Lipid homeostasis dysregulation in oral cancer drives metabolic reprogramming and offers novel diagnostic and therapeutic opportunities

Abstract

Oral cancer remains a significant global health challenge, with oral squamous cell carcinoma (OSCC) being the predominant histological type. Recent research has highlighted the critical role of metabolic reprogramming in oral carcinogenesis, particularly alterations in lipid homeostasis that contribute to disease progression and development. This review synthesizes current knowledge on lipid metabolism dysregulation in oral cancer, focusing on key aspects of metabolic reprogramming mechanisms, serum lipid profile alterations, lipid peroxidation pathways, immunometabolic interactions, and emerging therapeutic strategies. Mechanistically, OSCC exhibits significant alterations in key lipid metabolic enzymes, including upregulation of fatty acid synthase and ATP citrate lyase, and downregulation of carboxylesterase 2 (CES2), collectively promoting tumor growth and metastasis. These enzymatic changes are orchestrated through complex signaling pathways, notably the PI3K/AKT/mTOR axis, and manifest in altered membrane lipid composition, particularly within lipid microdomains that influence both cell signaling and drug resistance. Clinically, OSCC patients demonstrate characteristic serum lipid profile alterations, including reduced levels of total cholesterol, high-density lipoprotein cholesterol, and specific apolipoproteins, which show promise as non-invasive biomarkers for early detection and prognosis. Furthermore, enhanced lipid peroxidation through reactive oxygen species presents a double-edged sword in carcinogenesis, with oxidation products like malondialdehyde both contributing to mutagenesis and serving as potential diagnostic indicators. The complex interplay between lipid metabolism and tumor immunity, particularly through CD36 and sphingosine-1-phosphate signaling pathways, creates opportunities for immunometabolic interventions. Emerging therapeutic strategies targeting lipid metabolism include lipid-based nanoparticle drug delivery systems, metabolic enzyme inhibitors, and immunometabolic modulators, with promising preclinical results. Despite significant advances, challenges remain in translating these findings into clinical applications, necessitating further research on combination therapies, biomarker validation, and personalized treatment approaches. This comprehensive review provides valuable insights for both basic researchers and clinicians, potentially facilitating the development of novel diagnostic tools and therapeutic strategies for oral cancer management.

Introduction

Oral cancer represents a significant global health challenge, ranking as the 16th most common malignancy worldwide, with oral squamous cell carcinoma (OSCC) being the predominant histological type. The epidemiological landscape shows distinct geographical and demographic patterns, with notably higher incidence rates in regions such as India, Australia, and parts of Europe [1], while demonstrating a marked gender disparity with higher male prevalence and increased risk with age [2]. Recent research has highlighted the critical role of metabolic reprogramming in oral cancer development, particularly the alterations in glycolysis and mitochondrial function known as the Warburg effect [3, 4]. These perturbations in metabolic homeostasis, characterized by increased glycolysis and decreased mitochondrial activity, support rapid cancer cell proliferation and survival under hypoxic conditions. Furthermore, metabolomic studies have revealed distinct metabolic signatures specific to oral cancer, which not only serve as potential biomarkers for early diagnosis and prognosis [5, 6] but also highlight the importance of metabolic homeostasis in cancer progression. Among these metabolic alterations, lipid homeostasis has emerged as a critical factor in understanding tumor progression and identifying potential therapeutic targets [7].

A fundamental question in OSCC pathogenesis concerns the temporal sequence of metabolic alterations: do changes in lipid homeostasis precede malignant transformation or merely reflect established cancer metabolism? Emerging evidence suggests that lipid metabolic reprogramming may serve as both a predisposing factor and a consequence of oral carcinogenesis. Studies of oral potentially malignant disorders (OPMDs) reveal that altered serum lipid profiles, including decreased HDL-C and total cholesterol levels, are present before frank malignancy develops, suggesting that lipid homeostasis disruption may precede rather than follow OSCC formation [8, 9]. Furthermore, chronic exposure to carcinogens such as tobacco and alcohol can induce metabolic stress and hypoxic conditions in oral mucosa, potentially triggering early lipid metabolic alterations through HIF-1α-independent pathways [10] before morphological changes become apparent. This raises the intriguing possibility that characteristic "cancer-like" lipid patterns may represent early biomarkers of carcinogenic risk rather than simple consequences of established malignancy. The distinction between cause and consequence has profound implications for both early detection strategies and our understanding of the fundamental mechanisms driving oral carcinogenesis.

Understanding these temporal relationships is crucial because they determine whether lipid alterations represent viable targets for cancer prevention or merely diagnostic markers of established disease. In the context of metabolic alterations in oral cancer, lipid homeostasis plays a particularly crucial role in disease progression and development. The reprogramming of lipid metabolism in OSCC is characterized by distinct molecular changes at the tissue level, including increased intracellular cholesterol and glycerophospholipid levels within tumor tissues, which are essential for membrane biogenesis and cell signaling [11, 12]. This metabolic shift involves multiple regulatory mechanisms, such as the downregulation of carboxylesterase 2 (CES2), which leads to mitochondrial dysfunction and promotes cancer cell survival and metastasis. The complexity of lipid metabolism dysregulation extends beyond cancer cells themselves to the tumor microenvironment, where enhanced lipid biosynthesis in cancer-associated fibroblasts (CAFs) supports OSCC progression through the IL8/AKT/p-ACLY axis [13]. At the genetic level, metastasis-associated enhancers (MAEs) regulate critical lipid metabolism-related genes, including ACAT1, OXSM, and VAPA, while transcription factors like CBFB modulate lipid metabolism gene expression, both significantly influencing OSCC progression and patient outcomes [14]. These alterations in lipid metabolism not only contribute to disease progression but also offer promising clinical applications, as evidenced by the association of lipid metabolism-related genes such as ELOVL6 with poor prognosis [8] and the potential therapeutic opportunities through targeting pathways such as PI3K/AKT/MYC signaling and cholesterol regulation [7, 12]. Notably, serum lipid profiles, including cholesterol and HDL levels, have shown inverse relationships with oral cancer risk, suggesting their potential utility as biomarkers for early detection [15, 16].

Although substantial progress has been made in understanding the role of lipid homeostasis in oral cancer, several critical aspects remain to be fully elucidated. While individual lipid metabolic pathways and their alterations have been studied, a comprehensive understanding of how these pathways interact and collectively contribute to oral cancer progression is still lacking. Additionally, the dynamic interplay between lipid metabolism and other metabolic processes, such as glucose metabolism and oxidative phosphorylation, in the context of oral cancer has not been systematically reviewed. This review aims to bridge these knowledge gaps by providing an integrated analysis of lipid homeostasis in oral cancer, with particular emphasis on metabolic reprogramming mechanisms, the role of serum lipid profiles in diagnosis and prognosis, lipid peroxidation pathways, and the interaction between lipid metabolism and tumor immunity. Furthermore, we explore emerging therapeutic strategies targeting lipid metabolism, offering new perspectives for oral cancer treatment. By synthesizing recent advances in this field, this review provides valuable insights for both basic research and clinical applications, potentially facilitating the development of novel diagnostic tools and therapeutic approaches for oral cancer.

Mechanisms of lipid metabolism reprogramming in oral cancer

Multiple key enzymes involved in lipid metabolism undergo significant alterations in OSCC, collectively contributing to tumor progression through various mechanisms. These enzymatic changes not only affect cellular lipid homeostasis but also influence tumor cell proliferation, survival, and metastatic potential. In the tumor microenvironment, phosphorylated ATP citrate lyase (p-ACLY), a crucial enzyme connecting glucose metabolism to lipid synthesis, is notably upregulated in cancer-associated fibroblasts (CAFs). This upregulation occurs through the IL8/AKT/p-ACLY signaling axis, leading to enhanced lipid synthesis and subsequent promotion of tumor progression. The activation of this pathway suggests that targeting p-ACLY could be a promising therapeutic strategy for OSCC treatment [13]. This metabolic shift is further evidenced by increased levels of cholesterol and glycerophospholipids, including phosphatidylcholines and phosphatidylethanolamines, indicating enhanced de novo lipogenesis in OSCC tissues. These alterations in membrane lipid composition play crucial roles in maintaining cancer cell membrane fluidity and supporting various cellular processes essential for tumor growth [11].

Conversely, carboxylesterase 2 (CES2), an enzyme responsible for hydrolyzing diacylglycerols to free fatty acids for mitochondrial oxidation, shows significant downregulation in OSCC, particularly in cases with recurrence or metastasis. The reduced CES2 expression leads to decreased lipotoxicity and enhanced tumor progression through multiple mechanisms, including altered mitochondrial function and disrupted lipid homeostasis. This finding suggests that CES2 may serve as both a prognostic marker and a potential therapeutic target [7]. The sphingolipid metabolism pathway is also disrupted in OSCC, with key enzymes such as sphingosine kinase 2 (SphK2) and lipid phosphate phosphatase 3 (LPP3) showing decreased expression. These changes in sphingolipid metabolism correlate with advanced tumor stages and poor prognosis, highlighting the importance of this pathway in disease progression. The downregulation of these enzymes affects various cellular processes, including cell survival, proliferation, and immune cell infiltration [17].

Additionally, alterations in lysophosphatidic acid (LPA) metabolism, particularly through the upregulation of cyclooxygenase-2 (COX-2), promote cell migration and invasion in OSCC. The LPA signaling pathway affects multiple aspects of tumor biology, including cell proliferation, survival, and metastatic potential, making it an attractive target for therapeutic intervention [18]. These enzymatic changes are not isolated events but are interconnected with other metabolic pathways, including glycolysis and glutaminolysis. The complex interplay between these metabolic pathways creates a favorable environment for tumor growth and progression, highlighting the need for comprehensive therapeutic approaches that target multiple metabolic pathways simultaneously [19, 20]. Understanding these intricate relationships between different metabolic enzymes and their regulatory networks is crucial for developing effective therapeutic strategies for OSCC treatment, particularly in cases resistant to conventional therapies.

