Historical rise of cancer and dietary linoleic acid: Mechanisms and therapeutic strategies

Abstract

Over the past century, dietary intake of linoleic acid (LA), an essential omega-6 fatty acid, has risen markedly in industrialized regions, largely due to industrial seed oils (e.g., soybean oil). This trend parallels increased cancer incidence, though causality remains unestablished. LA’s susceptibility to oxidation may generate reactive species, such as 4-hydroxynonenal, potentially inducing oxidative stress and lipid peroxidation in cellular membranes. Furthermore, excess LA might elevate pro-inflammatory eicosanoid levels (e.g., prostaglandin E2) and disrupt gut microbiota, fostering dysbiosis and immune dysregulation. Evidence, however, derives primarily from preclinical studies, with limited human data but epidemiological signals are strongest for breast (age-standardized incidence, approximately 130/100000 women), colorectal (approximately 39/100000), prostate (approximately 112/100000 men) and cutaneous melanoma (approximately 26/100000) cancers, where higher LA biomarkers or intakes have been repeatedly observed. Ketogenic diets, historically prioritized for metabolic benefits, reduce blood glucose, an effect possibly beneficial in cancer contexts, but may impair gut health by restricting fermentable fiber, potentially decreasing short-chain fatty acid production. This review explores LA’s hypothetical role in cancer-related pathways and the trade-offs of carbohydrate restriction. A proposed “terrain restoration” protocol, emphasizing reduced LA intake, gradual carbohydrate reintroduction to support microbiota, and nutrients like pentadecanoic acid (C15:0) for mitochondrial function, lacks clinical validation. While optimizing diet to bolster metabolic and immune resilience holds promise for cancer prevention, rigorous research is essential.

Key Words: Linoleic acid; Cancer mechanisms; Oxidative stress; Mitochondrial dysfunction; Chronic inflammation; Gut microbiota dysbiosis; Dietary seed oils; Short-chain fatty acids; Terrain restoration

Core Tip: Industrial seed-oil boom has tripled linoleic acid (LA) intake since 1900, tracking the surge in cancer. This review synthesizes cutting-edge data showing how excess LA seeds oxidative lipid peroxidation, succinate-driven pseudohypoxia, mitochondrial dysfunction, hormonal-inflammatory amplification and gut dysbiosis that together create a “pro-cancer terrain”. It also challenges blanket ketogenic prescriptions, warning that carb exclusion can worsen LA-induced dysbiosis, and outlines a phased “terrain-restoration” plan: Slash dietary LA, reintroduce selective fibers, add odd-chain pentadecanoic acid and metabolic supports to revive mitophagy, microbiota and immune surveillance. The article spotlights urgent research gaps and testable clinical strategies.

INTRODUCTION

The 20^th century saw a marked increase in cancer incidence and mortality, particularly in breast, colorectal, prostate, and melanoma cancers, which show the strongest associations with elevated dietary linoleic acid (LA) exposure, parallel with significant changes in dietary patterns and lifestyle, including the widespread adoption of industrial seed oils. For example, Siegel et al’s analysis of cancer trends in the 20^th century identified notable increases in the incidence of breast, prostate, melanoma, lung, and colorectal cancers starting in the mid-1900s, a period that coincides with the widespread adoption of industrial seed oils[1]. The lifetime risk of developing cancer rose from approximately 5% in 1900 to over 30%-50% in contemporary populations. While advancements in longevity and diagnostic capabilities account for some of this rise, environmental factors, including dietary shifts, play a substantial role. A key dietary change has been the increased consumption of LA, an omega6 polyunsaturated fatty acid (PUFA) primarily sourced from vegetable oils[2,3]. Notably, LA is an essential fatty acid necessary in limited quantities for maintaining normal physiological functions; however, prolonged excessive intake may lead to adverse effects[4]. PUFAs such as LA are susceptible to oxidation, generating reactive lipid peroxides and aldehydes, including 4hydroxynonenal (4HNE), which can inflict damage on DNA, proteins, and cellular membranes[5]. Diets high in LA also lead to the accumulation of these oxidizable fats in tissues, thereby potentially exacerbating oxidative stress and inflammation[6]. Furthermore, LA serves as a precursor to arachidonic acid (AA), which is metabolized by enzymes like cyclo-oxygenase-2 (COX-2) to produce proinflammatory eicosanoids, such as prostaglandin E2 (PGE2)[7].

Before the industrial era, LA accounted for approximately 1%-2% of human caloric intake[8]. In contrast, contemporary western diets derive over 7% of calories from LA, representing a more than threefold increase[8]. This escalation in LA consumption is largely attributable to the substitution of traditional animal fats, such as butter and lard, with vegetable oils like soybean, corn, and other seed oils over the past century[9]. Notably, the widespread adoption of industrial seed oils, which are rich in LA, has led to a substantial rise in average LA intake[8]. Multiple independent lines of evidence, United States Department of Agriculture economic-disappearance tables and peer-reviewed nutritional analyses, agree that United States per-capita soybean-oil availability climbed from almost zero in the early 1900s to roughly 24-25 kg/person/year by the first decade of the 2000s[9]. During the same century-long window, population-level LA exposure rose about two- to three-fold, from approximately 3% to approximately 7% of total calories[2,10]. Notably, this escalation reflects a greater than 1000-fold increase in per-capita soybean oil availability from 1909 to 1999, paralleled by a 136% rise in LA content within human adipose tissue, from approximately 8% in 1960 to 18% by 2008[2,4,6]. This temporal alignment with the modern surge in obesity, type 2 diabetes mellitus, and cardiovascular disease (CVD) suggests that excessive dietary LA may contribute to the etiology of these chronic conditions, a hypothesis historically underscored by shifts in dietary fat composition.

