Driver Gene Mutations Reprogram Lipid Metabolism in Non‐Small Cell Lung Cancer

ABSTRACT

Non‐small cell lung cancer (NSCLC) is among the leading causes of cancer‐related deaths worldwide. Previous treatment regimens often have limited efficacy due to drug resistance and recurrence. Metabolic reprogramming participates in the initiation and progression of NSCLC, with prominent changes in lipid metabolism. Mutations in specific driver genes directly remodel lipid metabolic reprogramming in NSCLC by rewiring lipid synthesis, uptake, and catabolism, which confers cancer cells with enhanced proliferative and metastatic capacity. On this basis, targeted lipid metabolism reprogramming has become a promising new direction for the treatment of NSCLC. In this review, we examined the alterations in lipid metabolism in NSCLC, explored the mechanisms by which driver gene mutations change lipid metabolism in NSCLC, and provided possible therapeutic strategies targeting key lipid metabolism pathways at the current stage, aiming to offer a theoretical basis and prospects for the development of novel therapies targeting specific gene mutation subtypes of NSCLC.

1. Background

Globally, lung cancer is among the most studied malignant tumors and is characterized by high malignancy, with non‐small cell lung cancer (NSCLC) accounting for the majority of lung cancer cases [1]. Patients usually present with no obvious early symptoms, so most cases are diagnosed at advanced stages with poor clinical prognoses [2]. In clinical practice, common treatment methods for NSCLC include surgical resection, radiotherapy, and chemotherapy, as well as various other strategies, such as molecular targeted therapy and immunotherapy [3]. However, surgical treatment has certain limitations, and all other types of treatment have problems such as drug resistance, recurrence, and metastasis. Therefore, new treatment strategies for lung cancer need to be developed [4].

Metabolic reprogramming is a key biological feature of NSCLC that endows cancer cells with the ability to adapt to complex external environments and resist drug effects. By reshaping the metabolic product profiles inside and outside cells, lung cancer cells not only supply energy and biological raw materials for their own proliferation but also regulate their functional states and reshape the tumor microenvironment (TME), thereby driving the malignant progression of NSCLC [4, 5]. Metabolic reprogramming affects the occurrence and development of NSCLC to some extent, and this abnormal energy metabolism includes specific changes in lipid metabolism [6]. Lipids maintain cell structure, provide energy, and participate in cell signal transduction. Their metabolic processes generate a variety of biological intermediates, which can regulate multiple signaling pathways and thereby affect cell growth, proliferation, differentiation, and other processes [7]. NSCLC oncogenesis is driven by diverse oncogenic mutations, and sequential oncogenic events (oncogene activation and tumor suppressor loss) reshape its lipid metabolism. Driver genes cause metabolic characteristic changes in lung cancer cells, such as enhanced survival ability, evasion of immune surveillance, and proliferation. These driver genes (such as KRAS and EGFR) can regulate metabolism in an autonomous way in cells [8, 9]. Lipid metabolism reprogramming is associated with the increased invasiveness of cancer cells. Recent studies suggest that intervening in this abnormal metabolism can serve as a potential target for the treatment of NSCLC [10]. In this review, we explored the characteristics of lipid metabolism reprogramming in NSCLC, specifically the regulatory effects of different driver genes on lipid metabolism, and revealed that targeted lipid metabolism reprogramming is an effective strategy for the future treatment of NSCLC.

2. Alterations in Lipid Metabolism in NSCLC

Cells contain a rich variety of lipids, including fatty acids (FAs), triglycerides, phospholipids, and sterols. Lipids are widely distributed and are key components of biofilms, possessing functions such as energy storage and the regulation of physiological functions. Normal cells acquire exogenous fatty acids from circulation and rarely conduct de novo fatty acid synthesis. However, exogenous fatty acids fail to sustain the malignant proliferation of lung cancer cells, which consequently activate endogenous fatty acid biosynthesis. Moreover, all the key enzymes involved in endogenous FA metabolism in lung cancer cells are highly activated. In NSCLC, enhanced endogenous fatty‐acid biosynthesis represents a hallmark of lipid metabolism reprogramming in lung cancer cells [4, 5, 6].