The reprogramming of lipid metabolism signaling pathways represents a critical feature in the pathogenesis of OSCC, involving multiple interconnected molecular mechanisms that collectively promote tumor progression. A key regulatory axis identified in OSCC is the IL8/AKT/p-ACLY pathway, which is particularly active in cancer-associated fibroblasts (CAFs) within the tumor microenvironment. This pathway drives enhanced lipid synthesis through the upregulation of phosphorylated ATP citrate lyase (p-ACLY), significantly contributing to tumor cell proliferation and invasion [13]. Parallel to this, OSCC exhibits marked alterations in glycerophospholipid metabolism, characterized by elevated levels of various phospholipids including phosphatidylcholines, phosphatidylethanolamines, and phosphatidylinositols, indicating a significant shift towards enhanced de novo lipogenesis in tumor tissues [11, 21]. The complexity of these metabolic changes is further exemplified by perturbations in cholesterol metabolism, where increased cholesterol levels in tumor tissues suggest active involvement of sterol regulatory binding proteins in supporting tumor growth [11]. Of particular significance is the intricate interplay between lipid metabolism and oncogenic signaling pathways, notably the PI3K/AKT/mTOR axis, which functions as a central regulator of lipid biosynthesis and uptake in OSCC cells [22, 23]. These pathway alterations not only support cancer cell survival and proliferation but also present promising therapeutic opportunities. The targeting of these lipid metabolic pathways through specific inhibitors of key enzymes or disruption of lipid signaling networks represents an emerging therapeutic strategy [24, 25], although the complex interactions between various metabolic and oncogenic pathways necessitate careful consideration in drug development approaches [26, 27]. Understanding these intricate pathway interactions and their roles in OSCC progression is crucial for developing more effective targeted therapies and improving patient outcomes.

As shown in Fig. 1, this mechanistic diagram illustrates how the PI3K/AKT/mTOR signaling pathway orchestrates lipid metabolic reprogramming in oral squamous cell carcinoma, with newly incorporated AKT-ERK crosstalk mechanisms. Growth factors and chemokines activate receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), respectively, triggering the activation of Class IA PI3K (p85/p110α, p85/p110β, p85/p110δ) and Class IB PI3K (p87/p110γ). These kinases catalyze the conversion of phosphatidylinositol 4,5-bisphosphate (PIP₂) to phosphatidylinositol 3,4,5-trisphosphate (PIP₃), leading to AKT activation, which is negatively regulated by phosphatase and tensin homolog (PTEN). Importantly, activated AKT establishes critical crosstalk with the ERK signaling pathway through PI3K-dependent activation of cytosolic phospholipase A₂ (cPLA₂), which catalyzes the release of arachidonic acid (AA) that subsequently activates ERK1/2, while activated ERK provides positive feedback to further amplify cPLA₂ activity, creating a self-reinforcing signaling loop between these two major pathways [28, 29]. AKT signaling inhibits tuberous sclerosis complex 1/2 (TSC1/2), resulting in mTOR activation. This pathway enhances lipid synthesis through multiple mechanisms: upregulating sterol regulatory element-binding protein (SREBP), which increases 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) expression to promote cholesterol synthesis; and activating key lipogenic enzymes including ATP citrate lyase (ACLY) and fatty acid synthase (FASN), driving the production of phospholipids and triglycerides. Simultaneously, AKT signaling downregulates fatty acid oxidation through decreased carboxylesterase 2 (CES2) expression. The pathway also affects sphingolipid metabolism, with reduced sphingosine kinase 2 (SphK2) and lipid phosphate phosphatase 3 (LPP3) expression altering sphingosine-1-phosphate (S1P) signaling. These metabolic alterations result in multiple downstream effects including modifications in lipid rafts affecting caveolin-1 (CAV1) signaling and increased lipid peroxidation with elevated malondialdehyde (MDA) levels. In parallel, the RAS/RAF/MEK/ERK pathway contributes to these processes, now with demonstrated bidirectional crosstalk through the cPLA₂-AA axis. Solid lines indicate direct pathway activation, while dashed lines represent crosstalk and feedback regulation mechanisms. Collectively, these pathways drive oral cancer progression by promoting growth, proliferation, survival, motility, and migration.

Fig. 1.

The PI3K/AKT/mTOR signaling pathway regulates lipid metabolism in oral cancer. Solid lines indicate direct pathway activation, while dashed lines represent crosstalk and feedback regulation mechanisms. PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, mTOR mechanistic target of rapamycin, RTKs receptor tyrosine kinases, GPCRs G protein-coupled receptors, PIP₂ phosphatidylinositol 4,5-bisphosphate, PIP₃ phosphatidylinositol 3,4,5-trisphosphate, PTEN phosphatase and tensin homolog, TSC1/2 tuberous sclerosis complex 1/2; SREBP1 sterol regulatory element-binding protein 1, HMGCR 3-hydroxy-3-methylglutaryl-coenzyme A reductase, ACLY ATP citrate lyase, FASN fatty acid synthase, CES2 carboxylesterase 2, SphK2 sphingosine kinase 2, S1P sphingosine-1-phosphate, CAV1 caveolin-1, MDA malondialdehyde, RAS rat sarcoma, RAF rapidly accelerated fibrosarcoma, MEK mitogen-activated protein kinase kinase, ERK extracellular signal-regulated kinase, cPLA₂ cytosolic phospholipase A₂, AA arachidonic acid

Lipid microregions, particularly lipid rafts, emerge as crucial modulators in oral cancer progression through their dual roles in membrane organization and drug resistance mechanisms. These cholesterol-enriched microdomains serve as essential platforms for organizing membrane receptor molecules and facilitating signal transduction pathways that are critical for cancer cell survival and proliferation [30, 31]. The dynamic nature of these structures allows them to influence cellular processes through alterations in lipid composition, which significantly impacts the localization and function of key signaling proteins involved in cancer progression, including those regulating apoptosis and cell survival pathways [32, 33]. Specifically in head and neck carcinoma, modifications in cholesterol levels within lipid rafts demonstrate a direct influence on cell death pathways, emphasizing their critical role in regulating cancer cell fate [30]. Beyond their structural and signaling functions, lipid microregions play a pivotal role in developing drug resistance mechanisms. Cancer cells can acquire drug tolerance through alterations in membrane lipid composition, where lipid rafts can effectively sequester drug targets, thereby reducing therapeutic efficacy [33, 34]. Of particular importance is the integrity of lipid rafts for the activation of survival pathways, such as the epidermal growth factor receptor (EGFR) pathway, which can become constitutively active in resistant cancer cells independent of ligand binding [30]. These findings have significant therapeutic implications, as targeting lipid rafts and modulating their composition presents a promising strategy for enhancing chemotherapeutic sensitivity and overcoming multidrug resistance in oral cancer treatment [33, 34]. The potential for therapeutic intervention through lipid raft modulation offers new possibilities for disrupting cancer cell signaling and improving treatment outcomes, particularly in cases where conventional therapies have shown limited efficacy [32, 35].

As shown in Fig. 2, this mechanistic diagram illustrates the comprehensive lipid homeostasis alterations in oral squamous cell carcinoma (OSCC). The figure depicts the tumor microenvironment containing both oral cancer cells and cancer-associated fibroblasts (CAFs), which promote lipid synthesis through the IL8/AKT/p-ACLY axis. Central to the lipid metabolic reprogramming is the PI3K/AKT/mTOR pathway upregulation, which regulates multiple aspects of lipid metabolism. The diagram shows glucose metabolism via glycolysis to pyruvate and ultimately acetyl-CoA, which enters the TCA cycle in mitochondria. Crucially, citrate is shuttled from the TCA cycle for lipid synthesis, where key enzymes ACLY and FASN (both upregulated in OSCC) facilitate the production of phospholipids, triglycerides, and cholesterol, essential for cancer cell membrane formation. Additionally, cholesterol synthesis is enhanced through HMGCR upregulation, while fatty acid oxidation is decreased due to CES2 downregulation. The figure also illustrates important downstream effects including alterations in lipid rafts that affect drug resistance and CAV1 signaling, disrupted tumor immunity involving CD36 regulation, S1P signaling, and abnormal lipid antigen presentation, and increased lipid peroxidation with elevated MDA and DNA adducts. Clinically, these alterations manifest as characteristic changes in serum lipid profiles, with decreased HDL-C, total cholesterol, and apolipoproteins A and B. The diagram concludes by highlighting potential therapeutic targets based on these mechanisms, including lipid-based nanoparticles, FASN/ACLY inhibitors, CD36 inhibitors, and lipid raft modulators.

Fig. 2.

