Metabolic reprogramming in the pathogenesis and progression of nasopharyngeal carcinoma: molecular mechanisms and therapeutic implications

Abstract

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with a complex etiology involving genetic predispositions, environmental factors, and Epstein-Barr virus (EBV) infection. Despite progress in radiotherapy and chemotherapy, the prognosis for advanced NPC is still unfavorable, prompting the need for innovative therapeutic approaches. Metabolic reprogramming plays a crucial role in the development and progression of NPC, marked by substantial changes in glycolysis, lipid, and amino acid metabolism. These alterations aid tumor cell proliferation, survival under stress, and immune evasion, with features such as enhanced aerobic glycolysis (Warburg effect) and shifts in lipid and amino acid pathways. Oncogenic drivers like MYC, RAS, EGFR, and the loss of tumor suppressors such as TP53 and PTEN, along with key signaling pathways including mTOR, AMPK, and HIF-1α, orchestrate these metabolic changes. This review discusses the molecular mechanisms of metabolic reprogramming in NPC and outlines potential therapeutic targets within these pathways. Advances in metabolic imaging and biomarker discovery are also enhancing the precision of diagnostics and treatment monitoring, fostering personalized medicine in NPC treatment. This manuscript aims to provide a detailed overview of the current research and its implications for improving NPC management and patient outcomes through targeted metabolic therapies.

Introduction

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer originating in the epithelial cells of the nasopharynx, located behind the nose and above the back of the throat [1,2]. NPC exhibits unique geographical distribution patterns, being highly prevalent in Southern China, Southeast Asia, and North Africa, and less so in Western countries [3]. China exhibits a high incidence rate of the disease, reporting 51,010 new cases with an age-standardized incidence rate (ASIR) of 2.4 per 100,000 population in 2022. The disease demonstrates a north-to-south gradient in distribution, with the ASIR varying by as much as 50-fold, from 0.5 in North China to 25.0 in South China. Southeast Asia accounted for 29.8% of global cases, reporting 35,889 cases of NPC. In contrast, South Central Asia exhibits lower incidence rates, contributing only 7.7% of global cases, predominantly from India, with an ASIR of 0.45 per 100,000 individuals [4]. This malignancy is closely associated with both genetic predispositions and environmental factors such as Epstein-Barr virus (EBV) infection, dietary habits, and exposure to certain chemicals [5,6]. Despite advances in radiotherapy and chemotherapy, the prognosis for patients with advanced-stage NPC remains poor, with high rates of treatment failure and metastasis, underscoring the need for novel therapeutic approaches [1,7].

Recent advances in cancer biology have highlighted the pivotal role of metabolic reprogramming in the development and progression of various cancers [8-10]. Metabolic reprogramming refers to the alterations in cellular metabolism that enable cancer cells to sustain higher rates of proliferation, survive under stress conditions, and evade immune surveillance [11-13]. These metabolic changes are not simply passive responses to rapid cell growth but active adaptations driven by genetic and epigenetic alterations, facilitating the survival and colonization of tumor cells in distant organs [14,15]. Understanding these metabolic alterations is crucial in NPC. NPC cells exhibit profound changes in glucose, lipid, and amino acid metabolism. For instance, the Warburg effect, characterized by increased aerobic glycolysis, is prominently observed in NPC and is associated with aggressive tumor behavior and poor patient outcomes [16]. Moreover, altered lipid and amino acid metabolism in NPC supports the biosynthesis of cellular building blocks and signaling molecules, crucial for sustaining rapid tumor growth and promoting resistance to conventional therapies [17,18].

The molecular underpinnings of metabolic reprogramming in NPC involve the activation of oncogenes and the inactivation of tumor suppressor genes [19,20]. Key signaling pathways, including mTOR and AMPK, play instrumental roles in this metabolic shift, integrating signals from growth factors, nutrients, and energy status to remodel the metabolic landscape of NPC cells [21,22]. The crosstalk between metabolic pathways and cellular signaling networks offers potential nodes of intervention that can be targeted therapeutically [22]. Recognizing these metabolic shifts in NPC not only paves the way for identifying novel biomarkers that can predict disease progression and treatment response but also opens up new avenues for therapeutic intervention. Developing targeted therapies that disrupt the altered metabolic pathways specific to NPC may lead to more effective treatment options. For instance, targeting key enzymes involved in glycolysis, lipid synthesis, and amino acid metabolism, or modulating the activity of major signaling pathways such as mTOR and AMPK, holds promise for curtailing NPC progression and overcoming drug resistance.

This review article aims to dissect the roles of metabolic alterations in NPC, explore the molecular mechanisms underlying these changes, and evaluate the therapeutic implications of targeting metabolic reprogramming. By providing a comprehensive overview of the current landscape and future directions in NPC research, this review aims to enhance our understanding of NPC pathogenesis and foster the development of innovative treatment strategies.