FA synthesis occurs in the cytoplasm. This process begins with the production of citric acid by the tricarboxylic acid cycle, which can serve as a source of the synthetic precursor substance acetyl‐CoA (AcCoA). Under the catalytic action of ATP‐citrate lyase (ACLY), citric acid is converted into acetyl‐CoA. Subsequently, acetyl‐CoA carboxylase (ACC) will carboxylate it to form malonyl‐CoA. On this basis, fatty acid synthase (FASN) undergoes a series of condensation reactions and ultimately generates palmitic acid. This product can be further modified through carbon chain extension or desaturation to form various types of fatty acid molecules. In addition, the newly synthesized FA needs to be activated by acyl‐CoA synthase (ACSL) and converted into the acyl‐CoA form (Figure 1). This activation step is crucial for its subsequent participation in the biosynthesis of other lipids [2]. FASN plays a key role in lipid synthesis and is overexpressed in NSCLC. As mentioned above, FASN synthesizes palmitate (a long‐chain saturated fatty acid), which is an important component of other lipids. Enhanced FASN activity promotes NSCLC metastasis and mediates chemotherapy resistance, which is associated with a poor prognosis [11]. ACC is a key rate‐limiting enzyme in FA synthesis and regulates the neosynthesis of FA to meet the biosynthetic requirements of tumor growth [12]. In NSCLC, the upregulation of ACLY expression enhances the de novo synthesis of fatty acids, providing a sufficient supply of lipids for the unlimited proliferation of lung cancer cells and ultimately accelerating the progression of lung cancer [2, 13]. In vitro studies have shown that inhibiting ACLY can slow the growth of lung cancer cells and induce cell differentiation. Hanai et al. [14] demonstrated in their study using NSCLC cell lines that statins can promote apoptosis and differentiation by inhibiting ACLY. In addition to lipid synthesis, NSCLC cells can also obtain energy and maintain REDOX balance through the FA oxidation (FAO) pathway. FAO breaks down FA in mitochondria to generate AcCoA, NADH, and FADH2, which enter the tricarboxylic acid cycle (TCA) and the electron transport chain to produce ATP. This pathway enables lung cancer cells to adapt to nutrient‐deficient or hypoxic environments [15]. FAO also helps maintain REDOX homeostasis and neutralize reactive oxygen species (ROS) by generating NADPH, thereby reducing oxidative stress. In NSCLC, carnitine palmitoyltransferase 1 (CPT1), the key enzyme that regulates the entry of long‐chain FAs into mitochondria, is often highly expressed. Its inhibition can impede FAO, cause energy stress, and increase cell sensitivity to oxidative damage [16].

FIGURE 1.

Key enzymes in lipid metabolism and their inhibitors. Cellular lipid synthesis originates from acetyl‐CoA (AcCoA) provided by the tricarboxylic acid cycle in mitochondria, which is formed from citrate under the catalysis of ATP‐citrate lyase (ACLY). Through the catalysis of enzymes such as acetyl‐CoA carboxylase (ACC), fatty acid synthase (FASN), and acyl‐CoA synthetase (ACSL), various fatty acid molecules are subsequently converted into different types of lipids. Moreover, various fatty acid transporters mediate the uptake of exogenous fatty acids, collectively providing raw materials for the proliferation of lung cancer cells. Inhibitors targeting these enzymes hinder cancer cell proliferation by suppressing lipid synthesis and can be used in the clinical treatment of NSCLC.

Certain FA transporters are significantly correlated with the progression of NSCLC. For instance, CD36 is a scavenger receptor associated with the lipid uptake process and is highly expressed in lung cancer cells. Moreover, compared with that in primary lesions, the expression of CD36 is significantly greater in metastatic lesions [17]. CD8+ T cells with high expression of CD36 have reduced immune function. High‐level infiltration of this type of cell in the TME indicates a poor prognosis and poor therapeutic effects. Therefore, CD36 can be an effective target for the treatment of NSCLC [18]. Fatty acid‐binding proteins (FABPs) are a class of intracellular proteins. There are ten isomers in the human body that act as fatty acid transporters and are involved in the metabolism and signal transduction of FA. They are regarded as key mediators in metabolic and inflammatory processes. The abnormal expression of such proteins is closely related to the occurrence and development of NSCLC. For instance, the elevated expression of FABP4 (mainly found in adipose tissue) helps alleviate tumor growth and reduce lipid droplet content in tumor tissue, whereas the absence of FABP5 (mainly found in epidermal tissue) is associated with tumor metastasis [19].

Lipid synthesis in lung cancer cells increases, and its decomposition process is inhibited [20]. Lipid droplets are specialized organelles for excess lipid storage. Elevated lipid droplet abundance within lung cancer cells and adjacent tissues is therefore a hallmark metabolic feature of NSCLC. Lipid droplets can regulate the lipid metabolism of cells, provide the lipid components necessary for cell proliferation through lipophagy, and offer energy support for the proliferation and survival of cancer cells [21]. Studies have shown that an increase in lipid droplet content can promote the metastasis of NSCLC and mediate resistance to targeted therapy. The accumulation of lipid droplets in lung cancer cells leads to EGFR‐TKI resistance, which manifests as resistance to tyrosine kinase inhibitors (TKIs); patients with NSCLC treated with drugs that inhibit lipid droplets combined with TKIs have a better prognosis, suggesting that this treatment strategy may reverse the problem of TKI resistance [22].

There are significant differences in cholesterol metabolism between NSCLC cells and normal cells, involving enhanced absorption, synthesis, and accumulation of cholesterol but weakened excretion. This metabolic disorder promotes the occurrence and development of NSCLC [23]. Sterol regulatory element‐binding protein 2 (SREBP2) regulates cholesterol metabolism and promotes cholesterol synthesis. When the cholesterol level within cells decreases, SREBP2 is cleaved and activated from the complex state and then enters the nucleus and binds to the sterol regulatory element (SRE) sequence in the target gene, inducing the expression of genes involved in cholesterol synthesis (such as 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGCR)). Therefore, the upregulation of SREBP2 leads to increased cholesterol synthesis and absorption in lung cancer cells, providing energy and cell membrane components for tumor growth [24]. 27‐Hydroxycholesterol (27HC) is a cholesterol metabolite and has a dual regulatory effect on lung cancer cells [25]. On the one hand, 27HC, as a ligand of the liver X receptor (LXR), activates LXR and thereby upregulates the expression of cholesterol transporters, such as ATP‐binding cassette transporter A1 (ABCA1). The ultimate result is an increase in cholesterol excretion and a decrease in intracellular cholesterol levels. Moreover, 27HC downregulates the expression of SREBP2, thereby reducing the synthesis of cholesterol in lung cancer cells. These effects lead to the restricted growth of lung cancer cells, manifested as tumor suppressor effects [26]. On the other hand, 27HC can activate estrogen receptor β (ERβ), and ERβ is highly expressed in lung adenocarcinoma cells and is closely related to tumor progression. After ERβ activation, the activity levels of the NF‐κB and MAPK signaling pathways are increased, thereby promoting cell proliferation and migration. In addition, 27HC can increase the growth of lung cancer cells through the secretion of cytokines such as fibroblast growth factor 2 (FGF2) and IL‐6, demonstrating a tumor‐promoting effect [27, 28].