This shift in dietary patterns has significantly altered human biochemistry, with LA now constituting a larger proportion of fatty acids in cell membranes and adipose tissue compared to previous generations[4]. Analyses of human adipose tissue reveal that LA levels more than doubled from the 1960s to the early 2000s, a change that reflects the increased presence of omega-6 fatty acids in the food supply (Figure 1). For contrast, populations such as the Maasai and Tokelauans, whose diets maintain LA intake below 3% of total energy, exhibit negligible prevalence of CVD, obesity, and diabetes, whereas in the United States, adipose LA levels escalated to ≈ 18% by 2010, a concentration associated with cardiotoxic effects in preclinical studies[6]. This disparity underscores the potential protective role of low LA consumption, a dietary pattern historically prevalent prior to the industrial adoption of seed oils. This trend parallels the rise in vegetable oil consumption during the 20^th century. The elevated levels of unsaturated fatty acids in tissues may enhance susceptibility to lipid peroxidation and inflammation, thereby establishing a mechanistic connection between contemporary dietary habits and the prevalence of chronic diseases[4].

Figure 1 Dramatic four-decade rise in linoleic acid content of United States subcutaneous adipose tissue (1960-2008). Values are mean ± SD. Data sources by decade (mean ± SD,% total fatty acids): 1960, 8.0% ± 0.9%[257], 1970, 10.1% ± 1.2%[258], 1980, 12.1% ± 1.3%[259], 1990, 14.2% ± 1.0%[260], 2000, 16.2% ± 1.1%[261], 2010, 18.0% ± 1.0%[262]. The proportion of linoleic acid in United States subcutaneous adipose tissue more than doubled, from approximately 8% in 1960 to approximately 18% by 2010, mirroring the progressive incorporation of industrial seed oils into the food supply.

It is crucial to acknowledge that correlation does not imply causation; however, these parallel trends indicate that high dietary LA levels may contribute to creating an environment conducive to cancer development[11]. Additionally, it is essential to consider confounding factors such as population aging and advancements in cancer screening and detection[12], which have also contributed to the observed increase in cancer incidence.

Excessive dietary LA can stimulate the production of potent inflammatory mediators that are implicated in tumorigenesis[13]. Animal studies have consistently demonstrated that high-LA diets promote tumor growth more effectively than low-LA diets[14]. From an epidemiological perspective, the sharp increase in vegetable oil consumption since the mid-20^th century has coincided with rising rates of cancers such as breast and colon cancer, highlighting a potential association that merits further mechanistic exploration[15]. Recent research has also suggested that dietary LA may influence the composition of the gut microbiota and the integrity of the intestinal barrier, both of which are important factors in regulating systemic inflammation and overall disease risk[16].

The subsequent sections of this paper will examine the primary mechanisms through which excessive LA exposure may contribute to carcinogenesis. These mechanisms encompass alterations in the gut microbiota[17], disruptions in redox balance leading to the generation of reactive oxygen species (ROS) and lipid peroxidation[18], inhibition of autophagy and mitophagy resulting in organelle dysfunction[19], and the amplification of chronic inflammatory signaling through hormonal and metabolic pathways[20]. Additionally, the paper will explore therapeutic strategies aimed at restoring a healthy metabolic and inflammatory environment. This review examines: (1) Historical trends linking LA intake and cancer incidence[11]; (2) The role of excess LA in oxidative stress, mitochondrial dysfunction, impaired autophagy, and inflammation[4]; (3) The interplay between LA-driven dysbiosis and immune activation; (4) Potential pitfalls of strict carbohydrate restriction in a dysbiotic terrain[21]; and (5) A proposed “terrain restoration” dietary strategy combining LA reduction with phased carbohydrate reintroduction and supportive nutrients[21]. By integrating these areas, we aim to illuminate how reshaping the nutritional landscape might help restore a healthier biochemical and immunological terrain less conducive to cancer.

RISING LA INTAKE AND CANCER INCIDENCE TRENDS

At a mechanistic level, high levels of LA have been shown in preclinical studies to promote oxidative stress by increasing the production of lipid peroxides, such as 4-HNE, which can damage cellular components including DNA and membrane proteins[22]. However, these studies frequently employ supraphysiological doses, far exceeding the typical human dietary intake of 5%-10% of total energy, or rely on animal models, limiting their applicability to human physiology. Additionally, preclinical investigations have suggested that dietary LA might alter the gut microbiota composition and compromise intestinal barrier integrity, factors vital to maintaining a systemic terrain that modulates inflammation and disease susceptibility[23]. These studies, however, are predominantly conducted in animal models, and no robust human data currently substantiate a direct link between LA consumption and gut dysbiosis[24]. Notably, some individuals attempt to improve metabolic and oncologic outcomes through very-low-carbohydrate or ketogenic diets[25], but such interventions in the context of a damaged gut ecosystem could have drawbacks[26].

Isolating the impact of LA on cancer risk from historical data is challenging due to multiple confounding variables, such as shifts in smoking prevalence, exposure to environmental toxins, and advancements in diagnostic capabilities over the 20^th century[4]. Mechanistic reasoning provides some plausibility for a connection; for instance, high LA intake elevates linoleate content in cell membranes and lipoproteins, thereby increasing substrates available for oxidation into reactive compounds like lipid hydroperoxides. In this context, populations adhering to traditional diets low in seed oils, and thus low in LA, historically exhibited lower incidences of certain cancers compared to those in industrialized regions with elevated seed oil consumption[4] (Table 1). However, this temporal correlation between cancer incidence and dietary LA patterns does not establish causation and must be interpreted with caution[27]. Recent human data indicate that elevated LA exposure is linked to higher risk or progression of breast (especially triplenegative) cancer[28], colorectal cancer[29], and cutaneous melanoma[30], whereas systematic reviews suggest neutral or modestly protective associations for prostate cancer[31].

Table 1 Twentieth-century surge in dietary and adipose linoleic acid with parallel rise in United States cancer incidence.

Decade	Per-capita linoleic acid intake (% kcal)	Adipose-tissue linoleic acid (% fatty acid)	Age-adjusted total cancer incidence (per 100000)	Key dietary milestone
1900s	1-2	N/A	Approximately 90	Minimal seed-oil use
1950s	3-4	Approximately 8%	Approximately 180	Margarine adoption
1980s	6-7	Approximately 14%	Approximately 310	Widespread soybean oil
2000s	7-8	Approximately 18%	Approximately 460	Ultra-processed foods

N/A: Not applicable.