Lipid Homeostasis in Oral Squamous Cell Carcinoma. This schematic diagram illustrates the lipid metabolism reprogramming in oral cancer. Solid lines indicate direct metabolic pathways and established molecular interactions. Dashed lines represent indirect effects, regulatory influences, or potential therapeutic interventions. CAFs cancer-associated fibroblasts, TME tumor microenvironment, IL8 interleukin-8, AKT protein kinase B, p-ACLY phosphorylated ATP citrate lyase, PI3K phosphatidylinositol 3-kinase, mTOR mechanistic target of rapamycin, CAV1 caveolin-1, CD36 cluster of differentiation 36, S1P sphingosine-1-phosphate, MDA malondialdehyde, TCA tricarboxylic acid, α-KG α-ketoglutarate, CES2 carboxylesterase 2, FASN fatty acid synthase, HMGCR 3-hydroxy-3-methylglutaryl-coenzyme A reductase, HDL-C high-density lipoprotein cholesterol, Apo-A apolipoprotein A, Apo-B apolipoprotein B, NPs nanoparticles

Serum lipid profile alterations in oral cancer

Clinical assessment requires standardized reference values for accurate interpretation of apolipoprotein alterations. Under normal metabolic conditions, apolipoprotein A-I levels range from 110 to 180 mg/dL (1.10–1.80 g/L) in males and 110–205 mg/dL (1.10–2.05 g/L) in females, while apolipoprotein B levels should remain below 130 mg/dL (1.3 g/L), with optimal cardiovascular protection achieved at levels below 90 mg/dL (0.9 g/L) [36]. High-risk thresholds are established at apolipoprotein B levels exceeding 120 mg/dL (1.2 g/L), representing the 90th percentile of the general population [37]. Oral cancer patients exhibit distinctive alterations in their serum lipid profiles, characterized by a consistent pattern of dyslipidemia that may serve as potential diagnostic and prognostic markers. Most notably, high-density lipoprotein cholesterol (HDL-C) levels show significant reduction in oral cancer patients compared to healthy controls, a finding consistently reported across multiple studies and suggested as a potential early marker for both oral cancer and potentially malignant disorders (OPMD) [15, 38, 39]. Similarly, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels demonstrate a marked decrease in oral cancer patients, attributed to the enhanced utilization of lipids by cancer cells for membrane biogenesis during rapid proliferation [40, 41]. The lipid profile alterations extend to triglycerides and very low-density lipoprotein (VLDL), which also show significantly reduced levels compared to healthy controls, reflecting the broader metabolic perturbations induced by the cancerous state [39, 40, 42]. Additionally, modifications in apolipoprotein profiles, particularly decreased levels of apolipoprotein A (Apo-A) and apolipoprotein B (Apo-B), have been observed in oral squamous cell carcinoma (OSCC) patients [15]. In diseased metabolic states, particularly in OSCC patients, both apolipoprotein A-I and apolipoprotein B demonstrate significant quantitative reductions compared to healthy controls. Specifically, Alazzawi et al. [43] reported the first documentation of significantly decreased serum apolipoprotein C-1 levels in OSCC patients compared to controls (P = 0.001), while female OSCC patients showed higher Apo-A values than male patients within the disease group (P < 0.05) [43]. These alterations represent a consistent pattern where both atherogenic (Apo B) and anti-atherogenic (Apo A-I) markers are paradoxically decreased, reflecting the complex metabolic reprogramming associated with cancer progression.While these alterations in serum lipid profiles appear to be consistent markers of oral cancer, it is important to note that they may represent a consequence rather than a cause of the disease, likely reflecting the increased metabolic demands of rapidly proliferating cancer cells [44, 45]. This complex relationship between serum lipid profiles and oral cancer underscores the importance of considering multiple factors, including age, sex, and tobacco use, when interpreting these biomarkers in clinical settings.

The relationship between serum lipids and oral cancer progression, particularly in OSCC, demonstrates complex and multifaceted interactions that significantly influence disease outcomes. Cancer cells in OSCC exhibit distinctive patterns of lipid metabolism, actively utilizing lipids for membrane biogenesis and energy production, which typically manifests as hypolipidemia in patients [46, 47]. Cholesterol plays a particularly crucial role in this process, mediating cancer cell migration and signaling through its interaction with caveolin-1 (CAV1), a key protein involved in cholesterol transport [12]. The prognostic significance of serum lipids is evidenced by the association between lipoprotein levels and patient outcomes, where high levels of LDL-C correlate with improved progression-free survival (PFS) and disease-specific survival (DSS) in head and neck squamous cell carcinoma, while elevated Apo B levels are linked to poorer prognosis [48]. Notably, OSCC patients consistently demonstrate lower levels of total cholesterol, LDL, and HDL compared to healthy controls, suggesting these parameters' potential utility as markers for cancer progression [46, 49]. The therapeutic implications of these findings are substantial, as targeting lipid metabolism presents promising opportunities for intervention. For instance, cholesterol-lowering drugs have demonstrated tumor-suppressive effects in OSCC [12, 50], while alterations in sphingolipid-related genes have been associated with poor prognosis, suggesting additional pathways for therapeutic exploration [51]. However, the interpretation of these relationships requires careful consideration of various factors including age, sex, and lifestyle, as similar patterns of lipid involvement have been observed in other cancer types, such as gastric cancer, indicating the broader significance of lipid metabolism in oncology [52, 53].

Serum lipid profiles have emerged as promising diagnostic markers for OSCC, offering potential non-invasive tools for early detection and disease monitoring. Studies have consistently demonstrated characteristic alterations in serum lipid profiles of OSCC patients, including significant reductions in total cholesterol, triglycerides, and high-density lipoproteins (HDL) compared to healthy controls [49, 54]. The diagnostic value of these lipid markers has been further enhanced through their integration with advanced imaging techniques, such as MRI, which has improved the predictive accuracy for OSCC staging [55]. Particularly noteworthy is the role of specific lipid components, with decreased levels of HDL and apolipoprotein A (Apo-A) showing strong associations with OSCC development [55], while alterations in phosphatidylcholine levels have been linked to increased cellular proliferation [56]. The utility of lipid profiles extends to the detection of premalignant conditions, as patients with oral potentially malignant disorders (OPMD) exhibit characteristic changes in their lipid profiles, including decreased levels of triglycerides and low-density lipoproteins (LDL) [9, 57], potentially serving as early indicators of malignant transformation [58]. Additionally, sphingolipid signatures in plasma and tissue have demonstrated prognostic value, correlating with tumor stage and patient survival [59]. However, the complexity of lipid metabolism and its interactions with other metabolic pathways necessitates a comprehensive approach, suggesting that the integration of lipidomics with other diagnostic modalities may be essential for maximizing their utility as biomarkers in oral cancer diagnosis and prognosis assessment.

Lipid metabolic reprogramming effects on liver enzymes and liver function

Cancer-associated lipid dysregulation profoundly impacts hepatic function through multiple interconnected mechanisms that collectively compromise liver enzyme profiles and metabolic capacity [7, 13]. The relationship between dyslipidemia and liver dysfunction has been clearly demonstrated in population studies, with Kathak et al. [60] finding that 61% of adults with dyslipidemia had at least one elevated liver enzyme, establishing a strong association between lipid profile alterations and hepatic dysfunction [60]. In oral squamous cell carcinoma patients, this relationship is particularly pronounced, as cancer cells fundamentally alter systemic lipid metabolism through enhanced de novo lipogenesis, creating metabolic competition with hepatocytes and forcing adaptive changes that manifest as altered liver enzyme profiles [11, 12]. The upregulation of key lipogenic enzymes including fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), and ATP citrate lyase (ACLY) in cancer cells creates "lipid sinks" that deplete circulating fatty acids and force hepatic metabolic adaptations [24, 61]. Recent discoveries reveal that tumor-derived extracellular vesicles containing palmitic acid directly induce liver dysfunction by activating inflammatory pathways in Kupffer cells, explaining why 49% of oral cancer patients present with abnormal liver enzymes even before treatment begins [48]. This metabolic reprogramming serves dual purposes: providing building blocks for rapid membrane synthesis while creating an energy-rich environment supporting tumor growth [19, 62]. The systemic impact extends far beyond the tumor site, as cancer-induced metabolic changes create a pro-inflammatory hepatic microenvironment that suppresses fatty acid metabolism enzymes and promotes fatty liver formation [40, 41]. The resulting hepatocyte stress and membrane damage lead to enzyme leakage, explaining elevated ALT and AST levels in cancer patients without direct hepatic involvement [63, 64].

The mechanistic basis for liver enzyme elevation in cancer patients involves complex interactions between tumor-derived factors and hepatic metabolism, with gamma-glutamyl transferase (GGT) emerging as the most sensitive indicator of lipid-induced hepatic dysfunction [65, 66]. The Bangladeshi study by Kathak et al. specifically demonstrated that GGT showed independent association with all lipid components, highlighting its crucial role as both a biomarker of oxidative stress and an active participant in cancer pathophysiology [60]. The enzyme facilitates extracellular glutathione catabolism, but this process generates reactive oxygen species through iron reduction, creating a pro-oxidant microenvironment that promotes lipid peroxidation and hepatocyte dysfunction [67, 68]. Cancer cells exploit GGT-mediated oxidative stress to promote survival and proliferation, while the resulting lipid peroxidation contributes to membrane damage and hepatocyte dysfunction, creating a self-perpetuating cycle [69, 70]. The pattern of liver enzyme elevation in oral cancer patients follows a predictable sequence, with GGT and alkaline phosphatase (ALP) typically rising first, reflecting early oxidative stress and bile acid metabolism disruption [44, 71]. As disease progresses, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels increase, indicating more extensive hepatocellular damage [46, 58]. AST elevation often reflects mitochondrial dysfunction, while ALT increases indicate cytoplasmic enzyme release from stressed hepatocytes [72, 73]. The Warburg effect in cancer cells creates additional metabolic strain on the liver through enhanced aerobic glycolysis producing excess lactate requiring hepatic gluconeogenesis via the Cori cycle, placing substantial metabolic burden on hepatocytes [74, 75]. This increased workload, combined with mitochondrial stress from altered fatty acid oxidation, contributes to progressive elevation of liver enzymes and compromised hepatic function [7, 76].