While multiple studies have confirmed augmented de novo lipid synthesis in NSCLC, critical controversies persist in this field. For one thing, lipid metabolic remodeling displays subtype specificity: some NSCLC subtypes rely on endogenous lipogenesis, while others prioritize exogenous lipid uptake, suggesting this metabolic shift is not a universal tumor hallmark [29]. Secondly, the same lipid mediator (e.g., arachidonic acid metabolites) can exert dual tumor‐promoting or tumor‐suppressive effects at different concentrations or within distinct microenvironments, indicating that its regulatory impact follows a non‐linear pattern [30]. Furthermore, there are conflicting views regarding the functions of lipid droplets. Most studies hold that lipid droplets facilitate tumor progression and drug resistance, yet accumulating evidence suggests they exert protective effects by sequestering toxic lipid intermediates [31]. Taken together, the impacts of lipid reprogramming on NSCLC are highly dependent on genetic background, microenvironment, and metabolic status; simply categorizing them as either oncogenic or tumor‐suppressive would be biased.

Current knowledge regarding the molecular mechanisms underlying lipid metabolic reprogramming in NSCLC remains incomplete, with several critical unresolved questions. To begin with, the causal triggering hierarchy is poorly defined: it remains ambiguous whether oncogenic mutations directly trigger metabolic remodeling, or pre‐existing metabolic perturbations create a permissive microenvironment that facilitates mutant clone outgrowth, and the causal link between these two events has not been validated [32]. Second, synergistic and compensatory signaling crosstalk across interconnected lipid metabolic branches (synthesis, uptake, oxidation, and storage) is incompletely characterized. The mechanism through which tumor cells maintain adequate lipid availability upon blockade of a single lipid pathway remains unclarified, which greatly compromises the stability and efficacy of lipid‐targeted therapies [30]. Third, investigations dissecting how aberrant cholesterol metabolism promotes NSCLC progression are still at an early stage [30]. Addressing these mechanistic unknowns is an indispensable prerequisite to translate basic discoveries in this field into viable clinical regimens.

3. Lipid Metabolism Changes in NSCLC With Driver Gene Mutations

Metabolic reprogramming, as a hallmark feature of cancer, plays a key role in the occurrence and development of NSCLC. This metabolic disorder is often related to mutant genes. The upregulation of oncogenes and the downregulation of tumor suppressor genes mediate the metabolic reprogramming of cancer cells (Figure 2), enabling them to meet the high demands for energy production and macromolecular building blocks, thereby achieving rapid proliferation [9, 33, 34].

FIGURE 2.

Mutant driver genes regulate the lipid metabolism process. Mutant EGFR activates the PI3K/AKT and RAS/MAPK signaling pathways, whereas mTORC1, which acts as a common downstream node of both pathways, not only activates the transcription factor SREBP1 to upregulate the expression of lipid metabolism‐related genes (ACC, FASN, ACLY, and SCD1) but also increases the splicing efficiencies of lipid synthesis‐related genes by SR proteins through the activation of downstream S6K and serine/arginine‐rich protein kinase 2 (SRPK2). This ultimately leads to enhanced lipid synthesis and promotes the proliferation of lung cancer cells. Moreover, AKT inhibits the ability of glycogen synthase kinase 3 (GSK3) to reduce the ubiquitination‐mediated degradation of mature SREBP1, thereby increasing its stability. Additionally, mutant p53 inhibits AMP‐activated protein kinase (AMPK), which reduces the phosphorylation of SREBP1, resulting in upregulated SREBP1 activity and the production of effects similar to those of the aforementioned dual pathways.

3.1. KRAS Mutation

The KRAS gene is a member of the rat sarcoma virus oncogene family (RAS) and is located on the short arm of chromosome 12. From a functional perspective, KRAS is a membrane‐binding regulatory protein (G protein) that binds to guanine nucleotides. When it binds to GTP, it is activated and acts as a monomer or dimer to bind with its downstream molecules, mediating a series of signaling cascades [35]. KRAS is the oncogenic driver gene with the most mutations in NSCLC, with a mutation rate close to 30%. The codons G12 (90%), G13 (3%–6%), and Q61 (1%), which have the most mutations, are the causes of the dysfunctional GTPase proteins that lead to the persistent active state of GTP‐binding KRAS [36].