This ecological evidence provides a foundation for hypothesis generation regarding how LA might influence cancer-related pathways, such as oxidative DNA damage or altered immune surveillance[32]. Nevertheless, these historical observations are not conclusive and are best viewed as preliminary. For example, when confounding factors are accounted for, some epidemiological analyses have detected no significant elevation in cancer risk, such as for breast or colorectal cancers, with higher LA intake[33]. Overall, the historical correlations are intriguing but not definitive. They do, however, underscore the importance of exploring how chronic excess LA could biochemically condition the body’s terrain in ways that synergize with carcinogenesis[34].

Moreover, historical randomized controlled trials (RCTs) provide compelling evidence of LA’s potential toxicity. In a seminal 1965 RCT, Rose et al[34] administered approximately 95 g/day of corn oil, equivalent to 19 teaspoons, to patients with ischemic heart disease, observing a significantly elevated mortality rate in the intervention group compared to controls (P < 0.05), which necessitated premature termination of the study[35]. This finding, rooted in mid-20^th-century dietary intervention research, suggests that excessive LA intake may directly contribute to adverse health outcomes beyond its hypothesized role in carcinogenesis. In a similar vein, the Los Angeles Veterans Administration Trial demonstrated that men randomized to a diet deriving approximately 15% of total energy from LA exhibited a 25% higher incidence of cancer and cancer-related mortality compared to those consuming a diet rich in saturated fatty acids (P < 0.01)[36]. These data reinforce the notion that elevated LA consumption may enhance oncogenic processes, potentially through mechanisms involving oxidative stress and inflammation.

Similarly, re-analysis of the Sydney Diet Heart Study revealed that substitution of dietary saturated fats with safflower oil, a concentrated source of LA providing approximately 13% of energy, resulted in increased all-cause mortality [hazard ratio (HR) = 1.62, 95% confidence interval: 1.08-2.43], CVD mortality (HR = 1.70), and coronary heart disease mortality (HR = 1.74), despite a reduction in serum cholesterol levels[37]. This paradoxical outcome challenges the historical assumption that LA-mediated cholesterol reduction universally improves health outcomes. Furthermore, the Minnesota Coronary Experiment demonstrated that a corn oil-based diet, which lowered low-density lipoprotein (LDL) cholesterol by 14%, was associated with a 22% increase in mortality risk per 30 mg/dL reduction in LDL (P < 0.05), contradicting the long-standing diet-heart hypothesis that links reduced LDL with extended longevity[38]. These findings suggest that LA’s metabolic effects extend beyond lipid profiles, potentially exacerbating systemic risk factors for chronic disease. In this context, a meta-analysis encompassing over 76000 participants across classic diet-heart trials concluded that replacing saturated fatty acids with omega-6 LA conferred no cardiovascular benefit and exhibited a trend toward increased mortality risk [relative risk = 1.13, 95% confidence interval: 0.99-1.29], challenging decades of dietary recommendations advocating LA-rich vegetable oils[37]. This collective evidence underscores the need to reassess the safety of high LA intake in modern dietary patterns.

OPPOSING EPIDEMIOLOGICAL EVIDENCE FROM HUMAN COHORTS AND COUNTERANALYSIS

Several large prospective cohorts and pooled analyses report either neutral or modestly inverse relations between dietary or biomarker LA and common cancers. A 2020 review of 38 prospective studies found no significant association between total omega6 PUFA intake and overall cancer incidence[27]. A 2025 metaanalysis covering 150 cohorts (4.1 million participants) likewise observed no excess risk of sitespecific or allcause cancer mortality across the upper vs lower LA quintiles[32]. For breast cancer, pooled data from ten cohorts showed a non-significant 4% risk reduction per 5 g/day higher LA[39], while prostatecancer studies even suggest a weak protective effect[31]. These null or favorable outcomes, together with LAmediated LDLcholesterol lowering in cardiovascular trials, are often cited to argue that modern LA intakes pose little oncogenic threat.

Limits of the “nullrisk” inference

Closer inspection reveals that most human cohorts sample from a uniformly highLA world: Median exposures cluster between 5%-8% of total energy, far above the approximately 2% ancestral baseline[2,8]. There is therefore minimal exposure contrast to detect potential thresholds or Jshaped risk curves. Biomarker ranges are similarly compressed; United States adiposetissue LA spans barely threefold from 10% to 18% of fatty acids. By contrast, mechanistic work places the oxidative breakpoint for mitochondrial and immune dysfunction near 3%-4% of total energy.

NATURAL LOWLA COMPARATORS ARE VANISHINGLY RARE

Traditional groups with very low LA exposure (approximately 1%-3% of total energy), for example the Maasai of Kenya, atoll populations such as Tokelau and Pukapuka with coconut-based diets, and the Kitavans of Papua New Guinea, have historically reported low rates of cardiometabolic disease; systematic, site-specific cancer data are sparse. These populations illustrate that the “low-LA” quintile in Western cohorts may still lie well above truly low-exposure levels[40,41]. Their existence suggests that today’s “lowLA” quintile in western cohorts may already lie on the flat upper limb of the dose-response curve.

Intervention trials favor reduction

Randomized dietary-exchange studies that actively lower LA from approximately 7% to 2%-3% of total energy cut plasma 9- and 13-hydroxyoctadecadienoic acid (HODE), 4HNE adducts and oxidized LDL within weeks[42,43]. Such biochemical shifts map directly onto the oxidative-inflammatory cascade described throughout this review yet remain invisible to foodfrequencyquestionnaire epidemiology. Apparent epidemiological neutrality should therefore be interpreted with caution. When all study participants are already above the mechanistic risk threshold, classical cohort methods lose the power to detect harm. Until genuine lowLA exposure groups or longterm, adequately powered reduction trials are available, mechanistic, ecological and shortterm intervention data collectively justify reassessing current LA intakes. Table 2 summarizes recent epidemiological, mechanistic, and Mendelian randomization studies examining the association between LA and cancer incidence or progression across multiple sites.