Metabolic alterations in NPC

Dysregulated glycolysis in NPC

Glycolysis is a fundamental metabolic pathway that converts glucose into pyruvate, generating adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH) in the process. In cancer cells, glycolysis is often upregulated even under normoxic conditions, a phenomenon known as the Warburg effect. This altered metabolism provides cancer cells with the necessary energy and metabolic intermediates for rapid proliferation [23]. In NPC, aberrant glucose metabolism is frequently observed (Table 1). Multiple studies have reported the upregulation of glycolytic enzymes in NPC. For instance, GLUT1 plays a crucial role in facilitating the transport of glucose across cell membranes, ensuring a constant supply of glucose to meet cellular energy demands and glycolytic processes [24]. In NPC, GLUT1 expression is frequently upregulated, promoting increased glucose uptake and utilization, even under normoxic conditions [25]. HK2 is an enzyme involved in the first step of glycolysis, catalyzing the phosphorylation of glucose to glucose-6-phosphate [26]. Multiple studies have demonstrated that dysregulation of several glycolytic genes, including HK2, is a primary cause of upregulated glycolysis in NPC [27-29]. This metabolic shift may accelerate NPC progression. PFKFB3, a key regulatory enzyme involved in glycolysis, controls the rate of glycolysis by catalyzing the synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of phosphofructokinase-1 (PFK-1) [30]. In NPC, the increased expression and decreased degradation of PFKFB3 further enhance glycolysis [31,32]. Additionally, the key glycolytic enzyme PKM has been reported to be upregulated in NPC, potentially related to the decreased expression of TET2 [33]. Increased lactate production, glucose uptake, cellular glucose-6-phosphate levels, and ATP generation observed in NPC cells indicate that glycolysis is activated in this disease condition [27,34,35]. These alterations facilitate the rapid proliferation of NPC cells by providing adequate glycolytic intermediates for biosynthetic pathways while maintaining redox balance through NADH regeneration via lactate production.

Table 1.

Changes of glycolytic enzymes in NPC

Glycolytic enzymes	Changes in NPC	References
GLUT1	Upregulated expression [25]	Cai et al., 2017
HK2	Upregulated expression and increased activity [27-29]	Xu et al., 2021; Song et al., 2017; Xiao et al., 2014
PFKFB3	Upregulated expression and decreased degradation [31,32]	He et al., 2022; Wang et al., 2022
PKM	Upregulated expression [33]	Zhang et al., 2020

Altered lipid metabolism in NPC

Beyond glucose metabolism, emerging evidence underscores the significance of altered lipid metabolism in NPC pathogenesis. Lipid metabolic reprogramming encompasses increased de novo lipogenesis, augmented fatty acid uptake, and alterations in lipid droplet dynamics [36]. A clinical study utilized widely targeted quantitative lipidomics to measure and quantify the plasma lipid profiles of 179 patients with locoregionally advanced NPC. The results showed that 40 lipids were associated with distant metastasis, with six lipids significantly associated with immune and inflammation-related biomarkers [37]. Another study identified significant reductions in 19 lipids and increases in 2 lipids in NPC patients compared to controls, with distinct lipid distributions observed between patients with varying EBV antibody titers and those with or without metastasis [38]. These findings suggest that alterations in lipid metabolism may be associated with NPC progression. Basic research has also observed changes in lipid metabolism in NPC. Animal and cell experiments have shown that NPC exhibits elevated levels of triglycerides, cholesterol, and lipid droplet formation [39-42]. Upregulation of LDLR and FASN in EBV-infected cells may relate to fatty acid upregulation and lipid droplet aggregation [43]. Upregulation of FASN in NPC may be associated with tumor invasion, migration, and progression [40,44]. FAO in NPC is also activated, promoting tumor cell proliferation through nucleoside metabolism, potentially linked to upregulation of CPT1A [45]. Mechanistically, lipid metabolism may promote the progression of NPC by providing energy, components for biological membranes, and signaling molecules needed for proliferation, survival, invasion, metastasis [46]. For instance, acetyl-CoA, a product of lipid catabolism, regulate tumor cell proliferation through histone acetylation [47].

Altered amino acid metabolism in NPC

Amino acid metabolism is also perturbed in NPC, contributing to its metabolic heterogeneity and adaptive response to microenvironmental stresses. Glutamine, a non-essential amino acid, serves as a critical nutrient source for cancer cells, particularly under conditions of glucose deprivation or hypoxia [48]. NPC cells exhibit increased glutamine uptake and dependency, supporting energy production, nucleotide biosynthesis, and redox homeostasis through glutaminolysis. c-Myc upregulates KGA and GAC protein levels, leading to glutaminolysis activation, promoting mitochondrial metabolism and cell proliferation in EBV-infected cells [49]. Dysregulated branched-chain amino acid (BCAA) metabolism, characterized by altered expression of enzymes involved in BCAA catabolism, has been implicated in NPC progression and therapeutic resistance. The upregulation of BCAT1 in NPC is a significant factor in tumor cell proliferation [50].