KRAS mutations increase lipid metabolism levels and promote the occurrence and development of NSCLC. Mutant KRAS activates downstream signaling pathways, leading to an increase in lipid production in cancer cells and promoting cell proliferation and growth [37]. Metabolic reprogramming endows KRAS‐driven NSCLC with potent anabolism to sustain rapid proliferation, mainly via upregulated lipid metabolic rate‐limiting enzymes ACLY and ACSL3. These enzymes augment lung cancer cells' lipid synthesis, uptake, accumulation, and β‐oxidation. Tumors then generate abundant lipid mediators to build an immunosuppressive TME and utilize TME‐derived exogenous FA, forming a vicious cycle supporting malignant progression and metastasis [38, 39]. These findings can lead to new therapeutic strategies, namely, targeting the changes in lipid metabolism driven by KRAS in NSCLC. By inhibiting metabolic pathways dependent on KRAS‐mutant cells, it potentially promotes the apoptosis of cancer cells, reverses the immunosuppressive TME, enhances immune system function, and achieves better immunotherapy effects [39].

Mutation of the KRAS gene drives the progression of NSCLC by reprogramming lipid metabolism. On the one hand, it enhances the uptake of exogenous lipids, such as clearing serum lipids through the FA transporter CD36, and is further strengthened when the regulated in development and DNA damage responses 1 (REDD1) gene is deleted. It also coordinates endogenous synthesis and catabolism [40]. Despite the greater reliance of KRAS‐mutant cells on exogenous lipids, ACC and FASN are essential synthases whose suppression restrains tumor growth and disrupts signaling cascades, exemplified by FASN inhibition blocking the PI3K‐AKT–mTOR pathway. Meanwhile, KRAS upregulates SREBP1 and activates ACSL3 to boost FA oxidation, sustaining anabolism, mitochondrial function, energy supply, and antioxidant defense [41]. ACSL couples long‐chain FA with coenzyme A (CoA) to generate acyl‐CoA. Studies have shown that morphological defects do not occur in ACSL3 gene‐deficient mice but can prevent the occurrence of KRAS‐driven NSCLC. Therefore, ACSL3 may represent a very good therapeutic target. Although there is currently no specific inhibitor of ACSL3, there is evidence that inhibiting FASN has a similar effect on ACSL3 silencing, opening up possible avenues for new treatment strategies for NSCLC [42].

Precise stratification of KRAS‐mutant NSCLC requires comprehensive consideration of mutant subtypes, co‐mutation status, and treatment lines [39]. KRAS‐G12C is the dominant subtype. Around 24% of patients exhibit loss‐of‐allele KRAS (LAKR), characterized by loss of wild‐type KRAS alleles, presenting shorter median overall survival (16 vs. 30 months, p = 0.017) than non‐LAKR counterparts. LAKR cells overexpress FASN and fatty acids and are more sensitive to FASN inhibitors, making LAKR a predictive biomarker for such agents. Co‐administration of FASN inhibitors (TVB‐3664) and KRAS‐G12C inhibitors (MRTX849) produces synergistic antitumor activity in LAKR patients [43]. Distinct KRAS subtypes (G12C, G12D, G12V) exert divergent effects on lipid metabolism and the immune microenvironment, necessitating differentiated intervention strategies [39]. Advanced KRAS‐mutant NSCLC patients show heterogeneous responses to chemo‐ and immunotherapy. STK11 co‐mutation reduces lipid metabolic gene expression and shortens survival, indicating enhanced lipid‐targeted therapy is necessary. Lipid metabolic reprogramming targeting is a viable strategy after first‐line treatment failure. For sotorasib‐resistant patients, combined lipid metabolism inhibitors reverse resistance via autophagy‐dependent lipid peroxidation and ferroptosis [29]. These findings suggest that individualized combination therapeutic strategies should be formulated based on KRAS mutant subtypes, co‐mutation profiles (e.g., STK11, KEAP1, p53), and lines of treatment.

3.2. EGFR Mutation

Epidermal growth factor receptor (EGFR) belongs to the epithelial growth factor receptor (ErbB) family and is responsible for transmitting microenvironmental signals into cells, thereby mediating processes such as cell proliferation, migration, and differentiation [44]. Approximately 20% of NSCLC cases carry EGFR mutations, among which exon 19 deletion and amino acid substitutions in exons 18/21 are the most common. This mutant gene not only promotes tumor mitosis through related signaling pathways and enhances tumor invasion and antiapoptotic capabilities but also leads to metabolic remodeling, especially the reprogramming of lipid metabolism, which is closely related to EGFR signaling. A deeper understanding of these interaction mechanisms suggests potential strategies for treating this type of lung cancer by intervening in lipid metabolism [9, 10].

Mutant EGFR activates the PI3K/AKT and MAPK pathways, inducing adipogenesis. The PI3K/AKT and RAS/MAPK signaling pathways regulate lipid synthesis through multilevel mechanisms, supporting the growth of NSCLC. Among them, AKT can directly phosphorylate and activate ACLY, promoting the generation of AcCoA and providing raw materials for the synthesis of FA and sterols [45]. Moreover, these two pathways also activate the transcription factor SREBP1 through mTORC1, thereby upregulating key genes involved in FA synthesis, such as FASN. mTORC1 can also increase the activity of SREBP1 by inhibiting Lipin1. Among the members of the SREBP family, SREBP1 mainly regulates the synthesis of FA, phospholipids, and triglycerides, whereas SREBP2 is involved in cholesterol synthesis. Both are regulated by the PI3K/AKT pathway [46]. In addition, Myc can not only cooperate with SREBP1 to promote FA synthesis but also directly bind to the promoters of genes such as FASN and SCD to independently activate the synthetic pathway and participate in the regulation of FAO. In addition to the abovementioned pathways, signaling pathways such as the Hippo, Wnt/β‐catenin, and JAK/STAT3 pathways also play significant roles in lipid metabolism reprogramming [47].

