, the impact on normal cells, where these miRNAs are expressed at low levels, is smaller compared with that on cancer cells. Furthermore, certain ncRNAs bind to multiple sites simultaneously. For example, miR-498 binds GLUT1, HK2 and LDHA to inhibit cellular glycolysis (64). In mitochondria, miR-634 binds to multiple sites, including optic atrophy 1, lysosomal-associated membrane 2 gene and Nrf2, thereby regulating mitochondrial homeostasis, autophagy and the production of apoptosis-related proteins (237).

Medina et al (238) achieved complete tumor regression within days by pharmacologically inactivating miR-21, highlighting the key role of targeting ncRNAs in cancer therapy. A recent review has summarized the effectiveness of targeting ncRNAs in treating cancer and improving tumor resistance to treatment (239). Recently, emerging strategies have been developed to ensure the precise delivery of targeted ncRNAs to cancer cells (240,241).

The inherent instability of ncRNAs in the body makes them highly susceptible to degradation by RNases, which presents a notable challenge for therapeutic application. To overcome this, the development of effective delivery systems that ensure targeting specificity, decrease immunogenicity and maintain the stability of ncRNAs is crucial (242). Various approaches have been explored to address these challenges. Lin et al (243) developed a pH- and GSH-sensitive nanocarrier for the co-delivery of docetaxel and the miR-34 activator rubbone (RUB). This carrier demonstrates good stability in vitro, targets cancer cells efficiently and rapidly releases docetaxel and RUB into the cytoplasm, enhancing the sensitivity of tumor cells to docetaxel (243). Another study (244) designed GSH-sensitive nanoparticles. These nanoparticles lead to micellar degradation and facilitating drug release by reducing GSH to sulfhydryl groups. This strategy is used for the targeted delivery of GEM and miR-519c to pancreatic cancer tissue with elevated GSH levels, improving GEM resistance. Additionally, miR-519c decreases glycolysis and angiogenesis by inhibiting HIF-1α (244). In melanoma, Guo et al (245) employed liposomes containing miR-21-3p to regulate lipid metabolism. The nanoparticles deliver miR-21-3p into melanoma cells, promoting lipid peroxidation and lipid ROS production by inhibiting TXNRD1, which enhances the response of melanoma cells to immunotherapy (245). Similarly, lipid-coated calcium carbonate nanoparticles are used to deliver 5-FU and miR-375-3p to tumor cells in a weakly acidic environment (246). miR-375-3p interferes with thymidylate metabolism by targeting thymidylate synthase, enhancing the chemotherapy effect of 5-FU (246). Targeting mitochondrial dysfunction in cancer, nanoparticles modified with mitochondria-targeting peptides and tumor-targeting ligands efficiently deliver miR-125 to mitochondria within cancer cells. This approach regulates mitochondrial dynamics-associated proteins and suppresses intracellular ATP production (247). Bioengineered miRNAs targeting metabolic pathways have shown promise in cancer therapy (248,249). For example, the bioengineered tRNA/miR-328-3p enables controlled release of miR-328-3p in human osteosarcoma cells, inhibiting glycolysis and cell proliferation by targeting GLUT1 (249).

Exosomes serve a key role in intercellular communication and can be easily engineered with tumor-targeting properties through molecular biology techniques, making them a promising vehicle for ncRNA delivery (250). For example, exosomes targeting HER2 have been used to deliver oncomiR-21 inhibitors to CRC cells, successfully reversing 5-FU resistance in these cells (251). However, current research is mainly focused on encapsulating both antitumor drugs and ncRNAs within nanoparticles for synergistic antitumor effects (252), while the use of exosomes for concurrent delivery of drugs and ncRNAs remains underexplored. Stability issues surrounding dual delivery via exosomes need to be addressed in future studies. In addition to nanoparticle-based approaches, inhibition of miRNAs using antisense DNA oligomers that incorporate locked nucleic acids (LNAs) offers a promising strategy for gene therapy. A clinical trial investigated a 13-mer LNA inhibitor targeting miR-221 (LNA-i-miR-221) and found that, among 17 patients treated with this therapy, 16 demonstrated good tolerance, with eight achieving stable disease and one experiencing partial response (253). Furthermore, gene delivery systems based on viral vectors and clustered regularly interspaced short palindromic repeat-associated protein9 (Cas9) genome editing system have been explored for editing ncRNAs to hinder tumor progression (254).

In summary, ncRNAs exhibit specificity in targeting key pathways in tumor cell metabolism, serving a pivotal role in tumor growth and drug resistance. As such, ncRNAs represent valuable targets for metabolic regulation in treating drug-resistant cancer. Interfering with ncRNAs in tumor cells via targeted delivery systems, such as nanoparticles, can effectively modulate tumor metabolism and enhance the efficacy of anti-cancer therapy (Fig. 8).