Molecular mechanisms of metabolic reprogramming in NPC

Activation of oncogenes and inactivation of tumor suppressor genes

The metabolic landscape of NPC cells is heavily influenced by genetic alterations, including the activation of oncogenes and the inactivation of tumor suppressor genes. Oncogenes such as MYC, RAS, and EGFR are frequently overexpressed in NPC, driving numerous metabolic processes [19,51,52]. These oncogenes enhance glycolysis (Warburg effect), glutaminolysis, and lipid synthesis, crucial for providing ATP, building blocks, and signaling molecules necessary for cancer cell proliferation and survival. For example, EGFR/AKT/c-Myc signaling in NPC promotes cell growth by activating glycolysis, which, in turn, promotes tumor invasion and migration [52]. LMP1-mediated attenuation of the PI3K/Akt-GSK3β-FBW7 signaling axis results in c-Myc stabilization, exacerbating EBV-induced glycolysis [29]. Conversely, tumor suppressor genes like TP53, LKB1, and PTEN are often silenced or mutated in NPC [20,22,53]. The loss of these genes removes critical checks on cellular metabolism, allowing unchecked cellular growth and altered metabolic flux. PTEN normally inhibits the PI3K/AKT pathway; its loss leads to increased glycolytic activity and biomass production, supporting rapid tumor growth [22].

Involvement of key signaling pathways

Metabolic reprogramming is intricately linked to several signaling pathways, including mTOR, AMPK, PKB/AKT, HIF-1α, and PI3K [54,55]. The mTOR pathway, activated by upstream signals such as growth factors and nutrients, accelerates anabolic processes, including protein synthesis, lipid biogenesis, and nucleotide production [56]. The mTOR pathway directly enhances glycolysis and the pentose phosphate pathway, thus supporting rapid cell growth and providing antioxidants to combat reactive oxygen species produced during rapid cell metabolism [57]. Studies have shown that inhibition of mTOR signaling can enhance the radiosensitivity of NPC cells. For example, FBXW7 restrains mTOR levels by facilitating mTOR ubiquitination, which suppresses glycolysis and promotes radiation-induced apoptosis and DNA damage, thereby enhancing radiosensitivity in NPC [21]. AMPK, often considered the energy sensor of the cell, generally acts to maintain energy homeostasis by activating catabolic processes that generate ATP and inhibiting anabolic processes. In cancer, AMPK’s function can be subverted to support cancer cell survival under metabolic stress by adapting the metabolism to low energy states [58]. In NPC, AMPK activation may promote tumor progression by enhancing glycolysis [59]. However, AMPK can also enhance NPC radiosensitivity by promoting the DNA damage response [60]. HIF-1α is a master regulator of cellular response to hypoxia and plays a pivotal role in orchestrating metabolic adaptations to maintain cellular homeostasis. HIF-1α can upregulate key glycolytic enzymes such as HK2, PFK, and LDHA, while suppressing mitochondrial biogenesis genes like PGC-1α, thus promoting glycolysis and inhibiting oxidative phosphorylation (OXPHOS). In NPC, HIF-1α significantly promotes the expression of PKM2 and is associated with increased glucose consumption, lactate production, and LDH activity [61]. Furthermore, microenvironmental factors can regulate HIF-1α expression, which in turn increases FOXM1 expression, thereby regulating glycolysis and NPC proliferation through PDK1-mediated PDH phosphorylation [62]. These key signaling pathways play an essential role in NPC development by regulating metabolic reprogramming, thereby presenting potential therapeutic targets. Disrupting these regulatory pathways could impair tumor growth and enhance treatment effectiveness, highlighting the significance of metabolic reprogramming in cancer progression and therapy resistance.

Crosstalk between metabolic pathways and signaling networks in NPC

The metabolic flexibility of NPC cells is further enhanced by the crosstalk between metabolic pathways and cellular signaling networks. An example of this is the interplay between the PI3K/AKT pathway and glycolysis. AKT activation promotes glucose uptake by increasing glucose transporter translocation to the cell membrane and enhances glycolytic enzyme activity through phosphorylation [63]. PI3K/AKT also regulates glycolysis in NPC through mTOR signaling. Additionally, evidence suggests an interaction between this signaling pathway and microRNAs (miRNAs), a class of small noncoding RNAs [64]. HIF-1α also affects NPC progression by regulating angiogenesis [65]. This evidence demonstrates the widespread crosstalk between metabolic regulatory signals, shaping the tumor microenvironment through complex mechanisms and influencing NPC progression.

Impact of metabolic reprogramming on NPC progression and treatment resistance

Warburg effect promotes NPC progression and treatment resistance

As discussed, NPC exhibits metabolic reprogramming characterized by upregulated glycolysis under normoxic conditions, including increased expression of GLUT1, HK2, PFKFB3, and PKM2. Recent research has identified potential therapeutic targets in NPC, focusing on deregulated glycolytic enzymes and related signaling pathways. One significant finding relates to the downregulation of BPIFB1, which is critically underexpressed in NPC and associated with poor prognosis. BPIFB1 suppression increases GLUT1 transcription via the JNK/AP1 signaling pathway, enhancing glycolytic activity. This metabolic shift supports cancer cell energy needs while also affecting histone acetylation and vasculogenic mimicry-related gene expression, thereby promoting tumor progression and invasiveness [66].