As mentioned earlier, the accumulation of lipid droplets in NSCLC may be associated with the development of EGFR‐TKI resistance. In fact, lipid droplets can regulate the activation state of EGFR through multiple molecular pathways. The formation of lipid droplets helps to reduce the intracellular ROS level. This reducing environment can promote the phosphorylation of EGFR and further activate its downstream MEK/ERK signaling pathway. The accumulation of lipid droplets can also upregulate the activity of fatty acid synthase, enhancing the activation of EGFR through FASN‐mediated palmitoylation, a process that can be effectively inhibited by FASN inhibitors such as orlistat. Therefore, lipid droplet accumulation is an important link in promoting the continuous activation of EGFR through the regulation of ROS homeostasis and FASN activity. Accordingly, the development of drugs that can specifically inhibit lipid droplet formation may provide new therapeutic ideas for intervening in the EGFR pathway [48]. In addition, by phosphorylating stearoyl‐CoA desaturase‐1 (SCD1), EGFR interacts directly with and maintains the stability of the SCD1 protein, increasing the synthesis of monounsaturated FAs (MUFAs). An increased expression level of phosphorylated SCD1 indicates a poor prognosis for patients with NSCLC. These results collectively indicate that targeted lipid metabolism reprogramming is an effective approach for treating EGFR‐mutant NSCLC [49].

Acquired resistance following first‐line EGFR‐TKI therapy poses a major clinical challenge. Combined targeting of lipid metabolism may serve as an effective strategy to overcome drug resistance: the lipid metabolism inhibitor (20S)‐Protopanaxatriol (g‐PPT) markedly suppresses SCD1 expression and reduces lipid droplet abundance, and its combination with gefitinib reverses resistance and blocks the activation of phosphorylated‐EGFR (p‐EGFR) and downstream signaling cascades [50]. In addition, FASN inhibitors (e.g., AZ12756122) can reduce FASN expression and activity as well as suppress activation of the EGFR and AKT/mTOR pathways in EGFR‐mutant NSCLC cell models with EGFR‐TKI resistance. Systematic reviews and meta‐analyses are being conducted to evaluate regimens combining statins with EGFR‐TKIs for EGFR‐mutant NSCLC. Preclinical studies have demonstrated that statins may potentiate the antitumor activity of EGFR‐TKIs, yet clinical evidence remains inconsistent [51].

3.3. p53 Mutation

The tumor suppressor gene p53 is a common mutation gene in human tumors. p53 regulates the cell division cycle, promotes DNA repair, damages cell death processes, and inhibits tumourigenesis [52]. In addition, p53 has emerged as a key metabolic regulatory factor that controls the enzymatic biological activity of lipid metabolism. These metabolic regulatory effects differ before and after p53 mutation [53].

Wild‐type p53 (wtp53) may inhibit malignant transformation. It regulates multiple lipid‐metabolizing enzymes to promote lipid catabolism and facilitate cholesterol efflux. Specifically, wtp53 can transcriptionally activate a variety of enzymes that promote lipid catabolism, including acyl‐CoA dehydrogenase, which induces FA β‐oxidation; HMG‐CoA lysase‐like 1, which participates in ketone body metabolism; malonyl‐CoA decarboxylase, which converts malonyl‐CoA to AcCoA; and Lipin1, which supports lipid catabolism. The AcCoA produced by lipid decomposition can provide raw materials for the TCA cycle. In addition, wtp53 promotes cholesterol excretion and reduces intracellular lipid accumulation by activating ABCA1, phospholipid transfer lipoproteins, carboxyl ester lipase, and apolipoprotein B [52, 53]. Moreover, wtp53 inhibits the synthesis and uptake of cholesterol. ABCA1 is responsible for transporting cholesterol from the cell membrane to the endoplasmic reticulum. Wtp53 activates the ABCA1 gene through transcription, inducing this retrograde transport pattern of cholesterol and reducing cholesterol levels, thereby hindering the maturation of the SREBP2 protein (which mainly regulates genes involved in cholesterol synthesis), inhibiting the activity of the mevalonic acid pathway, and ultimately suppressing the occurrence and development of tumors [54].

Unlike wtp53 gene tumors, the expression levels of genes related to lipid catabolism and cholesterol efflux in mutant p53 (mutp53) tumors are decreased. Moreover, statins have been shown to have stronger antitumour effects on mutp53 lung cancer cells, suggesting that mutp53 may promote tumor growth by maintaining lipid anabolism; thus, cholesterol metabolism has become a potential therapeutic target for mutp53 tumors [55]. Mutp53 regulates lipid metabolism by interfering with the activity of AMPK. Specifically, AMPK, as a key upstream kinase, can reduce the synthesis of fatty acids by phosphorylating and inhibiting the activities of SREBP1 and ACC. However, mutp53 weakens this function of AMPK, resulting in increased inhibitory effects on SREBP1 and ACC. Eventually, they jointly promote the production of fatty acids and drive the growth of NSCLC [56]. Moreover, a lung cancer risk prediction model based on FA metabolism‐related genes also confirmed the lipid regulatory mechanism of mutp53. In this risk prediction model, the mutp53 group had a higher risk score, and AMPK is the binding site of p53, which inhibits FA synthesis by phosphorylating and inhibiting ACC and SREBP1. Mutp53 can not only increase FA synthesis by inhibiting AMPK but also promote the pathological progression of tumors. Therefore, the FA metabolic pathway may serve as a therapeutic target for mutp53‐related NSCLC [57].