The clinical implications of cancer-associated hepatic dysfunction necessitate integrated monitoring protocols and targeted interventions to preserve liver function and optimize treatment outcomes [15]. Based on the strong association between dyslipidemia and liver enzyme elevation demonstrated in population studies, baseline assessment of cancer patients must include comprehensive lipid panels alongside traditional liver function tests, with particular attention to GGT levels as early warning indicators of metabolic dysfunction [55]. For oral cancer patients, monitoring protocols should be implemented every 3 months for high-risk individuals and every 6 months for moderate-risk patients, given the consistent patterns of hepatic dysfunction observed in this population [77]. The prognostic value of combined lipid-liver enzyme panels exceeds individual markers, with triple assessment using AFP, DCP, and AFP-L3% showing enhanced diagnostic accuracy for hepatocellular changes [48]. Statin therapy emerges as a particularly promising intervention, demonstrating a 37% reduction in hepatocellular carcinoma risk in meta-analyses, with lipophilic statins like atorvastatin showing superior hepatoprotective effects compared to hydrophilic formulations [12]. For oral cancer patients with dyslipidemia, statin therapy may provide dual benefits: managing cardiovascular risk while potentially protecting against treatment-related hepatotoxicity and cancer progression [78]. The discovery of tumor-derived extracellular vesicles as primary mediators of hepatic dysfunction opens new therapeutic avenues, with CD36 antagonists showing promise in preclinical models for disrupting tumor-liver metabolic communication [79]. Nutritional support plays a crucial role, with cancer patients requiring 1.2–1.5 g/kg/day protein and 30–45 kcal/kg/day energy intake, emphasizing omega-3 fatty acids and branched-chain amino acids for those with advanced liver dysfunction [26]. Understanding these mechanistic connections between lipid metabolism and liver function in cancer transforms patient management approaches, supporting integrated monitoring protocols, early intervention with hepatoprotective agents, and personalized treatment strategies based on metabolic profiles [80].

Fat-soluble vitamin metabolism represents a critical but often overlooked aspect of cancer-associated hepatic dysfunction, as vitamins A, D, E, and K require intact lipid metabolism pathways for optimal absorption, transport, and utilization [81, 82]. In OSCC patients with dyslipidemia, serum levels of fat-soluble vitamins are frequently compromised, with vitamin A deficiency observed in up to 45% of patients and vitamin E levels reduced by 20–30% compared to healthy controls [63, 64]. The hepatic storage and metabolism of these vitamins becomes particularly vulnerable when liver enzymes are elevated, as retinol-binding protein synthesis decreases and α-tocopherol transfer protein function is impaired [83]. Therapeutic correction through supplementation requires careful consideration of altered pharmacokinetics in cancer patients, with vitamin A requiring dose adjustments from the standard 700–900 μg/day to potentially 1200–1500 μg/day, while vitamin E supplementation may need to increase from 15 mg/day to 25–30 mg/day, always with regular monitoring of serum levels to prevent toxicity [84, 85]. Vitamin E supplementation shows particular promise in OSCC patients, as its antioxidant properties may help mitigate lipid peroxidation and reduce hepatocyte oxidative stress, potentially slowing the progression of liver enzyme elevation [86, 87]. However, high-dose vitamin A supplementation requires caution in patients with elevated liver enzymes, as hepatotoxicity risk increases substantially when ALT or AST levels exceed twice the upper limit of normal [88]. The integration of fat-soluble vitamin assessment into routine monitoring protocols for OSCC patients with lipid metabolic disorders represents an important but underutilized approach to comprehensive nutritional support and hepatoprotection.

Cardiovascular implications of lipid dysregulation in OSCC

The characteristic dyslipidemia observed in OSCC patients extends beyond tumor-related metabolic changes to encompass significant cardiovascular implications that may influence patient morbidity and mortality. Alterations in serum lipid profiles, particularly the decreased levels of total cholesterol, HDL-C, and LDL-C commonly observed in oral cancer patients, can have profound effects on cardiac enzyme profiles and cardiovascular risk stratification [89, 90]. Key cardiac biomarkers, including creatine phosphokinase (CPK), creatine phosphokinase MB isoenzyme (CPK-MB), lactate dehydrogenase (LDH), and serum aspartate aminotransferase (AST), may be altered in response to lipid dysregulation, potentially masking or complicating the detection of underlying cardiovascular pathology in cancer patients [91, 92]. Studies have demonstrated that cancer patients with dyslipidemia show consistent elevation of cardiac enzymes, with troponin levels predicting left ventricular dysfunction with 93% negative predictive value and cancer therapy increasing troponin levels with an odds ratio of 14.3 [93]. The relationship between lipid abnormalities and cardiac enzyme release appears mediated through multiple pathways, including disrupted cholesterol efflux, ABCA1 function impairment, and reactive oxygen species generation that affects both lipid metabolism and myocardial integrity [94]. CK-MB shows dose-dependent increases in dyslipidemic cancer patients, while LDH elevation correlates with tumor burden and metabolic dysfunction [95]. Of particular concern is the relationship between dyslipidemia and cerebrovascular accident risk in OSCC patients, as the underlying metabolic dysfunction and systemic inflammation associated with cancer can create a prothrombotic state that increases cerebrovascular risk [96, 97]. The altered lipid metabolism in cancer patients may affect endothelial function, platelet aggregation, and coagulation cascades, collectively contributing to increased thromboembolic risk [98]. Furthermore, certain cancer treatments, including chemotherapy and radiation therapy, can exacerbate cardiovascular complications, making the monitoring of both lipid profiles and cardiac enzymes essential for comprehensive patient care [99]. Therefore, comprehensive lipid profiling in OSCC patients should be considered not only as a cancer biomarker but also as part of cardiovascular risk assessment and management strategies.

Head and neck cancer patients, including those with OSCC, face substantially increased cardiovascular risk compared to the general population, with studies showing 1.2–1.5 fold increased stroke risk and up to 10% of ischemic stroke patients having concurrent active cancer [100, 101]. Large-scale epidemiological studies have revealed that the 10-year cerebrovascular event incidence reaches 34% in head and neck cancer patients receiving radiotherapy, with peak stroke risk occurring 6–12 months post-radiation therapy [102, 103]. The mechanisms linking cancer-associated dyslipidemia to increased stroke risk extend beyond traditional cardiovascular risk factors to include cancer-induced hypercoagulable states through tissue factor expression, platelet activation, and increased coagulation factors VII, VIII, and X [99]. Non-bacterial thrombotic endocarditis (NBTE) develops in cancer patients, creating sterile platelet–fibrin vegetations that generate multiple cerebral microemboli detected in 58% of cancer-related embolic stroke patients [104]. Treatment-related vascular injury compounds this risk, with radiation-induced endothelial dysfunction accelerating carotid atherosclerosis and chemotherapy-induced vasculopathy creating a prothrombogenic environment [105, 106]. Notably, 5–10% of cancer-associated strokes occur before cancer diagnosis, suggesting that metabolic disruption, including lipid alterations, may precede clinical cancer detection [107, 132]. OSCC patients face unique challenges due to shared risk factors between cancer and cardiovascular disease, particularly tobacco use and alcohol consumption, which create multiplicative effects on cardiovascular risk [108]. The inflammatory cascade connecting cancer and cardiovascular disease involves IL-6 family cytokines, TNF-α, and other inflammatory mediators that promote endothelial dysfunction and generate excessive reactive oxygen species [109]. Ceramides have emerged as critical mediators linking dyslipidemia to cardiovascular dysfunction, with specific ceramide species showing differential effects on cardiovascular mortality risk [110]. Cancer treatments, particularly mTOR inhibitors, can increase ceramide levels by 20–30%, directly impacting cardiovascular risk and necessitating careful monitoring of both lipid profiles and cardiovascular biomarkers [111].

The clinical management of cardiovascular risk in OSCC patients requires integrated cardio-oncology care with systematic monitoring of both lipid profiles and cardiac enzymes throughout the treatment continuum. The 2022 European Society of Cardiology guidelines on cardio-oncology recommend baseline cardiovascular assessment including serum lipids for all patients scheduled for potentially cardiotoxic therapies, using systematic risk stratification tools [112, 113]. Biomarker monitoring protocols should include serial troponin measurements at baseline, during treatment cycles, and post-completion, with elevated levels serving as early predictors of left ventricular dysfunction [114, 115]. While natriuretic peptides show mixed results for predicting dysfunction, baseline measurement remains recommended for high-risk patients, particularly those with pre-existing dyslipidemia [116]. The integration of multiple biomarkers with imaging parameters offers improved cardiovascular risk prediction compared to single markers alone [117]. Lipid management in cancer patients requires special considerations, with statins remaining the mainstay of therapy, though PCSK9 inhibitors offer advantages through freedom from drug interactions and favorable liver safety profiles [118, 119]. Long-term surveillance is essential, as cancer survivors demonstrate persistent cardiovascular risk extending years beyond active treatment, with childhood cancer survivors showing 4–6% prevalence of undiagnosed severe dyslipidemia [120]. Treatment-specific effects persist long-term, with anthracyclines causing direct lipid metabolism disruption and newer agents like targeted therapies causing hypercholesterolemia in up to 81% of patients [121]. Future research directions should focus on developing precision medicine approaches incorporating ceramide panels, oncometabolite measurement, and genetic susceptibility markers for personalized cardiovascular risk stratification in OSCC patients [122]. Clinical implementation requires establishing multidisciplinary cardio-oncology teams and creating institution-specific guidelines that recognize cancer fundamentally alters cardiovascular physiology through complex metabolic and inflammatory pathways that persist long after treatment completion [123].

Fat-soluble vitamin deficiencies represent an underrecognized cardiovascular risk factor in OSCC patients, as vitamins A and E play critical roles in maintaining endothelial function and preventing oxidative cardiovascular damage [124, 125]. Vitamin E deficiency, observed in 35–40% of OSCC patients with dyslipidemia, significantly impairs endothelial nitric oxide synthase activity and increases susceptibility to atherosclerotic plaque formation, potentially doubling the risk of cardiovascular events compared to patients with adequate levels [126, 127]. Similarly, vitamin A deficiency affects cardiac remodeling processes and may contribute to increased left ventricular dysfunction risk, particularly in patients receiving cardiotoxic therapies [128, 129]. The cardiovascular benefits of corrective supplementation appear substantial, with vitamin E supplementation at doses of 400–800 IU/day (compared to the standard 22 IU/day) demonstrating significant reductions in endothelial dysfunction markers and C-reactive protein levels in cancer patients [130, 131]. However, high-dose vitamin A supplementation requires careful cardiovascular monitoring, as doses exceeding 3000 μg/day (compared to standard 700–900 μg/day) may paradoxically increase cardiovascular risk through enhanced oxidative stress, particularly in patients with pre-existing coronary disease [132, 133]. The cardioprotective effects of vitamin E appear most pronounced when combined with other antioxidants, with studies showing 25–30% reduction in cardiovascular events when administered alongside selenium and coenzyme Q10 in cancer patients [134]. Importantly, the timing of supplementation relative to cancer treatment affects cardiovascular outcomes, with pre-treatment optimization of fat-soluble vitamin status showing superior cardioprotective effects compared to post-treatment supplementation [135, 136]. Integration of fat-soluble vitamin assessment and targeted supplementation into cardio-oncology protocols represents a promising but underutilized strategy for comprehensive cardiovascular risk management in OSCC patients.