Therapeutically, agents like Compound H target both the EGFR tyrosine kinase ATP-binding site and GLUT1-mediated energy metabolism. By inhibiting these pathways, Compound H reduces cellular ATP levels, matrix metalloprotease activity, lactic acid production, and nuclear EGFR transfer, effectively stalling NPC progression [67]. MicroRNAs (miRNAs), including hsa-miR-9-5p and miR-9-1, also play crucial roles in regulating glycolytic enzymes [27,68]. These miRNAs specifically target hexokinase 2 (HK2), reducing glycolysis, inhibiting cell growth, and enhancing radiosensitivity in NPC. Modulating HK2 via miRNAs illustrates a promising approach to improving radiation therapy efficacy in NPC. Enzymes like PFK1 and PFKFB3, which catalyze critical glycolysis steps, are notably altered in NPC. Overexpression of PFK1 and PFKFB3 correlates with increased tumor aggressiveness and poor outcomes. Knockdown of these enzymes reduces NPC cell proliferative and metastatic potential and induces apoptosis, highlighting their potential as therapeutic targets [69,70]. Other molecular entities, such as CYLD and LINC00930, contribute to regulating NPC metabolism and tumorigenesis [31,32]. CYLD acts as a tumor suppressor, and its restoration inhibits glycolysis through p53 stabilization, suppressing PFKFB3 transcription. Conversely, LINC00930 enhances glycolysis and cell proliferation by epigenetically activating PFKFB3, underscoring the complexity of metabolic regulation in NPC. Moreover, the EGFR-PKM2 axis drives NPC progression by facilitating PKM2 nuclear translocation and activating metastasis-associated genes [71]. Overexpression of JMJD2A and LDHA correlates with poorer clinical outcomes, as these proteins enhance glycolysis, proliferation, and invasion [72]. Targeted inhibition of this axis could offer a novel therapeutic approach to managing NPC effectively. Research on glycolysis driving tumor progression provides valuable insights into the molecular basis of NPC and emphasizes several potential therapeutic targets. Understanding these pathways will facilitate developing more effective, targeted treatments that could improve prognosis and quality of life for NPC patients.

Lipid metabolism regulates NPC progression and treatment resistance

Recent research has highlighted specific alterations in lipid metabolism pathways in NPC, identifying potential therapeutic targets. One significant finding is the impact of Epstein-Barr virus-encoded RNA (EBER) on lipid metabolic processes. Gene Ontology analysis indicates that EBERs upregulate genes involved in cellular lipid metabolism, including LDLR and FASN [43]. NPC cells show increased LDLR and FASN expression and dependency on LDL for proliferation. Quercetin, known for inhibiting FASN, effectively reduces NPC cell proliferation, suggesting a therapeutic avenue by targeting lipid synthesis pathways.

Carnitine palmitoyl transferase 1A (CPT1A), a key enzyme in fatty acid oxidation (FAO), is markedly overexpressed in NPC cells and biopsies. CPT1A enhances several malignant characteristics, including cell proliferation and tumor formation. High levels of CPT1A correlate with poor survival outcomes in NPC patients, especially those undergoing radiotherapy. This enzyme supports core metabolic pathways crucial for ATP generation and nucleotide biosynthesis and facilitates fatty acid trafficking from lipid droplets to mitochondria via its interaction with Rab14, enhancing radiation resistance. Thus, targeting CPT1A could impair NPC cell survival and radio-resistance [17,45]. The solute carrier family 27 member 6 (SLC27A6) enhances intracellular triglyceride and cholesterol levels in NPC cells, promoting lipid biosynthesis and increasing metastatic potential. High expression of SLC27A6 is associated with increased NPC cell migration and invasion, further implicating lipid metabolism in NPC pathophysiology [41]. Hypoxia-inducible lipid droplet-associated protein (HILPDA) also plays a role in NPC’s adaptive response to hypoxia and radiotherapy. It regulates lipid droplet formation and intracellular lipid remodeling, including mitochondrial cardiolipin (CL), crucial for mitophagy in response to irradiation. HILPDA’s inhibition of PINK1-mediated CLS1 ubiquitination and degradation underscores a complex mechanism where lipid remodeling contributes to radio-resistance [39]. Regulation of leptin and sterol regulatory element-binding protein 1 (SREBP1) in NPC cells highlights the interconnectedness of lipid signaling pathways. Leptin downregulation reduces lipid accumulation and levels of triglycerides and cholesterol by suppressing SREBP1 and its downstream targets, including FASN and stearoyl-CoA desaturase-1 (SCD1). Conversely, SREBP1 overexpression can counteract leptin silencing effects, underscoring the potential of targeting these pathways to control lipid metabolism and NPC cell survival [40].