Mutp53 status has emerged as a critical biomarker for predicting the therapeutic efficacy of statins. A retrospective analysis based on Taiwan's National Health Insurance Research Database demonstrated that statin treatment reduced the 5‐year mortality rate by 57% among patients with early‐stage lung cancer (OR = 0.43, p < 0.001) [55]. In vitro experiments verified that NSCLC cells carrying mutp53 or p53 deletion exhibit markedly higher sensitivity to lovastatin compared with wtp53 cells [58]. For patients with mutp53 NSCLC who experience disease progression after first‐line chemotherapy or targeted therapy, combination therapy incorporating statins may serve as an effective later‐line treatment option. Furthermore, in NSCLC harboring concurrent p53 and KRAS mutations, mutp53 can boost tumor immunogenicity and improve responses to immunotherapy. These observations indicate that p53 mutational status not only modulates sensitivity to lipid metabolism‐targeted therapies but also facilitates efficacy stratification for immunotherapies [55].

3.4. AKT Mutation

AKT is composed of three homologous genes, AKT1, AKT2 and AKT3, and plays a significant role in cell signal transduction. Its downstream effects include inhibiting apoptosis, regulating the cell cycle and promoting tumorigenesis [59]. The upregulation of the PI3K/AKT/mTOR signaling pathway has been confirmed in a considerable proportion of patients with NSCLC, and the prognosis of these patients is often poor [6, 60].

As mentioned above, de novo lipid biosynthesis is enhanced in NSCLC, providing raw materials for the formation of cell membranes and supporting their accelerated growth and proliferation. AKT phosphorylates ACLY and other lipid synthases, enhancing the de novo lipid synthesis process and promoting the production of AcCoA in the cytoplasm for FA synthesis [61, 62]. The AKT signaling pathway mainly promotes de novo lipid synthesis in NSCLC through the activation of the SREBP transcription factor family. In the inactive state, SREBP localizes to the endoplasmic reticulum. Its activation depends on the release of the N‐terminal domain by protein cleavage, which then translocates to the nucleus and binds to sterol regulatory elements, thereby upregulating the expression levels of various FA and sterol synthases, including ACLY. AKT regulates SREBP through two key downstream pathways: one is to promote its processing and nuclear translocation via mTORC1, and the other is to reduce the ubiquitination‐mediated degradation of mature SREBP by inhibiting GSK3, thereby increasing its stability. In addition, S6K downstream of mTORC1 can phosphorylate and activate the splicing kinase SRPK2, thereby regulating the function of the SR protein, enhancing the splicing efficiency of mRNA related to lipid synthesis, and further supporting lipid generation. Owing to the high expression levels of SREBPs, SRPK2 and the synthases they regulate, they have become promising targets in the treatment of NSCLC [61, 62]. The AKT pathway plays a significant role in lipid metabolism, promoting lipid synthesis through multiple mechanisms and providing the energy and lipids necessary for the growth of cancer cells. The development of inhibitors targeting these mechanisms, such as ACLY, SREBP and SRPK2 inhibitors, may provide new strategies for cancer treatment.

4. Targeted Lipid Metabolism Reprogramming for NSCLC

4.1. Lipids Act as Biomarkers

Lipids themselves are the main components of cell membranes and play crucial roles in the occurrence and development of NSCLC [63]. Studies on the role of lipid spectroscopy in NSCLC have shown that lipids can be used to identify tissue molecules, determine treatment outcomes, and develop new treatment regimens and cancer biomarkers. For instance, sphingomyelin (SM) is downregulated in NSCLC tissues, which may be related to its role in cell signal transduction and cell death. In addition, research has shown that the expression of phosphatidylcholine (PC) is also downregulated in NSCLC tissues, which may be related to its role in the structure and function of cell membranes [64]. Type II alveolar epithelial cells synthesize and secrete pulmonary surfactants, whose main components are phospholipids and surfactant proteins [65]. In pathological research on NSCLC, the content of dipalmitoyl phosphatidylcholine (DPPC) in cancer tissues has been confirmed to be lower than that in healthy tissues. DPPC is the phospholipid present in the greatest proportion (approximately 85%) in pulmonary surfactant, and its primary function is to maintain alveolar stability and prevent their collapse. Studies have shown that the dysfunction of Type II alveolar epithelial cells and the subsequent disruption of pulmonary surfactant homeostasis are very likely important factors promoting the occurrence and development of NSCLC [66].

Sphingomyelin (SM) is a major bioactive component on cell membranes and is involved in cell proliferation and survival. Research showed that the SM (d35:1) level of patients in the postoperative recurrence group of lung adenocarcinoma was significantly greater than that in the nonrecurrence group. Furthermore, the results indicated that the level of sphingosine‐Cer(d42:0) in the recurrence group was also elevated and positively correlated with SM(d35:1), suggesting that the increased transformation from ceramide (Cer) to SM might have promoted the growth and survival of tumor cells. Sphingomyelin (d35:1), as a biomarker for postoperative recurrence of lung adenocarcinoma, has potential clinical application value and can guide clinical practice in conducting more precise recurrence risk assessments and formulating treatment plans [67, 68]. Disorders of lipid metabolism are closely related to the occurrence and development of NSCLC. Lipids such as DPPC and SM can serve as potential markers for NSCLC and can be used for early screening, diagnosis, and prognosis assessment. Further research on the role of biomarkers by lipid spectroscopy in NSCLC is conducive to the development of new diagnostic and therapeutic methods.