Table 2 Associations between linoleic acid and cancer risk or progression.

Cancer type	Study design	Key findings/interpretation	Ref.
Breast (ER+/ER-)	Mendelian randomization (United Kingdom Biobank)	Genetically elevated plasma LA was associated with increased risk of ER+ breast cancer. This suggests a potential causal relationship, though dietary intake thresholds were not assessed. No control population consuming < 5% LA of total daily energy	[263]
Triple-negative breast cancer	Tumor metabolomics + xenograft	LA served as a key metabolic substrate driving tumor progression via upregulated β-oxidation and PPARα signaling. In vivo, LA supplementation accelerated triple-negative breast cancer tumor growth. Effect not observed under low-LA feeding	[13]
Prostate	Dose-response meta-analysis of prospective cohorts	No consistent association between dietary or biomarker LA and prostate cancer risk. Studies lacked low-LA intake arms (< 5% of daily calories), limiting ability to detect nonlinear effects	[31]
Non-small-cell lung	United Kingdom Biobank (plasma LA)	Higher circulating LA associated with significantly reduced incidence of non-small-cell lung. LA was inversely associated with time to diagnosis and overall risk. Relationship limited to biomarker data; dietary LA thresholds not stratified	[264]
Lung (all histologies)	Prospective cohort (plasma fatty acids)	Circulating LA inversely associated with lung cancer risk across histologic subtypes. No evidence of U-shaped risk or high-LA threshold effects. No low-intake (< 5% energy) group included	[265]
Pancreatic	Case-control (PanC Consortium)	Slight inverse association between LA intake and pancreatic cancer risk. Association was non-linear, with attenuation at higher intakes. No stratification by low-LA consumption	[266]
Colorectal	Meta-analysis of dietary + biomarker studies	Pooled analysis found modestly increased colorectal cancer risk with higher LA intake. Effect stronger for dietary LA vs plasma biomarker. Studies lacked representation of < 5% LA intake groups	[29]
Colorectal (sub-site stratified)	Pooled analysis (54 studies + 4 Mendelian randomization)	Increased risk particularly for rectal cancer. No protective effect observed. Sub-group analysis suggests dose-response relationship, but low-LA intake not studied	[11]
Colon	Animal + human tissue (CYP- epoxyoctadecenoic acids mechanism)	LA-rich diets led to higher levels of pro-inflammatory epoxyoctadecenoic acids via CYP metabolism, promoting colonic tumorigenesis. Effects confirmed in human samples. No low-LA comparator group included	[267]
Colon and rectum	EPIC-InterAct (plasma phospholipid LA)	Plasma LA not significantly associated with colorectal cancer risk. Null finding, but biomarker variability may mask associations. No data on dietary intake below 5% energy from LA	[268]
Kidney	Pan-cancer Mendelian randomization	Genetically predicted higher LA levels associated with increased kidney cancer risk. Suggests possible causal effect. No reference to real-world low-LA cohorts	[269]
Hepatocellular carcinoma	Tumor microenvironment analysis	LA uptake enhanced tumor cell proliferation via upregulation of LINC01116 and fatty acid metabolism genes. Supported LA’s role as an oncometabolite in hepatocellular carcinoma	[270]
Hepatocellular carcinoma	TCGA/ICGC multi-omics prognostic modeling	High LA metabolic activity (gene expression signature) correlated with reduced survival and more aggressive tumor phenotypes. LA-related metabolic pathways proposed as therapeutic targets	[271]
Gastric adenocarcinoma	EPIC-EURGAST (plasma phospholipids)	No significant association between plasma LA and gastric cancer risk. Very limited range of dietary intake in cohort; < 5% energy LA group not present	[272]
Cervical	Radiotherapy cohort (serum + fecal metabolomics)	Patients with low serum and fecal LA at baseline showed poorer nutritional status and worse treatment response. Unclear if LA was causally protective or a marker of overall intake	[273]

ER: Estrogen receptor; LA: Linoleic acid; CYP: Cytochrome P450; EPIC: European Prospective Investigation into Cancer and Nutrition; TCGA: The Cancer Genome Atlas; ICGC: International Cancer Genome Consortium; EURGAST: European Gastric Cancer Study; PPARα: Peroxisome proliferator-activated receptor-alpha.

Excess LA can promote a cascade of oxidative and inflammatory effects at the cellular level. Chemically, LA’s polyunsaturated structure (18:2, n-6) is highly prone to peroxidation, a chain reaction initiated by ROS. When cell and lipoprotein membranes enriched in LA are exposed to ROS, LA readily oxidizes into reactive aldehydes and other oxidized LA metabolites (OXLAMs)[4]. Notably, a study showed that high-LA diets increased tissue levels of volatile aldehydes, such as malondialdehyde (MDA), by 40%[44]. In that study, inhibiting 5-lipoxygenase significantly reduced aldehyde production and oxidative damage[45]. These findings illustrate how LA, as an oxidative fuel, generates secondary products that can attack proteins, membranes, and DNA[5]. However, this study’s findings could reflect broader dietary influences beyond LA alone, such as antioxidant status, which was not fully controlled. For instance, high MDA levels might stem from oxidative stress unrelated to LA.

Furthermore, the human metabolic apparatus lacks sufficient enzymatic capacity, such as delta-6 desaturase, to rapidly metabolize excess LA, leading to its pronounced bioaccumulation in adipose tissue and cellular membranes[4]. This accumulation renders these tissues highly susceptible to lipid peroxidation, generating reactive species such as MDA and OXLAMs, including 9- and 13-HODE, which exacerbate inflammation and mitochondrial dysfunction. In preclinical models, for example, LA-derived OXLAMs have been shown to increase hepatic interleukin-6 (IL-6) expression by 30%, highlighting their role in transforming cellular structures into a primed state for oxidative damage[46].