These findings emphasize the pivotal role of lipid metabolism in NPC progression and resistance to therapies. Targeting key components of lipid metabolic pathways offers promising strategies for developing more effective treatments for NPC, aiming to disrupt the metabolic adaptations that cancer cells exploit for survival and growth.

Amino acid metabolism regulates NPC progression

Research has highlighted significant roles for glutaminase (GLS) and branched-chain amino acid transaminase 1 (BCAT1) in driving NPC pathogenesis through amino acid metabolic pathways. GLS, particularly overexpressed in NPC cells and tissues, has been identified as a poor prognostic marker for overall survival in NPC patients. GLS catalyzes the conversion of glutamine to glutamate, a crucial step in glutaminolysis. GLS overexpression enhances malignant behaviors, including cell cycle progression, proliferation, colony formation, and migration. These effects are mediated through Cyclin D2 (CCND2) regulation via the PI3K/AKT/mTOR signaling pathway. The GLS inhibitor CB-839 has demonstrated potential in suppressing these tumor-promoting functions, indicating a promising therapeutic avenue for targeting glutamine metabolism in NPC [18].

In EBV-infected cells, GLS1 isoforms KGA and GAC are upregulated by c-Myc, which also increases intracellular glutamate levels. Additionally, the expression of mitochondrial glutamate dehydrogenase 1 and 2 (GLUD1 and GLUD2) is elevated, leading to increased production of alpha-ketoglutarate, indicating active glutaminolysis. Inhibitors targeting KGA/GAC and GLUD1 significantly reduce cell proliferation and viability in these EBV-infected cells, underscoring the critical role of glutaminolysis in the EBV-related pathogenesis of NPC [49]. On another front, the protein FLOT2 has been found to upregulate BCAT1 expression in NPC cells. BCAT1, involved in branched-chain amino acid metabolism, supports NPC cell proliferation and counteracts the inhibitory effects induced by FLOT2 depletion. Knockdown of BCAT1 substantially reduces the pro-proliferative effects triggered by FLOT2 overexpression. The relationship between FLOT2 and BCAT1 is further complicated by their mutual regulation through c-Myc, a positive transcription factor for BCAT1. Additionally, FLOT2 suppresses miR-33b-5p, a microRNA that inhibits c-Myc, thereby promoting BCAT1 transcription. This intricate regulatory network underscores the significance of BCAT1 in NPC progression, with its expression positively correlated with FLOT2 in NPC tissues and inversely correlated with patient prognosis [50].

These findings illustrate the crucial roles of GLS and BCAT1 in modulating amino acid metabolism in NPC, affecting tumor growth and progression. Modulating these metabolic pathways offers potential therapeutic targets, providing a basis for developing treatments that disrupt the metabolic dependencies of NPC cells. As research advances, targeting metabolic enzymes like GLS and BCAT1 could become integral components of effective strategies against NPC, particularly in overcoming resistance to conventional therapies such as radiotherapy.

In summary, altered metabolic pathways in NPC, including glycolysis, lipid metabolism, and amino acid metabolism, promotes tumor progression through various mechanisms (Figure 1). Related studies on metabolic reprogramming driving NPC progression are shown in Table 2.

Figure 1.

Metabolic reprogramming drives NPC progression. In NPC, altered metabolic pathways, including glycolysis, lipid metabolism, and amino acid metabolism, promotes tumor progression through various mechanisms.

Table 2.