4.2. Lipid Metabolism Enzyme Inhibitors

Lipid synthesis is regulated by multiple factors, including oncogenes such as KRAS, EGFR, and AKT, as well as tumor suppressor genes such as p53. Alterations in the expression of these genes and signaling pathways lead to an increase in the expression of lipogenic enzymes. Inhibiting fat synthase has been proven to have antitumour effects in the clinical treatment of NSCLC and is thus a potential therapeutic strategy [69].

FASN is a key enzyme in the de novo synthesis of FA and can promote the metastasis of NSCLC cells and their resistance to cisplatin [4]. In NSCLC, mutant EGFR activates FASN mediated by SREBPs, thereby promoting the palmitoylation of EGFR and leading to TKI resistance. Orlistat can inhibit these effects [48]. TVB‐2640 is a new type of FASN inhibitor that not only has an inhibitory effect on FASN but can also reduce lipid production. Clinical trials of TVB‐2640 as a monotherapy and in combination with paclitaxel for the treatment of advanced NSCLC are ongoing. Studies have shown that the disease control rate (DCR) of TVB‐2640 monotherapy is 42%, and the DCR of combined paclitaxel treatment reaches 70%, with a partial response (PR) observed. In addition, TVB‐2640 enhances antitumour immunity by improving T‐cell function and reducing lipid droplet accumulation, especially in NSCLC with KRAS mutations [70, 71].

ACC is a key enzyme that activates FA synthesis in NSCLC and is highly expressed in NSCLC cells; its activity is crucial for the growth and survival of NSCLC cells. ND‐646 is an orally bioavailable ACC inhibitor that binds to the BC domain of ACC and disrupts the dimerization of enzymes, thereby inhibiting their activity and blocking the synthesis of FA. ACC inhibitors may affect the FA synthesis process in normal cells, and further research on the safety of ACC inhibitors is needed [72]. Similarly, ACLY also plays a core role in the cholesterol and fatty acid synthesis pathways and is an ideal antitumour target. This enzyme is responsible for catalyzing the conversion of citric acid to acetyl‐CoA. This product is not only an important precursor for lipid synthesis but also mediates cellular processes such as protein acetylation. The key role of ACLY in the occurrence and development of NSCLC and its targeted value have been confirmed by multiple studies [2]. Hanai et al. [14] constructed ACLY knockdown A549 cells through RNA interference and found that cell proliferation was impaired and that apoptosis was increased, accompanied by differentiation and mesenchymal–epithelial transition phenomena. The Hatzivassiliu team also confirmed that inhibiting ACLY through RNA interference or using the small‐molecule inhibitor SB‐204990 could significantly suppress the proliferation of A549 cells, and it was observed in mouse models that ACLY knockdown led to a significant reduction in tumor volume [73]. These results consistently indicate that targeting ACLY can effectively inhibit the formation of new fat and induce growth arrest. In terms of regulatory mechanisms, the acetylation of lysine residues at positions 540, 546, and 554 (3 K sites) on the ACLY polypeptide chain can promote lipid synthesis and tumor growth. These sites can also be ubiquitinated, and there is a competitive relationship between the two modifications. In lung cancer tissues, the acetylation level of ACLY significantly increases, especially under high‐glucose conditions. There is a significant increase in the acetylation level of ACLY in lung cancer tissues, which is characteristic of tumor lipid metabolism reprogramming. P300/calcium‐binding protein‐related factor acetyltransferase stabilizes the ACLY protein by preventing its ubiquitination‐mediated degradation and enhancing its lipid synthesis capacity [74]. As a core molecule connecting glucose metabolism and lipid metabolism, the activity of ACLY is precisely regulated by posttranscriptional modifications and plays a key role in the development of NSCLC. Inhibiting ACLY not only affects the neosynthesis of FA but also may influence epigenetic modifications and cellular metabolic states by altering AcCoA levels, thus making it a potential target for the treatment of NSCLC [4].