The inner mitochondrial membrane (IMM) is primarily composed of phospholipids, with cardiolipin constituting approximately 20% of the total phospholipid content[47]. Cardiolipin, a unique dimeric phospholipid, is essential for maintaining the structure and function of the electron transport chain (ETC) within mitochondria[48]. Typically, cardiolipin incorporates LA as a major component of its fatty acyl chains. While other PUFAs can be incorporated, LA is predominant in many species, including humans. In metabolically active tissues such as the heart, liver, and brain, maintaining LA at levels exceeding 50%-80% of the fatty acids in cardiolipin is crucial for optimizing mitochondrial function, specifically in the efficient production of ATP[49].

One of the primary biological functions of LA is to enhance the flexibility of mitochondrial cristae, the inner membrane folds within mitochondria[3,50]. This flexibility enables the formation of curved structures that facilitate the assembly of supercomplexes, multimeric assemblies of ETC components, such as complexes I, III, and IV, which optimize electron flow for ATP synthesis[51]. This role is particularly prominent in mitochondrial-dense tissues, such as the heart, liver, and brain, where energy demands are exceptionally high[52]. For example, in cardiac muscle, mitochondria constitute approximately 35% of the cell volume to meet the relentless ATP requirements of contractile activity, while in hepatocytes, mitochondrial density supports metabolic processes like gluconeogenesis[53]. Historically, LA-mediated cristae bending has been recognized as a critical determinant of respiratory efficiency, enhancing the spatial organization of ETC components for maximal energy yield[50].

The IMM serves as the epicenter of cellular energy production, hosting the ETC responsible for ATP synthesis. While ROS have been recognized as deleterious to cellular function since the mid-20^th century, with mitochondria identified as a primary ROS source[54], a more precise mechanism has been elucidated. This mechanism centers on the excessive accumulation of LA, specifically in the non-cardiolipin fraction of the IMM[55]. This phenomenon, driven by modern high LA intakes, represents a novel insult to human biology and underpins the profound cellular damage linked to cancer and accelerated aging. The IMM hosts the ETC, driving ATP synthesis, and mitochondria are indeed a ROS source, as noted since the 1950s[56]. However, the claim that excess LA in non-cardiolipin phospholipids specifically may drive cancer and aging lacks direct evidence at this time.

Protected by antioxidants such as manganese superoxide dismutase and glutathione, cardiolipin’s LA content is tightly regulated and does not pose a primary threat[57]. In contrast, the remaining 80% of the IMM comprises non-cardiolipin phospholipids, including phosphatidylcholine and phosphatidylethanolamine, which are highly susceptible to LA enrichment[58]. When LA in these phospholipids exceeds 7%-8%, with levels like 23% observed in cell cultures, membrane dysfunction risk reportedly increases threefold[59,60]. However, these thresholds are derived from in vitro studies, which may not reflect physiological conditions where antioxidant defenses or other fatty acids could mitigate effects.

The mechanism of destruction hinges on LA’s propensity to undergo lipid peroxidation under oxidative stress, generating toxic byproducts such as 4-HNE. This reactive aldehyde directly damages ETC components, notably complexes I and III, impairing ATP production and amplifying ROS generation in a vicious cycle[61]. While 4-HNE production in the cytoplasm or outer cellular membranes contributes to localized damage, disrupting hepatic or cardiac function, for example, its impact pales in comparison to the devastation wrought within the IMM[62]. Here, the proximity to the ETC amplifies 4-HNE’s destructive potential, disrupting energy metabolism at its core and driving cellular dysfunction. Consequently, this IMM-specific damage emerges as the primary driver of biological collapse, far outweighing secondary effects in other cellular compartments[62].

One particularly toxic LA-derived aldehyde is 4-HNE[63]. Once formed, 4-HNE forms covalent adducts with proteins, impeding their function, and can instigate a vicious cycle of cellular damage. Specifically, 4-HNE reduces complex I activity by 25%, triggering apoptosis in vitro[64]. Furthermore, 4-HNE attacks lysosomal membranes and key chaperone proteins, thereby impairing autophagy, the cell’s housekeeping and organelle-recycling process. In primate studies, exposure to 4-HNE led to a loss of intact lysosomes with a concomitant buildup of dysfunctional autophagosomes, indicating failure of autophagic flux[65]. Impaired autophagy can allow damaged mitochondria and proteins to accumulate, promoting genomic instability and a protumorigenic state in cells[66]. Yet, these effects may not be LA-specific, as 4-HNE from other sources could similarly disrupt autophagy. Moreover, linking this to cancer remains speculative without longitudinal data showing LA-driven tumorigenesis.

MECHANISTIC PATHWAYS LINKING EXCESS LA TO CARCINOGENIC TERRAIN

Oxidative stress and lipid peroxidation

Historically, strategies to counteract ROS prioritized broad-spectrum mitochondrial antioxidants, yet the pivotal role of LA in noncardiolipin phospholipids was largely ignored[62]. This oversight is significant, as the threshold-dependent nature of LA-induced damage offers a precise target for intervention[67]. For example, maintaining LA below 8% in these phospholipids preserves ETC integrity, whereas levels approaching 23% correlate with a near-complete loss of mitochondrial efficiency[60,68].

Approximately 30% of proteins modified by 4HNE in cells are mitochondrial proteins, underlining how LA peroxidation preferentially harms these organelles[69]. 4HNE modification of respiratory enzymes further diminishes mitochondrial function and can initiate a feedback loop: Dysfunctional mitochondria generate more ROS, causing more lipid peroxidation and damage[65]. Reducing LA intake, conversely, has been shown to rapidly diminish levels of these harmful oxidation compounds and markers of oxidative stress in humans[43]. For instance, a 50% reduction in dietary LA lowered plasma HODE levels within two weeks[70].

Mitochondrial dysfunction and βoxidation overload

Mitochondria are central to cellular metabolism, particularly in energy production via oxidative phosphorylation, and their dysfunction, often characterized by altered metabolic pathways such as the Warburg effect, is a hallmark of cancer cells[71]. Diets high in LA can impair mitochondrial performance through multiple routes[32]. First, an overload of fatty acids from high fat intake, especially unsaturated fats, can stress the β-oxidation pathways in mitochondria[72]. β-oxidation of fatty acids generates abundant nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂), which drive reverse flow in ETC. In the context of excess fat supply, the ETC becomes over-reduced and leaks electrons, generating excess ROS[49,73,74].