Related research on metabolic reprogramming driving NPC progression

Related metabolic pathways	Study models	Related study results	References
Glycolysis	Mice, Cells	BPIFB1 downregulation in NPC is linked to poor prognosis, enhancing GLUT1-mediated glycolysis and tumor progression through JNK/AP1 signaling, increasing histone acetylation and vasculogenic mimicry genes [66].	Jiang et al., 2022
Glycolysis	Mice, Cells	Compound H inhibits NPC progression by targeting EGFR and GLUT1, reducing ATP, mitochondrial membrane potential, lactic acid, and EGFR nuclear transfer [67].	Wang et al., 2024
Glycolysis	Mice, Cells	hsa-miR-9-5p inhibits HK2, enhancing radiosensitivity and reducing NPC cell proliferation while increasing apoptosis and inhibiting tumor growth in vivo with radiation therapy [68].	Zhan et al., 2021
Glycolysis	Mice, Cells	miR-9-1 inhibits NPC progression by targeting HK2, reducing glycolysis, lactate production, glucose uptake, and ATP generation, and suppressing tumor proliferation [27].	Xu et al., 2021
Glycolysis	Cells	PFK1 overexpression in NPC promotes cell growth, invasion, and metastasis. Knockdown inhibits these processes and induces apoptosis in NPC cells [69].	Li et al., 2021
Glycolysis	Cells	PFKFB3 upregulation in NPC regulates proliferation, metastasis, and apoptosis, promoting HUVEC proliferation, migration, and angiogenesis [70].	Gu et al., 2017
Glycolysis	Mice, Cells	LINC00930 promotes glycolysis and cell proliferation in NPC by recruiting RBBP5 and GCN5 to epigenetically activate PFKFB3 [31].	He et al., 2022
Glycolysis	Cells	CYLD deficiency in NPC leads to enhanced glycolysis. Restoring CYLD stabilizes p53, inhibiting PFKFB3 transcription and suppressing glycolysis [32].	Wang et al., 2022
Glycolysis	Mice, Cells	EGFR signaling activates PKM2 nuclear translocation, promoting NPC metastasis through novel genes like F3, FOSL1, EPHA2, ANTXR2, and AKR1C2 [71].	Chen et al., 2020
Glycolysis	Cells	High JMJD2A expression in NPC correlates with poor prognosis. JMJD2A regulates LDHA, influencing glycolysis, ATP levels, and tumor progression [72].	Su et al., 2017
Lipid metabolism	Mice, Cells	EBERs upregulate lipid metabolism in NPC, with LDLR and FASN promoting LDL-dependent cell proliferation. Quercetin inhibits NPC cell proliferation by targeting FASN [43].	Daker et al., 2013
Lipid metabolism	Mice, Cells	CPT1A overexpression in NPC promotes malignancy by enhancing metabolic pathways for ATP and nucleotide biosynthesis. Knockdown disrupts cell cycle progression [45].	Tang et al., 2022
Lipid metabolism	Cells	CPT1A upregulation in radiation-resistant NPC promotes fatty acid trafficking and ATP production. Targeting CPT1A reduces radiation resistance by disrupting lipid metabolism [17].	Tan et al., 2018
Lipid metabolism	Mice, Cells	SLC27A6 increases triglycerides and cholesterol in NPC cells, enhancing lipid biosynthesis and metastatic potential by promoting cell migration and invasion [41].	Zhong et al., 2022
Lipid metabolism	Cells	HILPDA induces lipid droplet formation and mitochondrial cardiolipin remodeling, enhancing mitophagy and radioresistance. Inhibiting mitophagy increases NPC radiosensitivity [39].	Zhang et al., 2023
Lipid metabolism	Cells	Leptin downregulation reduces lipid accumulation and inhibits SREBP1, FASN, and SCD1, attenuating triglyceride levels, cholesterol levels, and NPC cell survival [40].	Luo et al., 2022
Amino acid metabolism	Mice, Cells	GLS overexpression in NPC predicts poor prognosis, promoting cell cycle progression and proliferation via the PI3K/AKT/mTOR pathway. Inhibition of GLS shows anti-NPC effects [18].	Su et al., 2023
Amino acid metabolism	Cells	Increased GLS1 isoforms in EBV-infected cells elevate glutamate and alpha-ketoglutarate levels, promoting glutaminolysis. Inhibitors reduce proliferation and viability of infected cells [49].	Krishna et al., 2020
Amino acid metabolism	Mice, Cells	FLOT2 upregulates BCAT1, promoting NPC cell proliferation. FLOT2 maintains c-Myc levels, antagonizing miR-33b-5p, which inhibits BCAT1, correlating with poor prognosis [50].	Liu et al., 2021

Metabolic imaging and biomarkers in NPC

Recent advances in metabolic imaging and identifying metabolic biomarkers have considerably enhanced the diagnostic precision and therapeutic management of NPC, offering new insights into its metabolic reprogramming.

Metabolic imaging, particularly fluorodeoxyglucose positron emission tomography (FDG-PET), has become a cornerstone in the diagnostic landscape of NPC. FDG-PET leverages heightened glucose uptake and glycolytic activity of cancer cells to provide a functional imaging perspective that complements anatomical insights from CT and MRI scans [73]. In NPC, FDG-PET aids in initial tumor detection and staging by identifying metabolically active tumor regions and assists in delineating the tumor from surrounding tissues and lymphoid structures, which is crucial given the complex nasopharyngeal anatomy [74,75]. Moreover, FDG-PET is instrumental in monitoring treatment response in NPC patients. The technique is sensitive to changes in metabolic activity often preceding anatomical tumor reduction, serving as an early predictor of response to chemotherapy and radiation therapy [76,77]. This early assessment helps tailor treatment protocols to individual patient responses, potentially leading to adjustments in therapy that can improve outcomes and minimize unnecessary toxicity. Research into metabolic biomarkers has provided significant strides in understanding NPC. Metabolic biomarkers in NPC typically involve alterations in pathways related to glycolysis, glutaminolysis, and lipid metabolism, which are influenced by genetic mutations and viral interactions. For instance, elevated levels of enzymes such as lactate dehydrogenase (LDH) and GLS have been correlated with poor prognosis and are considered potential biomarkers for NPC [78-80]. These enzymes are integral to the altered metabolic pathways in NPC cells, with LDH facilitating anaerobic glycolysis leading to lactate production, and GLS catalyzing the conversion of glutamine to glutamate, a key step in supporting the bioenergetic and biosynthetic demands of tumor cells [18,81]. Furthermore, integrating EBV DNA quantification in plasma or serum as a biomarker has been transformative in NPC management [82]. EBV-related nucleic acids can be detected at diagnosis and monitored during treatment, providing a non-invasive marker correlating with disease burden and therapy response [83]. This biomarker is particularly useful in predicting relapse, as increases in circulating EBV DNA often precede clinical signs of recurrence [84,85].