4.3. Lipid Metabolism Inhibitors Combined With Immunotherapy

Lung cancer cells produce large amounts of fatty acids through de novo synthesis pathways, leading to FA enrichment in the tumor microenvironment (TME). This reprogramming of lipid metabolism can affect the function of immune cells, thereby influencing the responses of patients with NSCLC to immune checkpoint inhibitors. The accumulation of FAs can affect the function of effector T cells and M1‐type macrophages and promote the production of regulatory T cells (Tregs) and M2‐type macrophages, ultimately leading to an immunosuppressive tumor microenvironment. In addition, lipid metabolism reprogramming in NSCLC activates metabolic checkpoints within immune cells, further creating an immunosuppressive environment [75, 76]. Lung cancer cells utilize these metabolic pathways and simultaneously secrete immunosuppressive factors to evade immune responses and suppress antitumour immunity. These metabolic interactions highlight the crucial role of lipid metabolism reprogramming in shaping the immunosuppressive microenvironment of NSCLC, suggesting a novel therapeutic target [5]. The particularity of lung cancer cell metabolism is directly related to its characteristics, such as invasion and metastasis. Therefore, blocking changes in the metabolic and energy acquisition methods of lung cancer cells may increase the efficacy of other therapies (such as immunotherapy) and prolong the survival period of patients [77]. FASN is a key enzyme in the fatty acid synthesis pathway. FASN inhibition can reduce the production of fatty acids by tumor cells, thereby improving the immunosuppressive tumor microenvironment. FASN inhibitors, such as C75, have been combined with PD‐1 inhibitors in clinical trials for the treatment of various cancers, including NSCLC, to enhance the antitumour immune response [76]. Although immunotherapy aimed at restoring T‐cell function in the immune microenvironment has achieved certain therapeutic effects, some patients experience irreversible adverse reactions during the treatment period. Studies have shown that the immune response of tumor cells to T cells is enhanced after lipid metabolism is improved in lung cancer cells, suggesting the potential role of combined targeted lipid metabolism and immunotherapy. In mouse experiments, avasimibe demonstrated anticancer effects by inhibiting acyltransferases, especially when combined with anti‐PD‐1 drugs [78]. Targeting tumor lipid metabolism is an effective approach for the synergistic treatment of NSCLC. Combining lipid metabolism inhibitors with immunotherapy aims to create a more favorable metabolic environment for immune cells and ultimately enhance the efficacy of antitumour immune responses [79].

4.4. Targeting Cholesterol Metabolism in NSCLC

Abnormal cholesterol metabolism within cells is considered an emerging marker of NSCLC. Intervening in the synthesis and transport of cholesterol has become a key link in inhibiting the progression of this tumor type. At present, the main strategies focus on its biosynthetic pathways, such as the use of statins to inhibit the activity of the rate‐limiting enzyme HMGCR. In addition, the targeted transportation and delivery of drugs using cholesterol carrier systems also demonstrate good therapeutic potential [80]. Statins are safe and effective and have few side effects when used in clinical antitumour drugs. These drugs reduce low‐density lipoprotein‐cholesterol (LDL‐C) levels and increase high‐density lipoprotein‐cholesterol (HDL‐C) levels by inhibiting HMGCR [81]. Studies have shown that patients with hypercholesterolaemia have a lower risk of lung cancer when they consume larger amounts of statins. Statins can also significantly prolong the overall survival period of patients with lung cancer. In addition to influencing cholesterol metabolism in lung cancer cells, statins can effectively regulate the TME of lung cancer cells. That is, they reverse the immune‐cold (limited tumor invasion) TME of NSCLC to an immune‐hot TME through the cholesterol synthesis pathway, significantly enhancing the efficacy of immune checkpoint blockade, thereby inhibiting tumor progression and improving the effect of immunotherapy [82, 83]. Statins combined with other antitumour therapies are gradually showing potential. One study revealed that the overall survival of patients with NSCLC treated with statins combined with TKI drugs is longer than that of patients treated with TKI monotherapy, and it can also improve the resistance to gefitinib, although this effect was observed only in vitro experiments. In addition, Chen et al. [84, 85] reported that after treatment with atorvastatin, the level of KRAS protein in tumor cells from patients with KRAS‐mutant NSCLC decreased, and resistance to gefitinib decreased.

5. Discussion

Lipid metabolism reprogramming can promote the occurrence and development of NSCLC, which involves the enhanced functions of various FA synthases and FA transporters, as well as the accumulation of lipid droplets in lung cancer cells. Moreover, the corresponding metabolic enzymes and metabolites involved in cholesterol metabolism in NSCLC also exhibit cancer‐promoting characteristics. Mutations in certain driver genes regulate lipid metabolism reprogramming, further promoting the occurrence, development, and drug resistance of NSCLC. The relevant oncogenic signals promote the proliferation and metastasis of lung cancer cells by activating related transcription factors and metabolism‐related signaling pathways and synergistically upregulating metabolic processes such as FA synthesis, uptake, and oxidation. Among them, the SREBP transcription factor family is the common point of action through which several driver genes regulate lipid metabolism mechanisms and may be ideal therapeutic targets. Thus, lipid metabolism can be regarded as a downstream effector of mutant driver genes, and, in combination with other lung cancer treatment options (such as immunotherapy), drug resistance can be reduced. In the future, efforts can focus on exploring the rational combination of lipid metabolism inhibitors with various approaches, including targeted therapy, immune checkpoint inhibitors, and chemotherapy, with the aim of synergistically killing tumors and reversing drug resistance. For distinct driver mutations, targeted interventions against lipid metabolism should be stratified according to mutant subtypes, co‐mutation profiles, and treatment phases. Meanwhile, disease staging as well as first‐line and drug‐resistance clinical settings shall be integrated to develop individualized combination therapeutic strategies, thereby enabling precise clinical decision‐making. In conclusion, targeting lipid metabolism reprogramming, understanding its association with mutant driver genes, and combining it with existing treatment methods are expected to open a new path for the treatment of NSCLC with driver gene mutations.

Author Contributions

Jinxing Lin: writing – original draft, writing – review and editing. Zhonghao Pang: writing – review and editing, methodology. Zhihua Jiang: methodology, resources. Feng Li: supervision, investigation.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.