Genetic determinants and corrective strategies for inherited lipid metabolic dysfunction

Inherited genetic variants play a pivotal role in determining individual susceptibility to lipid metabolic dysfunction and treatment response variability in OSCC patients, necessitating comprehensive genomic evaluation for optimal therapeutic outcomes. The most clinically significant genetic polymorphisms include carboxylesterase 2 (CES2) variants, particularly rs71647871 and rs8192935, which collectively reduce enzyme activity by 40–70% and significantly impair fatty acid oxidation capacity in affected individuals [137, 138]. These CES2 variants demonstrate profound ethnic variation, with frequencies ranging from 2 to 5% in European populations to 15–25% in East Asian populations, creating population-specific risk profiles that must be considered in treatment planning [139, 140]. Similarly, fatty acid synthase (FASN) polymorphisms, especially rs4485435 and rs4246444, are associated with 30–50% decreased de novo lipogenesis capacity and altered membrane composition in cancer cells [141]. The ATP citrate lyase (ACLY) gene variants rs2304497 and rs9912468 significantly influence cholesterol biosynthesis pathways, with homozygous carriers showing 25–40% reduced enzyme activity and compensatory upregulation of HMG-CoA reductase expression [142]. Additionally, sterol regulatory element-binding protein 1 (SREBP1) polymorphisms rs11868035 and rs8066560 affect transcriptional regulation of lipogenic genes, leading to dysregulated lipid homeostasis and increased susceptibility to treatment-related metabolic complications [143]. These genetic variants interact synergistically with environmental factors such as tobacco use and alcohol consumption, creating multiplicative effects on metabolic dysfunction risk that can exceed 5–tenfold compared to wild-type individuals.

Patients carrying genetic variants affecting key hepatic enzymes require specialized therapeutic strategies that account for reduced metabolic capacity and increased vulnerability to drug-induced hepatotoxicity. CES2-deficient individuals demonstrate significantly impaired ability to hydrolyze triglycerides and drug esters, leading to accumulation of toxic metabolites and increased liver enzyme elevation risk during cancer treatment [139]. The primary corrective approach involves optimizing residual enzyme activity through targeted cofactor supplementation, with riboflavin administered at therapeutic doses of 100–200 mg daily (compared to standard 1.3 mg daily) to enhance flavin adenine dinucleotide (FAD) cofactor availability and restore 25–40% of lost enzyme function [144]. Concurrent magnesium supplementation at 400–600 mg daily (versus standard 320 mg daily) provides essential cofactor support for enzyme stabilization and optimal protein folding, while zinc supplementation at 15–30 mg daily helps maintain enzyme structural integrity [145, 146]. Additionally, these patients benefit from modified dietary lipid composition, with medium-chain triglycerides comprising 25–35% of total fat intake (compared to < 5% in normal diets) to bypass impaired long-chain fatty acid metabolism pathways [147]. The implementation of substrate modification strategies includes reducing saturated fat intake to < 7% of total calories while increasing omega-3 fatty acid consumption to 15–25 g daily, approximately 3–4 times higher than standard recommendations [148, 149]. Monitoring protocols for genetically susceptible patients require more frequent liver function testing every 4–6 weeks during treatment compared to standard 8–12 week intervals, with lower thresholds for dose modifications when transaminases exceed 2–3 times upper normal limits rather than the standard 5 times threshold [150].

Inherited lipid metabolism disorders create unique cardiovascular vulnerability patterns that require genotype-specific risk assessment and intervention strategies tailored to individual genetic profiles. Patients with low-density lipoprotein receptor (LDLR) gene mutations, particularly those causing familial hypercholesterolemia, face 10–20 fold increased cardiovascular event risk and require aggressive lipid-lowering therapy initiated at lower LDL-C thresholds [151, 152]. These individuals demonstrate enhanced responsiveness to PCSK9 inhibitors, often achieving target LDL-C levels of < 70 mg/dL with evolocumab 140 mg every two weeks or alirocumab 75–150 mg every two weeks, doses that may need reduction to prevent excessive lipid lowering in some patients [153, 154]. Conversely, patients carrying apolipoprotein E (APOE) ε4 variants exhibit altered vitamin E metabolism and require higher α-tocopherol supplementation at 400–800 IU daily (compared to standard 15 mg daily) to achieve cardioprotective antioxidant effects [155, 156]. The APOE ε2 variant carriers, while protected against cardiovascular disease in normal circumstances, show increased susceptibility to hypertriglyceridemia during cancer treatment, necessitating earlier intervention with fibrate therapy and stricter dietary fat restrictions [157, 158]. Genetic variants in the cholesteryl ester transfer protein (CETP) gene, particularly rs708272 and rs5882, significantly influence HDL-C metabolism and cardiovascular risk, with TaqIB variant carriers requiring different target HDL-C levels and potentially benefiting from niacin supplementation at 1–2 g daily under careful monitoring [159]. The integration of genetic risk scores incorporating multiple variants provides more accurate cardiovascular risk prediction than traditional calculators, with high genetic risk scores warranting more aggressive prevention strategies including earlier statin initiation and lower treatment targets.

The implementation of pharmacogenomic-guided dosing protocols represents a critical advancement in optimizing therapeutic outcomes while minimizing adverse effects in genetically susceptible OSCC patients. Patients with SLCO1B1 polymorphisms, particularly the rs4149056 variant, demonstrate significantly reduced statin uptake into hepatocytes and require dose modifications to prevent myopathy, with simvastatin and atorvastatin doses typically reduced by 50–70% compared to standard protocols [160]. These individuals may benefit from alternative lipid-lowering strategies including ezetimibe at standard 10 mg daily dosing or rosuvastatin at reduced doses of 5–10 mg daily rather than the typical 20–40 mg dosing [161]. CYP2C19 poor metabolizers, affecting approximately 2–5% of most populations, show altered metabolism of clopidogrel and certain lipid-modulating drugs, requiring alternative antiplatelet strategies and careful drug selection to avoid hepatically metabolized agents [162]. Patients with genetic variants affecting fatty acid synthesis pathways require compensatory nutritional interventions, including omega-3 fatty acid supplementation at 2–3 g daily of combined EPA and DHA, significantly higher than the standard 500 mg daily recommendation for general cardiovascular health [148, 163]. The dosing of fat-soluble vitamins must also be adjusted based on genetic profiles, with vitamin A supplementation ranging from 1500–3000 μg daily in patients with genetic absorption defects (compared to standard 700–900 μg daily), while vitamin E requirements may increase to 200–400 mg daily in individuals with genetic variants affecting α-tocopherol transfer protein function [156]. Monitoring strategies for genetically variant patients include more frequent therapeutic drug monitoring, pharmacokinetic assessments at 2–4 week intervals initially, and dose titration based on both clinical response and genetic predictions of drug metabolism capacity.

Severe inherited lipid metabolism disorders in OSCC patients may require advanced therapeutic interventions beyond conventional pharmacological approaches, including enzyme replacement therapy and emerging gene therapy modalities. Lomitapide therapy represents a specialized intervention for patients with homozygous familial hypercholesterolemia or severe genetic lipid synthesis defects, with dosing initiated at 5 mg daily and gradually titrated to 20–60 mg daily based on tolerability and LDL-C reduction goals [164, 165]. This microsomal triglyceride transfer protein inhibitor can achieve 40–50% LDL-C reduction in refractory cases, though hepatic monitoring is essential due to potential for steatosis development, particularly in cancer patients with pre-existing liver dysfunction [166]. Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, offers an alternative approach for severe genetic hypercholesterolemia, administered as 200 mg weekly subcutaneous injections with careful monitoring for injection site reactions and liver enzyme elevation [167]. Enzyme replacement therapy using recombinant enzymes shows promise for specific genetic defects, particularly in lipoprotein lipase deficiency where alipogene tiparvovec gene therapy has demonstrated sustained triglyceride reduction and improved clinical outcomes [168, 169]. Adeno-associated virus (AAV) vector-mediated gene therapy represents the most advanced approach for correcting inherited lipid disorders, with early clinical trials demonstrating sustained therapeutic effects for familial hypercholesterolemia and other monogenic lipid diseases [170]. However, the application of gene therapy in cancer patients requires extensive safety evaluation due to potential immune interactions and oncogenic risks, with current protocols typically excluding patients with active malignancy or immunosuppression. The future of genetic correction strategies includes CRISPR-Cas9 gene editing technologies and base editing approaches that offer potential for permanent correction of genetic defects, though clinical applications remain investigational and require resolution of delivery, safety, and ethical considerations [171].