The exploration of novel metabolic biomarkers continues with advanced proteomic and metabolomic techniques that enable the profiling of broader metabolic alterations in NPC [86,87]. These studies aim to identify specific metabolic signatures that could predict therapeutic response, survival, and potential therapeutic targets. For example, alterations in the metabolites of the pentose phosphate pathway and the tricarboxylic acid cycle have been noted in NPC, offering insights into the metabolic dependencies of the tumor [88,89].

Thus, the application of metabolic imaging techniques such as FDG-PET and the ongoing identification and validation of metabolic biomarkers are pivotal in improving the diagnostic accuracy and therapeutic management of NPC. These approaches not only enhance our understanding of the metabolic underpinnings of NPC but also pave the way for personalized medicine strategies that could significantly improve patient outcomes. As research progresses, these tools will likely become integral components of routine clinical practice, offering more nuanced and effective management options for NPC patients.

Therapeutic strategies targeting metabolic reprogramming in NPC

Targeted metabolic signals for the treatment of NPC

As previously mentioned, signals including mTOR, AMPK, and HIF-1α significantly affect glycolysis, lipid metabolism, and amino acid metabolism in NPC, thereby influencing tumor progression. Targeting mTOR-mediated metabolic reprogramming in NPC represents a compelling avenue for therapeutic intervention, given mTOR’s critical role in regulating cell growth, survival, and metabolism. In NPC, mTOR activation promotes glycolysis, protein synthesis, and lipid biosynthesis by enhancing the expression and activity of key enzymes and regulatory proteins involved in these pathways [90].

Huang et al. found that the mTOR inhibitor temsirolimus inhibits proliferation and induces apoptosis in a panel of NPC cell lines. Importantly, temsirolimus acts synergistically with radiation and is effective against radio-resistant cells. Using a radio-resistant xenograft mouse model, they validated temsirolimus’s efficacy in preventing tumor formation and inhibiting tumor growth, suggesting that temsirolimus overcomes radio-resistance in NPC via inhibiting mTOR signaling [91]. Mechanistically, temsirolimus may promote NPC cell death and increase radiotherapy sensitivity by inhibiting aerobic glycolysis and the Warburg effect. Additionally, artesunate has been found to alleviate NPC progression by inhibiting the Akt/mTOR pathway [92]. AMPK serves as a cellular energy sensor, regulating energy balance and metabolic stress. Inhibiting AMPK disrupts the energy homeostasis in cancer cells, limiting their adaptive capacity to metabolic stress and therapeutic insult [93]. CASC19 siRNA (siCASC19) suppresses cellular autophagy by inhibiting the AMPK/mTOR pathway and promotes NPC cell apoptosis through the PARP1 pathway [94]. HIF-1α stimulates several glycolytic enzymes and promotes angiogenesis, facilitating tumor growth and metastasis. Targeted inhibition of HIF-1α could stifle NPC progression by curtailing its ability to adapt to hypoxic conditions and by reducing its metabolic flexibility [95].

Targeted metabolic pathways for the treatment of NPC

Glycolysis, the primary pathway for glucose metabolism in cancer cells, is often upregulated in NPC. Key enzymes like HK2, PFKFB3, and LDHA are pivotal targets. HK2 catalyzes the first step of glycolysis, converting glucose to glucose-6-phosphate, crucial for trapping glucose within cells and maintaining high glycolysis rates [96]. PFKFB3 regulates the synthesis of fructose-2,6-bisphosphate, a powerful activator of glycolysis, thereby enhancing glycolytic flux [97]. LDHA facilitates pyruvate conversion to lactate, regenerating NAD+ essential for continued glycolytic processing [98]. Inhibiting these enzymes can starve NPC cells of energy and biosynthetic precursors, hindering their growth and survival. As mentioned, the expression and activity of HK2, PFKFB3, and LDHA are upregulated in NPC and drive NPC progression. Therefore, targeting these metabolic enzymes’ inhibition may help provide ideas for NPC treatment. Notably, targeted inhibition of glycolytic enzymes has been successful in some basic cancer research [99-101].