Researchers tested the hypothesis that LA or OXLAMs provided directly through the diet are involved in the development of hepatic injury. C57BL/6 mice were fed an isocaloric high-fat diet containing low LA, high LA, or OXLAMs for 8 weeks. The livers of OXLAM-fed mice showed lower triglyceride concentrations, but higher FA oxidation and lipid peroxidation in association with increased oxidative stress. OXLAM-induced mitochondrial dysfunction was associated with reduced complex I protein and hepatic ATP levels, as well as increased mitochondrial biogenesis and cytoplasmic mitochondrial DNA. Oxidative stress increased thioredoxin-interacting protein in the liver and stimulated the activation of mitochondrial apoptosis signal-regulating kinase 1 Leading to apoptosis. They also found increased levels of NOD-like receptor protein 3 inflammasome components and Caspase-1 activation in the livers of OXLAM-fed mice[75]. This study identified key mechanisms by which dietary OXLAMs contribute to non-alcoholic steatohepatitis development, including mitochondrial dysfunction, hepatocyte cell death, and NOD-like receptor protein 3 inflammasome activation. These mechanisms mirror those observed in atherosclerosis and neurodegeneration, suggesting that LA-driven oxidative stress and inflammation may underpin a spectrum of chronic pathologies, including cancer.

Impaired autophagy and mitophagy

In this context, LA in cardiolipin stabilizes respiratory supercomplexes, enhancing ATP output by up to 30% in cardiac tissue. High levels of LA in cardiolipin are crucial for the formation and stability of respiratory super-complexes in the ETC, which in turn maximize ATP production[48]. The LA components are vulnerable to oxidative stress; thus, their integrity is preserved by mitochondrial antioxidant systems, including superoxide dismutase 2, a manganese-dependent enzyme, and glutathione[76]. However, if antioxidants fail, LA’s benefit could become a liability, though this applies to all PUFAs.

When cardiolipin undergoes peroxidation, it triggers significant downstream consequences[77]. Peroxidized cardiolipin destabilizes the IMM, promoting the release of pro-apoptotic factors, such as cytochrome c, from the intermembrane space into the cytosol, thereby initiating the apoptotic cascade, a programmed cell death pathway[78]. Additionally, peroxidized cardiolipin serves as a molecular signal, marking the damaged mitochondrion for selective degradation via mitophagy[79]. However, if mitophagy is impaired, as observed in conditions like aging or neurodegenerative diseases such as Parkinson’s, these damaged mitochondria accumulate, leading to cellular dysfunction and contributing to tissue pathology over time[80].

Notably, healthy cells can usually remove damaged mitochondria via mitophagy[81]. High-fat feeding is known to hyper-activate the mechanistic target of rapamycin (mTOR) pathway, a nutrient-sensing kinase that inhibits autophagy[82]. By upregulating mTOR and downregulating AMP-activated protein kinase (AMPK) an LA-rich obesogenic diet can block the mitophagic clearance of defective mitochondria[83]. Thus, cells are left with a higher load of malfunctioning, ROS-leaking mitochondria, a scenario that resembles cancer cells and creates a chronically oxidative intracellular environment conducive to DNA mutations[84,85].

Inflammation and immune activation

Dietary LA overload also tilts cellular signaling towards a pro-inflammatory state[86]. OXLAMs such as 9- and 13-HODE act as potent lipid mediators that activate inflammatory pathways by engaging toll-like receptors on macrophages[87]. High LA intake increases tissue levels of AA, fueling greater production of pro-inflammatory eicosanoids like PGE2 and leukotriene B4[88]. Excess LA has been associated with elevated oxidized LDL and systemic inflammatory biomarkers in some observational studies[89]. In the brain, preclinical research indicates that surplus dietary LA heightens vulnerability to neuroinflammation, likely through its oxidized lipid byproducts[42].

Oncometabolites and pseudohypoxia (succinate/hypoxia-inducible factor-1α)

Dysregulated mitochondrial metabolism from high LA intake can lead to the accumulation of certain metabolites that activate oncogenic pathways[90]. One such metabolite is succinate, a citric-acid-cycle intermediate[91]. In normal metabolism, succinate is readily oxidized to fumarate by succinate dehydrogenase (SDH), which is also complex II[92]. However, when the tricarboxylic-acid cycle or ETC is overloaded, as typically occurs with high fatty-acid flux and mitochondrial dysfunction, succinate may accumulate[93]. Excess succinate inhibits prolyl hydroxylase enzymes that mark hypoxia-inducible factor-1α (HIF-1α) for degradation[94]. Consequently, succinate buildup leads to stabilization of HIF-1α even in the presence of oxygen, a state of “pseudohypoxia”[91] (Figure 2). HIF-1α orchestrates cellular adaptation to low oxygen, including upregulation of glycolysis and angiogenesis via vascular endothelial growth factor[95]. In cancer, HIF-1α activation is a well-known driver of aggressive behavior[96]. By causing succinate to accumulate, an LA-induced mitochondrial dysfunction might trigger HIF-1α pathways similar to those seen in hereditary tumors with SDH mutations[4]. The result is promotion of a Warburg-like metabolic reprogramming that can facilitate malignant transformation and progression[97].

Figure 2 Linoleic acid-induced succinate build-up triggers pseudohypoxic hypoxia-inducible factor-1α stabilization and tumor-promoting glucose transporter type 1/vascular endothelial growth factor signaling. Excess β-oxidation of linoleic acid overloads succinate dehydrogenase, elevating mitochondrial succinate that inhibits prolyl-hydroxylase, thereby stabilizing hypoxia-inducible factor-1α despite normoxia (“pseudohypoxia”). The resulting transcription of glucose transporter type 1 and vascular endothelial growth factor supports glycolytic flux and neovascularization, hallmarks of aggressive tumor growth. LA: Linoleic acid; 4-HNE: 4-hydroxynonenal; OXLAMs: Oxidized linoleic acid metabolites; ROS: Reactive oxygen species; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells.