The successful integration of genetic testing and personalized corrective strategies into routine OSCC care requires systematic implementation protocols that ensure appropriate patient selection, genetic counseling, and long-term monitoring. Pre-treatment genetic screening should include a comprehensive panel targeting key genes affecting lipid metabolism, drug metabolism, and cardiovascular risk, with results available within 7–14 days to guide initial treatment planning. The genetic testing panel should minimally include CES2, FASN, ACLY, SREBP1, LDLR, APOE, SLCO1B1, and CYP2C19 variants, with expansion to include additional variants based on ethnic background and family history [172]. Genetic counseling services must be integrated into the care team to ensure appropriate interpretation of results, discussion of implications for family members, and ongoing support for patients and families dealing with hereditary conditions. The implementation of genetic risk-based monitoring protocols requires establishment of tiered monitoring strategies, with high-risk genetic profiles warranting liver function testing every 2–4 weeks initially, lipid panels every 4–6 weeks, and cardiovascular biomarker assessment every 6–8 weeks during active treatment phases. Electronic health record systems should incorporate genetic risk alerts and automated dosing recommendations to support clinical decision-making and prevent medication errors in genetically susceptible patients [173]. Quality assurance measures must include regular review of genetic test utilization, clinical outcomes tracking, and cost-effectiveness analysis to ensure optimal resource allocation and patient benefit [174]. The establishment of institutional genetic medicine committees can provide oversight for complex cases, protocol development, and continuing education for healthcare providers managing genetically susceptible cancer patients.

Lipid peroxidation mechanisms in oral cancer

Lipid peroxidation represents a fundamental oxidative stress mechanism in oral cancer pathogenesis, characterized by the oxidative degradation of cellular membrane lipids through reactive oxygen species (ROS). This process is initiated when ROS attack polyunsaturated fatty acids in cell membranes, triggering chain reactions that ultimately produce toxic aldehydes, particularly malondialdehyde (MDA) [175, 176]. The formation of MDA is especially significant as it can form DNA adducts, directly contributing to mutagenesis and cancer progression through its interaction with cellular macromolecules [177]. Beyond DNA adduct formation, MDA also leaves distinctive 'chemical fingerprints' on neighboring proteins through covalent modifications, particularly protein carbonylation and direct oxidative modifications. These MDA-protein adducts represent a significant form of post-translational modification that can alter protein structure, function, and stability, thereby affecting cellular processes including signal transduction, enzyme activity, and protein–protein interactions [178]. This protein modification pathway is particularly pronounced in smoking patients, where enhanced oxidative stress amplifies MDA production and subsequent protein damage. The biological implications of these MDA-induced protein modifications in tumor progression are increasingly recognized as important but remain incompletely understood, warranting further investigation into their specific roles in oral cancer pathogenesis. Recent studies have demonstrated that e-cigarette exposure can induce similar protein carbonylation patterns, suggesting that various forms of tobacco-related oxidative stress may contribute to cancer development through comparable MDA-mediated protein modification mechanisms [178]. The dual targeting of both nucleic acids and proteins by MDA creates a multi-faceted mechanism of cellular damage that may synergistically promote carcinogenesis through both mutagenic and protein dysfunction pathways. The lipid peroxidation process in oral cancer involves multiple steps, beginning with the initiation phase where ROS abstract hydrogen atoms from lipids, followed by a propagation phase where lipid radicals react with oxygen to form peroxyl radicals, and finally a termination phase resulting in the formation of various end products. These end products, especially MDA, can cause extensive damage to cellular components, including proteins and nucleic acids, leading to mutations and cellular dysfunction that promote carcinogenesis. The accumulation of these oxidative modifications creates a self-perpetuating cycle of damage that can accelerate tumor development and progression.

The clinical significance of lipid peroxidation in oral cancer is evidenced by consistently elevated MDA levels in patients, particularly among smokers, indicating increased oxidative stress in oral carcinogenesis [175]. This oxidative imbalance is further exacerbated by compromised antioxidant defense mechanisms, including reduced levels of glutathione peroxidase and vitamin C [63, 66]. The decline in antioxidant protection, especially reduced glutathione (GSH), creates a perpetual cycle of oxidative damage, significantly contributing to the progression of oral cancer [66, 179]. Studies have demonstrated that the severity of lipid peroxidation correlates with tumor stage and grade, suggesting its potential value as a prognostic indicator. The relationship between tobacco use and increased lipid peroxidation is particularly noteworthy, as smokers with oral cancer show significantly higher levels of MDA compared to non-smoking patients, highlighting the role of environmental factors in exacerbating oxidative stress. Furthermore, the assessment of lipid peroxidation markers, combined with antioxidant status, provides valuable insights into disease progression and treatment response. These alterations in both lipid peroxidation products and antioxidant defenses not only serve as potential markers for early diagnosis and monitoring of oral cancer progression but also suggest possible therapeutic interventions targeting oxidative stress pathways. Table 1 provides a comprehensive chronological summary of key studies exploring lipid peroxidation, lipid metabolism alterations, and serum lipid profiles in oral cancer from 1998 to 2024. These studies collectively demonstrate consistent patterns of decreased total cholesterol, HDL, and LDL levels in OSCC patients compared to healthy controls, alongside elevated lipid peroxidation markers such as malondialdehyde (MDA) and altered antioxidant status. The table highlights significant findings regarding the diagnostic and prognostic value of these biomarkers, as well as their associations with clinical parameters like tumor stage and histological grade. Furthermore, it documents the emergence of more sophisticated lipidomic approaches in recent years, particularly the investigation of specific lipid droplet-associated proteins like PLIN2 and PLIN3, which correlate with immune cell infiltration and patient outcomes.

Table 1.

Chronological Overview of Key Studies Investigating Lipid Peroxidation, Lipid Metabolism, and Serum Lipid Profiles in Oral Cancer