Lipid metabolism is another vital pathway altered in NPC. Key enzymes such as CPT1A and FASN are strategic targets. CPT1A is crucial for transporting fatty acids into mitochondria for β-oxidation, a major energy source for cancer cells. Inhibiting CPT1A can deplete energy reserves and essential lipid-derived molecules [102]. FASN, involved in fatty acid synthesis, supports membrane biosynthesis and signaling lipid production; its inhibition can disrupt cellular structures and signaling pathways critical for NPC cell viability and proliferation [103]. Targeted inhibition of CPT1A and FASN may hold potential in NPC treatment [17,40,43-45]. Amino acid metabolism, particularly involving glutamine and branched-chain amino acids, is essential for NPC growth. GLS converts glutamine into glutamate, which is further metabolized to fuel the TCA cycle and nucleotide biosynthesis [104]. BCAT1 is involved in branched-chain amino acids metabolism, crucial for protein synthesis and as metabolic fuel [105]. Inhibiting GLS and BCAT1 can deprive NPC cells of essential nutrients and biosynthetic capabilities, leading to reduced growth and enhanced treatment susceptibility. Targeted inhibition of GLS and BCAT1 may be a strategy for treating NPC in the future [18,49,50]. Overall, targeting the metabolic adaptations of NPC provides a promising therapeutic strategy. By disrupting the glycolytic, lipid, and amino acid metabolic pathways, these treatments can effectively compromise NPC cell viability, offering a potentially valuable addition to existing treatment modalities. Continued research and clinical trials are essential to fully realize the potential of these metabolic inhibitors in the treatment landscape of NPC. The translational potential of metabolic reprogramming in NPC diagnosis and treatment is summarized in Figure 2.

Figure 2.

Translational potential of metabolic reprogramming in NPC diagnosis and treatment. The research in metabolic imaging, metabolic biomarkers, metabolic signals, and metabolic pathways plays an important role in the future development of NPC diagnosis and treatment.

Conclusion and future perspectives

The understanding of metabolic reprogramming in the pathogenesis and progression of NPC has significantly expanded, unveiling novel therapeutic targets and diagnostic markers that hold promise for the future of precision medicine in oncology. As delineated in this review, the multifaceted alterations in glucose, lipid, and amino acid metabolism in NPC underscore the disease’s complexity and highlight the potential for targeted therapeutic interventions finely tuned to the specific metabolic dependencies of NPC cells.

Translating metabolic reprogramming insights into clinical practice for NPC offers a promising avenue for improving patient outcomes. By targeting the metabolic peculiarities specific to NPC, such as the Warburg effect, altered lipid metabolism, and unique amino acid dependencies, therapies can disrupt these crucial survival pathways, thereby enhancing the efficacy of existing treatments and overcoming resistance mechanisms. Metabolic imaging, including FDG-PET, has emerged as a critical tool in this context, providing real-time assessment of tumor metabolism and treatment response, which is invaluable for optimizing therapeutic strategies and patient management.

However, integrating these metabolic-targeted therapies into routine clinical practice requires rigorous validation through clinical trials. The effectiveness of these treatments must be demonstrated not only in terms of tumor regression but also in improving survival rates and quality of life for patients. Additionally, the development of resistance to metabolic inhibitors, a common hurdle in targeted therapy, necessitates ongoing research into combination therapies that can prevent or overcome such resistance.

One of the main challenges in the clinical translation of metabolic-targeted therapies lies in the heterogeneity of NPC. The disease exhibits varying metabolic profiles depending on genetic, epigenetic, and environmental factors. Thus, a personalized approach is crucial, where the metabolic landscape of each patient’s tumor is mapped out to tailor the most effective treatment regimen. This requires the integration of comprehensive metabolic profiling into the diagnostic process, posing logistical and technological challenges but also presenting an opportunity to revolutionize cancer treatment. Another significant challenge is the potential toxicity and side effects associated with targeting fundamental metabolic pathways that are also important to normal cells. Careful consideration and design of therapeutic agents that selectively target cancer cells without harming normal tissues are paramount. This specificity could potentially be achieved through delivery systems that target drugs directly to the tumor microenvironment or by designing agents that are activated specifically within the metabolic milieu of cancer cells. Future research should focus on unraveling the deeper layers of metabolic regulation and interaction in NPC. Studies exploring the interplay between metabolic pathways and the tumor microenvironment, including immune cells, could unveil new targets and strategies for therapy. Additionally, the exploration of genetic and epigenetic modulators of metabolic pathways in NPC could provide insights into the mechanisms of disease progression and therapy resistance. Emerging technologies such as CRISPR-Cas9 and single-cell sequencing offer exciting opportunities to dissect the molecular intricacies of metabolic reprogramming at unprecedented resolution and scale. These technologies could identify novel therapeutic targets and biomarkers critical for NPC progression, which have yet to be fully exploited.

In conclusion, the field of metabolic reprogramming in NPC is poised at a transformative junction, with the potential to significantly impact the clinical management of the disease. By continuing to integrate and leverage insights from basic research, the development of innovative, metabolic-targeted therapies can provide a beacon of hope for patients suffering from this challenging malignancy, ushering in a new era of precision oncology.

Disclosure of conflict of interest

None.