Gut dysbiosis and immune-metabolic interplay

Interestingly, the gut microbiome may also contribute to circulating succinate levels[98]. A high-fat, low-fiber diet can shift microbial fermentation patterns, sometimes leading to an increase in microbial production of succinate, which is normally a transient intermediate in fiber fermentation. If fiber-derived nutrients are scarce, succinate-producing bacteria may dominate while succinate-consuming microbes decline, so more succinate can escape into the host circulation. This microbial succinate can then engage the host’s succinate receptors on immune cells, further aggravating inflammation, or reinforce the pseudohypoxic signaling via HIF-1α[94].

Integrative perspective and dietary mitigation

Interestingly, the fatty-acid composition of the remaining 80% of phospholipids in the IMM can be modulated through dietary interventions or targeted mitochondrial supplementation[99]. By strategically reducing the incorporation of LA through diet it may be possible to decrease the overall vulnerability of the membrane to oxidative damage[100]. This approach could help protect mitochondrial integrity while preserving the beneficial effects of LA in cardiolipin, thereby offering a potential therapeutic strategy to enhance mitochondrial function in conditions associated with oxidative stress, such as cancer. While reducing LA intake might alter IMM composition, currently evidence that this prevents cancer is lacking. Collectively, an LA-rich internal environment is characterized by oxidative hits on biomolecules, mitochondrial injury, deficient autophagy and mitophagy repair, chronic inflammatory signals, dysbiotic metabolite production, and pseudohypoxic gene activation, features that converge to create a tumor-promoting terrain[4] (Figure 3; Table 3).

Figure 3 Proposed oxidative cascade linking excess linoleic acid to mitochondrial dysfunction and tumor promotion: Oxidation of membrane-bound linoleic acid yields 4 hydroxynonenal and related oxylipins, which impair mitochondrial respiration, elevate reactive oxygen species, and activate nuclear factor kappa-light-chain-enhancer of activated B cells-dependent inflammatory circuits; concurrent gut dysbiosis amplifies systemic cytokine tone, together fostering DNA damage and tumor promotion. Quantitative insets reflect representative preclinical data. GLUT-1: Glucose transporter 1; VEGF: Vascular endothelial growth factor; HIF-1α: Hypoxia-inducible factor-1α; ETC: Electron transport chain; SDH: Succinate dehydrogenase; LA: Linoleic acid.

Table 3 Mechanistic evidence linking high dietary linoleic acid metabolic and microbial dysregulation, and the remaining research gaps.

Mechanism	Preclinical finding (model, effect size)	Corresponding human data	Evidence gap
Lipid peroxidation and 4-HNE	Mouse skeletal muscle, 4-HNE adducts rise 3 ×	Elevated plasma F2-isoprostanes with high-LA diets	Need RCTs on LA lowering
Mitochondrial dysfunction	LA-rich cardiolipin increases ETC ROS 2 × in vitro	Limited biopsy evidence	Human tracer studies
Succinate/HIF-1α axis	Succinate rose 2 ×, HIF-1α stabilized in LA-fed rats	Not yet tested	Clinical metabolomics
Gut dysbiosis	High-LA diet reduces Faecalibacterium 40% (mouse)	Small keto-diet trial shows similar trend	Large human cohorts

4-HNE: 4-hydroxynonenal; HIF-1α: Hypoxia-inducible factor-1α; LA: Linoleic acid; RCTs: Randomized controlled trials; ETC: Electron transport chain; ROS: Reactive oxygen species.

EXCESS LA INTAKE SPARKS OXIDATIVE GUT DYSBIOSIS, ELEVATES SYSTEMIC INFLAMMATION

Excessive dietary LA can also disrupt the intestinal microbiome, leading to dysbiosis that promotes inflammation[24]. High-omega-6 fat intake alters gut microbial composition by favoring bile-tolerant, pro-inflammatory microbes at the expense of beneficial commensals[24]. Excessive dietary LA accelerates lipid peroxidation within intestinal epithelial membranes, generating cytotoxic aldehydes such as 4-HNE[23]. Colonocytes, the turnover of which is normally < 5 days, are especially vulnerable to these oxidants[23]. When colonocyte injury outpaces restitution, two cascading disruptions ensue.

First, the compromised epithelial monolayer loses its tight metabolic coupling to the gut lumen, permitting molecular oxygen from the richly perfused mucosa to diffuse inward. Oxygen tensions can rise from < 5 mmHg (anaerobic baseline) to > 30 mmHg, a level that selectively suppresses obligate anaerobes like Faecalibacterium prausnitzii while sparing facultative organisms[101]. Second, the ecological void created by dying obligate anaerobes is rapidly filled by facultative anaerobes like Escherichia coli, whose lipopolysaccharide (LPS) carries a hexa-acylated lipid A noted for heightened Toll-like receptor-4 activation[102]. Historically, fermentable fibers have been championed for promoting short-chain fatty acid (SCFA) synthesis; however, in this altered microbiota they provide excess carbohydrate substrate that fuels facultative anaerobe expansion and amplifies luminal LPS[103]. The resulting surge in systemic LPS further inhibits mitochondrial respiration, mirroring the bioenergetic stress induced by microplastics and chronic LA overload[4].

Beyond the colon, microbial metabolism of LA can yield inflammatory and carcinogenic byproducts. Gut bacteria can oxidize unsaturated fatty acids, producing compounds that trigger epithelial stress or even enter systemic circulation. For example, certain LA-derived oxylipins and secondary bile acids which increase on high-fat diets have been implicated in DNA damage and tumor promotion in the gastrointestinal tract[104]. Conversely, beneficial microbes like Lactobacillus and Bifidobacterium that produce SCFAs may be diminished when fermentable fiber is lacking and fats predominate[105]. Overall, an LA-driven microbiome shift tends to favor pro-inflammatory pathways, including increased LPS (endotoxin) from Gram-negative bacteria, which can contribute to systemic chronic inflammation and impaired immune surveillance against nascent tumor cells[106].