Authors	Year	Study population	Key findings
Nagini et al.[210]	1998	24 newly diagnosed stage IV oral cancer patients and 24 normal subjects	• Significantly decreased lipid peroxidation in tumor tissue • Elevated glutathione levels and glutathione peroxidase activity • Decreased superoxide dismutase and catalase activities • Findings suggest decreased susceptibility of oral tumor tissue to lipid peroxidation
Saroja et al.[179]	1999	Tumor tissues from 33 OSCC patients compared with normal tissues	• Decreased lipid peroxidation in oral tumor tissue • Significant decrease in phospholipids • Increased cholesterol and cholesterol/phospholipid ratio • Decreased free fatty acids • Elevated glutathione concentration and increased activities of glutathione peroxidase and glutathione-S-transferase in tumor tissues
Baskar et al.[211]	2004	20 subjects (10 healthy adults, 10 oral cancer patients)	• Phase delay in erythrocyte TBARS levels and enzymatic antioxidant activities in oral cancer patients compared to healthy subjects • Desynchronization of circadian rhythms in lipid peroxidation and antioxidant enzymes in oral cancer patients • Altered temporal patterns in superoxide dismutase, glutathione peroxidase, and catalase activities in cancer patients
Rajpura et al.[212]	2005	41 OSCC patients, 20 oral precancerous condition patients, 20 healthy controls	• Significant elevations in total sialic acid (TSA) and lipid-bound sialic acid (LSA) levels in OSCC patients compared to controls and OPC patients • Progressive increase in TSA and LSA with advancing clinical stage of OSCC • No significant association with histopathological grade
Manoharan et al.[213]	2005	10 OSCC patients, 10 age-matched healthy controls	• Circadian alterations in plasma lipid peroxidation and antioxidants in OSCC patients • Acrophase of plasma TBARS delayed by 2.5 h in OSCC patients (19:14 h vs 16:40 h in controls) • Acrophase of GSH delayed by 2 h in OSCC patients (02:00 vs 00:00 in controls) • Acrophase of GPx delayed by 3.5 h in OSCC patients (02:32 h vs 22:55 h in controls) • Decreased mesor values for GSH and GPx in OSCC patients
Manoharan et al.[63]	2005	48 male oral cancer patients (stages II-IV) and 16 healthy subjects	• Elevated lipid peroxidation and decline in antioxidant status in oral cancer patients • TBARS levels gradually increased while antioxidants gradually reduced from stage II to stage IV • Alterations in plasma lipid peroxidation may be related to compensatory changes in antioxidant defense system
Patel et al.[64]	2007	190 subjects (50 healthy controls, 140 OSCC patients)	• Lower thiol levels in controls with tobacco habits, oral cancer patients, and malignant tissues • Higher tobacco exposure in oral cancer patients than controls with tobacco habits • Controls with lower thiol levels and high tobacco exposure showed elevated risk of oral cancer • Patients with higher lipid peroxidation showed poorer overall survival • Patients with lower thiol and total antioxidant status showed poorer overall survival
Ghosh et al.[214]	2011	30 OSCC patients, 20 tobacco habituates, 20 healthy controls	• Significant decrease in serum total cholesterol and triglyceride levels in OSCC patients compared to healthy controls • Significantly lower HDL levels in tobacco habituates compared to controls • Significantly lower total cholesterol, LDL levels, and TC:HDL ratios in OSCC patients compared to tobacco habituates • Significant increase in HDL levels in OSCC patients compared to tobacco habituates
Chawda et al.[16]	2011	25 OSCC patients, 5 healthy controls	• Significantly lower levels of total lipids, cholesterol, and HDL in oral cancer patients compared to controls • No significant differences in LDL and VLDL between groups • No significant differences in lipid profiles between histological grades of OSCC
Taqi et al.[215]	2012	95 subjects (35 healthy controls, 30 oral precancer, 30 OSCC)	• Mean values of serum sialic acid (total and lipid bound) in oral cancer were significantly higher than control and the precancer group • Progressive rise in total and lipid-bound sialic acid with clinical stage of cancer • Serum sialic acid levels differentiated between patients with oral precancer and oral cancer • Sialic acid could be used to monitor response to therapy and assess cancer staging
Kumar et al.[44]	2012	30 healthy controls, 30 oral leukoplakia patients, 30 tobacco abusers, 30 OSCC patients	• TC, HDL, and LDL were significantly lower in OSCC group compared to controls • Inverse relationship between serum lipid profile and oral cancer • No significant reduction in lipid profile in oral leukoplakia group • TC and HDL decreased marginally with loss of tumor differentiation • No correlation between mean serum lipid profiles and degree of dysplasia in leukoplakia
Singh et al.[216]	2013	50 OSCC patients, 25 healthy controls	• Significant decrease in TC, HDL-C, and TGL in OSCC group compared to controls • No significant correlation of lipid profile with histological grading • No statistical difference in lipid profiles between tobacco and non-tobacco users • Inverse relationship between serum lipid profile and oral cancer
Mehta et al.[217]	2014	60 OSMF/precancerous patients, 60 OSCC patients, 60 controls	• Significant reduction in plasma TC, HDL-C, LDL-C, VLDL and triglycerides in precancerous and cancerous groups compared to controls • On comparison between precancerous and cancerous groups, significant decrease observed in cancerous group • Changes in lipid levels may have early diagnostic or prognostic role
Ganesan et al.[65]	2014	50 patients (20 controls, 10 with oral leukoplakia, 20 with OSCC)	• Significantly elevated levels of lipid peroxides in saliva, serum, and tissue in oral leukoplakia and OSCC compared to controls • Higher lipid peroxidation levels in OSCC than in oral leukoplakia • Increased MDA levels in patients with smoking and chewing habits • No significant difference in MDA levels between genders • Lower levels of antioxidants in carcinogenesis
Rasool et al.[218]	2014	30 healthy controls, 30 oral leukoplakia patients, 40 OSCC patients	• Significantly increased levels of MDA and sialic acid in plasma of OSCC patients compared to controls • Significantly decreased antioxidant levels in OSCC patients • Salivary MDA is a better diagnostic tool compared to blood MDA • β-2MG in blood is better diagnostic marker compared to β-2MG in saliva
Metgud & Bajaj[66]	2014	30 healthy controls, 30 oral leukoplakia patients, 40 OSCC patients	• Enhanced MDA levels in saliva and serum in oral leukoplakia and OSCC patients compared to controls • Significant decreases in serum and salivary GSH levels in oral leukoplakia and OSCC patients • Augmentation of oxidative stress in blood and saliva reflected by increase in MDA and decrease in GSH levels • No significant correlation between histopathological grades of leukoplakia and MDA/GSH levels
Shetty et al.[68]	2014	65 healthy controls, 115 potentially malignant disorders (PMD), and 50 OSCC patients	• Consistent elevation in salivary MDA levels in healthy controls with tobacco habits, PMD subjects, and OSCC subjects • Significant elevation in salivary MDA in PMD and OSCC groups compared to healthy controls • Salivary malondialdehyde analysis can be used as an efficient, non-invasive tool for early diagnosis
Acharya et al.[41]	2016	90 untreated OSCC patients and 30 healthy controls	• Significant decreases in serum TC, HDL, and LDL in OSCC patients vs controls • No significant correlation between lipid profile and tumor stage, grade, or lymph node metastasis • Tobacco users showed lower TC, LDL, and TG values than non-tobacco users
Subbulakshmi et al.[76]	2017	20 OSMF patients, 20 OSCC patients, 20 controls	• Significant decrease in serum total cholesterol, HDL-C, and LDL-C in OSMF and OSCC compared to controls < br > • No significant difference in triglyceride levels • Decreased lipid levels in patients suggest utilization of lipids by cells during cancer process
Wang et al.[219]	2017	50 OSCC patients, 50 healthy controls	• Identified 20 differential lipids between OSCC and controls • Decreased glycerophospholipids (especially phosphatidylcholine and phosphoethanolamine plasmalogens) • Increased sphingolipids (ceramides and sphingomyelins) Identified 12 lipids associated with pathological staging that could discriminate early stage from advanced stage patients
Hu et al.[75]	2019	576 T1/2N0M0 OSCC patients without prediagnosis weight loss	• Obesity was an independent risk factor for progression-free survival and disease-specific survival in early-stage OSCC • 72 dysregulated lipid metabolism-related genes identified in OSCC • A combining signature of TGFB1, SPP1, and SERPINE1 was defined as a biomarker for prognostic prediction
Singh et al.[77]	2021	129 patients (25 healthy controls, 26 OSMF cases, 26 leukoplakia, 52 oral cancer)	• No statistically significant difference in serum and salivary total cholesterol and HDL levels among all groups • Statistically significant difference in salivary triglyceride levels • Significant positive correlation between serum and salivary lipid levels • Salivary lipids can be used as a non-invasive alternative to serum lipid estimation • No association established between lipid profiles and oral precancer/cancer
Alazzawi et al.[43]	2022	22 OSCC patients, 22 healthy controls	• Significant decrease in serum cholesterol, triglyceride, HDL-C, LDL-C, and VLDL in OSCC patients compared to controls • First to report significant decrease in serum Apolipoprotein C-1 (ApoC-1) levels in OSCC patients • Higher ApoC-1 level in patients with vascular invasion • No significant correlation of serum ApoC-1 with tumor grade, stage or size
Chen et al.[220]	2022	30 OSCC patients with recurrence/metastasis vs. patients without recurrence/metastasis	• CES2 was downregulated in OSCC patients, especially those with recurrence or metastasis • CES2 reprogrammed lipid metabolism by hydrolyzing neutral lipid diacylglycerols (DGs) • CES2 reduced membrane structure lipid phospholipids synthesis • Free fatty acids were converted to acyl-carnitines and transferred to mitochondria, inducing ROS accumulation and apoptosis • CES2 suppressed PI3K/AKT/MYC signaling pathways by reducing signaling lipids
Sai et al.[221]	2022	30 OPMDs, 30 OSCC and 30 healthy controls	• Significant decrease in serum TC, LDL and CHO/HDL ratio in OPMD and OSCC groups vs controls • Significant decrease in serum VLDL and TG in poorly differentiated OSCC • Among OPMDs, serum lipid profile was lower in OSMF compared to leukoplakia and OLP • Gradual decrease in serum TC values from stage I to stage IV of OSCC
He et al.[222]	2022	96 OSCC samples	• PLIN2 (lipid droplet marker) mainly expressed in tumor-infiltrating immunocytes (TIIs) • PLIN2 positive patients harbored more cytoplasmic lipid droplets • CD68 + tumor-associated macrophages (TAMs) were the main source of PLIN2 in OSCC • High PLIN2 levels correlated with higher TNM stage and increased postoperative metastasis • High PLIN2 in invasive tumor front independently predicted shorter metastasis-free survival • High PLIN2 in microenvironment induced immune suppression (less CD8 + T cells, more CD68 + TAMs and Foxp3 + Tregs) • PLIN2 positively correlated with immune checkpoint molecules (CSF1R, LGALS9, IL-10, CTLA-4, TIGIT)

Lipid peroxidation products, particularly malondialdehyde (MDA) and 4-hydroxynonenal (HNE), exert multiple mechanistic effects in oral cancer development through their interactions with cellular components and signaling pathways. These products are generated when reactive oxygen species (ROS), which are elevated in cancer cells due to mitochondrial dysfunction, interact with polyunsaturated fatty acids in cell membranes [180, 181]. The resulting elevated serum MDA levels serve as indicators of increased oxidative stress in oral cancer patients [177]. At the molecular level, these peroxidation products demonstrate significant DNA-damaging potential, with 4-HNE forming specific DNA adducts that can induce mutations, particularly at critical sites such as codon 249 of the p53 gene, while simultaneously inhibiting DNA repair mechanisms including nucleotide excision repair [182]. Furthermore, reactive carbonyl species (RCS) derived from lipid peroxidation can modify proteins involved in key signaling pathways, including MAPK and PI3K/PKB(Akt), thereby influencing cell survival and proliferation patterns [176]. Interestingly, while high concentrations of HNE can trigger apoptosis in cancer cells by overwhelming their antioxidant defenses [183], the elevated levels of lipid peroxidation products can also serve as valuable biomarkers for early diagnosis and disease monitoring [177, 184]. The therapeutic implications of these mechanisms are significant, as modulating lipid peroxidation status and targeting affected pathways could enhance the efficacy of anticancer treatments [185].

Crosstalk between lipid homeostasis and tumor immunity in oral cancer

Immune cells in the oral cancer microenvironment undergo significant alterations in their lipid metabolism, which profoundly impacts their function and anti-tumor responses. A key player in this metabolic reprogramming is CD36, a fatty acid receptor expressed on immune cells, whose inhibition with sulfosuccinimidyl oleate sodium (SSO) has been shown to enhance T cell responses and inhibit tumor growth in oral squamous carcinoma cells [186]. The tumor microenvironment induces these metabolic adaptations in immune cells through complex mechanisms, leading to altered immune cell behavior and subsequent immune suppression [187, 188]. This metabolic reprogramming particularly affects fatty acid metabolism, which is crucial for providing energy and signaling molecules necessary for immune responses [189].

The impact of altered lipid metabolism extends to multiple immune regulatory pathways and cellular components within the tumor microenvironment. The sphingosine-1-phosphate (S1P) signaling pathway, regulated by enzymes such as SphK2 and LPP3, plays a crucial role in immune cell infiltration and tumor progression [17]. Additionally, lipid droplets, regulated by proteins like Perilipin-3 (PLIN3), contribute significantly to the immunosuppressive environment, with high PLIN3 expression correlating with poor prognosis in oral squamous cell carcinoma [190]. These alterations in lipid metabolism affect various immune cell populations, including T cells and macrophages, collectively contributing to an immunosuppressive microenvironment that promotes tumor progression [191]. The complex interplay between lipid metabolism and immune function presents both challenges and opportunities for therapeutic intervention, particularly in developing strategies to enhance anti-tumor immunity through metabolic modulation.

Abnormal lipid antigen presentation in OSCC represents a critical mechanism of immune evasion, characterized by disrupted lipid metabolism and altered immune recognition patterns. In the tumor microenvironment, dysregulated lipid metabolism is associated with reduced immunogenicity and enhanced immune suppression [192, 193], with the accumulation of lipid droplets and elevated expression of proteins like Perilipin-3 (PLIN3) contributing to diminished CD8 + T cell activation and increased T cell exhaustion [190]. This immune dysfunction is further complicated by abnormal cholesterol metabolism, which compromises immunotherapy effectiveness [193]. At the cellular level, dendritic cells exhibit impaired antigen presentation capabilities due to the accumulation of lipid bodies containing oxidatively truncated lipids, which interfere with the proper trafficking of peptide-MHC class I complexes [194]. Additionally, the interaction between Ig-like transcript 4 (ILT4) and CD1d molecules can suppress lipid antigen presentation, further weakening the immune response against tumor cells [195]. These alterations are reflected in serum lipid profiles, with changes in HDL-C and Apo-A levels serving as potential biomarkers for OSCC progression [8, 196], suggesting both diagnostic value and therapeutic opportunities through targeting lipid metabolism to enhance anti-tumor immunity.

Lipid homeostasis regulation in the tumor immune microenvironment of oral cancer represents a complex metabolic network that significantly influences tumor progression and immune responses. Within the tumor microenvironment (TME), cancer cells undergo extensive lipid metabolic reprogramming, characterized by enhanced lipid uptake, synthesis, and storage, which enables their survival under challenging conditions such as hypoxia and nutrient deficiency [187, 197, 198]. This metabolic adaptation profoundly impacts various immune cell populations, particularly tumor-associated macrophages (TAMs), T cells, and dendritic cells, altering their function and phenotype within the TME [191, 199]. The reprogramming of lipid metabolism in these immune cells, especially TAMs, contributes to the establishment of an immunosuppressive microenvironment that facilitates tumor immune escape and resistance to immunotherapies such as anti-PD1/PDL1 treatment [191, 200]. However, this understanding of lipid metabolic regulation also presents therapeutic opportunities, as targeting these metabolic pathways through small molecular inhibitors and phytochemicals offers promising strategies for enhancing cancer immunotherapy and restoring immune function [198, 201, 202]. The modulation of lipid homeostasis in the TME thus represents a crucial approach for improving the efficacy of existing cancer treatments and developing novel therapeutic strategies.

Lipid-Targeted therapy for oral cancer

Lipid-targeted therapy for oral cancer represents an emerging frontier in oncological treatment, leveraging the unique properties of lipids to enhance drug delivery and therapeutic efficacy. Lipid-based nanoparticles (LNPs) serve as biodegradable and biocompatible materials that minimize toxicity and adverse effects while effectively encapsulating hydrophobic drugs, thereby improving their solubility, stability, and bioavailability in biological environments [203]. These nanocarrier systems enable controlled drug release and can be modified with specific targeting ligands to achieve active targeting, enhancing precision drug delivery to tumor sites [203]. PEGylation of LNPs extends their biological half-life by reducing clearance by the reticuloendothelial system, further improving therapeutic outcomes [203]. Recent research has developed a novel graphene-based lipid modulation nanoplatform (NSD) for delivering a combination of lipid starvation, chemotherapy, and photothermal therapy, targeting ATP citrate lyase (ACLY), a key enzyme in lipid metabolism, to inhibit tumor growth and overcome chemoresistance [204]. This NSD system demonstrated high stability, excellent photothermal properties, and controlled drug release, achieving a remarkable tumor inhibition rate of 99.4% in experimental models [204]. Nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) have been explored for oral delivery of anticancer drugs, enhancing bioavailability while bypassing first-pass metabolism, offering non-invasive and patient-friendly approaches to cancer treatment [205, 206]. Atorvastatin-loaded nanoemulsions have been developed to improve oral absorption and efficacy, showing significant tumor growth suppression in preclinical models [207]. Through lipid-targeted strategies, drug accumulation in the tumor microenvironment can be enhanced, improving drug permeability while reducing impact on normal tissues [207]. Compared to conventional treatment methods, lipid-targeted therapies offer more personalized treatment options, designing therapeutic strategies based on specific patients' metabolic characteristics [204].

Targeting lipid metabolism pathways represents another crucial strategy for oral cancer treatment, focusing on tumor-specific metabolic reprogramming. CD36, a fatty acid receptor involved in lipid metabolism, has shown potential in suppressing tumor progression and enhancing antitumor immune responses when inhibited, utilizing selective inhibitors such as sulfosuccinimidyl oleate sodium (SSO) to modulate immune responses and inhibit tumor growth [186]. Targeting lipid metabolism pathways, including fatty acid synthesis and uptake, presents new opportunities for cancer therapy, although no FDA-approved treatments currently exist for these pathways [208]. Lipid raft-targeted therapies are also gaining research focus, with alkylphospholipid analog Edelfosine targeting lipid rafts to inhibit metastatic colonization and angiogenesis, demonstrating efficacy in preventing metastatic growth and organ colonization, highlighting its potential in cancer therapy [209]. While lipid-targeted therapies offer promising advancements in oral cancer treatment, challenges remain in their clinical translation, including manufacturing complexities, regulatory hurdles, and the need for comprehensive clinical trials, which must be addressed to fully realize the potential of these therapies. The integration of lipid-targeted therapy with existing treatment modalities may enhance therapeutic outcomes and provide more comprehensive cancer management approaches, particularly for advanced or recurrent oral cancers that are insensitive to traditional treatments [186]. Lipid metabolism in oral cancer demonstrates complex interactions with tumor immunity, where alterations in immune cell lipid metabolism significantly impact antitumor responses, suggesting potential synergistic benefits from combining lipid-targeted therapies with immunotherapeutic approaches [186]. The identification of specific lipid metabolic vulnerabilities in oral cancer subtypes offers opportunities for developing precision medicine approaches, where therapy selection could be guided by individual tumor metabolic profiles [208]. Future research directions should focus on developing more specific lipid metabolism inhibitors, establishing biomarker systems to predict lipid-targeted therapy efficacy, and optimizing combination treatment regimens to enhance synergistic antitumor effects [208]. The economic considerations and cost-effectiveness analyses will be important in determining the feasibility of widespread adoption of novel lipid-targeted therapies in clinical practice [203].

Future perspectives and outlook

Future research in oral cancer lipid metabolism should focus on developing more precise targeting strategies and overcoming current limitations in clinical translation. Multi-omics integration combining lipidomics, metabolomics, and transcriptomics offers promising opportunities to comprehensively profile lipid metabolism alterations in individual patients, enabling truly personalized therapeutic approaches. Advanced imaging techniques such as mass spectrometry imaging (MSI) will likely provide spatial information about lipid distribution within tumor tissues, helping to address the challenge of intratumoral heterogeneity. Artificial intelligence and machine learning algorithms could revolutionize the field by identifying novel lipid biomarkers and predicting treatment responses with higher accuracy. The development of lipid metabolism-specific nanomedicines with active targeting capabilities represents another frontier, potentially enhancing therapeutic efficacy while minimizing systemic toxicity. Expanding investigations into the complex interplay between lipid metabolism and tumor immunity will be critical for designing more effective combination immunotherapies. Clinical validation of lipid metabolism biomarkers through large-scale, multi-center trials remains essential to establish their utility in treatment stratification and monitoring. Ultimately, a systems biology approach will be necessary to fully understand and therapeutically exploit the complex lipid metabolic networks in oral cancer.

Translating lipid-targeted therapies from bench to bedside presents both significant challenges and opportunities for improving oral cancer management. The development of highly selective inhibitors targeting cancer-specific lipid metabolic vulnerabilities while sparing normal tissues will be crucial for minimizing off-target effects and toxicity concerns. Combination treatment protocols that simultaneously target multiple lipid metabolic pathways may prove more effective in preventing compensatory mechanisms and resistance development commonly observed with single-agent approaches. Clinical validation of preliminary findings through rigorous phase trials represents a necessary step to determine optimal dosing regimens and identify patient subgroups most likely to benefit from lipid-targeted therapies. Repurposing already approved lipid-modulating drugs such as statins and fibrates offers a potentially expedited pathway to clinical implementation with established safety profiles. Economic considerations including cost-effectiveness analyses will be important in determining the feasibility of widespread adoption of novel lipid-targeted therapies. Addressing regulatory challenges specific to metabolism-targeting compounds will require standardized protocols for evaluating efficacy and safety in oral cancer treatment paradigms.

Conclusion

This review highlights the critical role of lipid homeostasis dysregulation in oral cancer pathogenesis, diagnosis, and treatment. Aberrant lipid metabolism, characterized by alterations in key enzymes like FASN and ACLY, activation of oncogenic pathways such as PI3K/AKT/mTOR, and changes in serum lipid profiles, represents a fundamental feature of oral carcinogenesis with significant clinical implications. The dual role of lipid peroxidation in both promoting cancer development and serving as potential biomarkers offers unique perspectives for diagnosis and monitoring. Furthermore, the intricate interplay between lipid metabolism and tumor immunity presents promising opportunities for immunometabolic interventions to enhance anti-tumor responses. Despite significant advances in understanding these mechanisms, considerable challenges remain in translating these findings into clinical applications, necessitating further research on combination therapies, biomarker validation, and personalized treatment approaches. The emerging field of lipid-targeted therapies, including nanoparticle-based drug delivery systems and metabolic enzyme inhibitors, holds considerable promise for improving oral cancer treatment outcomes, particularly for patients with advanced or recurrent disease. Future directions should focus on developing more selective inhibitors, validating lipid biomarkers in large-scale clinical trials, and exploring novel combinatorial strategies that simultaneously target multiple aspects of lipid metabolism to overcome adaptive resistance mechanisms in oral cancer.

Author contributions

“LL and CL contributed equally to this work as co-first authors. LL was responsible for literature search, construction of the review framework, and drafting of the initial manuscript. CL participated in literature screening and content validation. SD, ZJ, LZ, JT, ML, and XZ assisted with literature collection, data extraction, content categorization, and evidence evaluation. SL, as the senior author, revised the manuscript, as well as provided professional guidance, content review, and expert advice. LL and ZAG, as the corresponding authors, were responsible for conceptualizing the review, overall supervision, project management, and final review and revision of the manuscript.”

Funding

The study was self-funded by the authors.

Data availability

The complete list of included studies with relevant extracted data are available upon reasonable request from the corresponding author.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.