CARBOHYDRATE RESTRICTION: METABOLIC EFFECTS IN CANCER

The high-fat, low-carbohydrate (HFLC) ketogenic diet is increasingly explored in cancer management, leveraging the Warburg effect, where tumor cells preferentially rely on glucose fermentation for energy[107]. This approach posits that reducing carbohydrate intake could starve tumor cells of glucose, potentially slowing their growth[108]. Preclinical evidence, such as studies in glioblastoma models, suggests that ketogenic diets may suppress tumor progression by lowering circulating glucose and insulin levels[109]. Yet, these effects are complex and context-dependent, particularly with high LA intake, revealing potential drawbacks alongside benefits[20].

When carbohydrates are restricted, the body activates adaptive mechanisms to maintain euglycemia. Hormones such as glucagon, epinephrine, and cortisol are released, stimulating gluconeogenesis, the synthesis of glucose from non-carbohydrate substrates like lactate or glycerol[110]. This process may transiently elevate blood glucose, potentially undermining the goal of glucose deprivation for tumors[111]. However, while human metabolic studies confirm this gluconeogenic response, its contribution to tumor glucose supply and cancer progression lacks direct evidence from RCTs[112]. Furthermore, the metabolic shift associated with HFLC diets can alter the gut microbiota. Reduced carbohydrate intake may limit substrates for bacteria producing tumor-suppressive metabolites like butyrate, though this depends on dietary fiber inclusion[113]. However, this effect is contingent on the overall dietary composition; for instance, a well-formulated ketogenic diet that includes non-starchy vegetables and prebiotic fibers may mitigate this concern[114].

Shifting to fat metabolism heightens dependence on fatty acid oxidation[115]. High LA intake amplifies this oxidative demand[115]. Compared to saturated fats, PUFAs generate greater quantities of ROS during mitochondrial metabolism, which could exacerbate oxidative stress and chronic inflammation, conditions both implicated in tumorigenesis[15]. Thus, in the context of high LA exposure, carbohydrate withdrawal may introduce physiological stresses that counteract the intended therapeutic benefits of the diet[116]. The impact of HFLC diets on insulin sensitivity adds further complexity. In some cases, prolonged HFLC adherence may induce insulin resistance in skeletal muscle, impairing glucose uptake[117].

However, this effect is not universal and appears to depend on factors such as the fatty acid profile of the diet and individual metabolic variability[118]. For example, diets rich in saturated fats have been more frequently linked to insulin resistance than those emphasizing unsaturated fats[119]. Yet, evidence also shows improved insulin sensitivity with ketogenic diets high in monounsaturated fat or omega-3 PUFAs, highlighting variability[120]. Nonetheless, when insulin resistance occurs, it may result in compensatory hyperinsulinemia, elevating circulating insulin and insulin-like growth factor-1 (IGF-1), both recognized mitogens that could stimulate proliferation in certain malignancies[121].

Clinical data on ketogenic diets in cancer reveal inconsistent results[122]. A pilot trial (NCT03962647) in breast cancer patients combining ketogenic diets with standard treatments showed mixed outcomes, with some achieving stable disease or partial remission, while others progressed[123]. These findings emphasize the importance of tailoring dietary strategies to individual patients. Moreover, human metabolic studies have yet to definitively establish whether the gluconeogenic response to carbohydrate restriction significantly enhances tumor glucose availability or adversely impacts cancer progression[124].

While the theoretical foundation for carbohydrate restriction in cancer therapy is rooted in sound scientific reasoning, its practical execution, particularly in the presence of high LA intake, may introduce metabolic complexities that undermine its efficacy[125]. The interplay of gluconeogenesis, microbiota alterations, oxidative stress, and insulin dynamics highlights the need for a nuanced and personalized approach to dietary interventions in oncology, acknowledging both potential benefits and limitations supported by ongoing research[126].

STRESS-INDUCED GLUCONEOGENESIS

As noted, strict carbohydrate limitation or metabolic stress engages the body’s fight-or-flight hormones, which can inadvertently support tumor growth[127]. A key mechanism is stress-induced gluconeogenesis driven by the hypothalamic-pituitary-adrenal axis. Under perceived starvation or chronic stress, adrenal cortisol rises and triggers the liver to convert amino acids from muscle protein into glucose[128]. This gluconeogenesis serves to maintain blood sugar for vital organs, but in the cancer context it can act as an undesired lifeline for malignant cells[129]. Tumors often upregulate glucose transporters and can scavenge this stress-induced glucose even in the absence of dietary carbs[130]. Elevated cortisol also has immunosuppressive and pro-inflammatory effects that can facilitate tumor progression[128]. For example, repeated activation of this stress metabolism, as might occur with an unbalanced high-fat diet or chronic psychosocial stress, leads to catabolic muscle wasting and systemic inflammation, both of which worsen cancer outcomes[131].

Importantly, high-LA diets may inherently provoke greater hypothalamic-pituitary-adrenal axis activity[132]. Some studies suggest that long-term high-fat intake acts as a mild chronic stressor, elevating basal glucocorticoid levels and exaggerating cortisol responses to additional stressors[133]. This hyperactivation of cortisol drives hepatic gluconeogenesis, raising blood glucose that can feed tumor cells. Recent work has confirmed that chronic glucocorticoid exposure upregulates hepatic gluconeogenic enzymes and elevates systemic glucose, which tumor cells exploit for rapid proliferation[134,135]. It also induces a state of insulin resistance and visceral fat deposition, creating a pro-inflammatory endocrine profile[136]. In parallel, stress hormones can compromise anti-tumor immunity[137]. Breaking this vicious cycle requires interventions to manage stress and stabilize blood glucose, topics addressed in our therapeutic section.

HORMONAL AMPLIFICATION OF INFLAMMATION

Excess LA intake can amplify inflammatory signaling through interactions with the endocrine system[138]. One prominent example is the prostaglandin-estrogen feedback loop in adipose tissue[139]. LA-derived AA is the substrate for COX-2, which produces PGE2. In obesity, COX-2 expression is elevated in inflamed adipose tissue. The resulting excess PGE2 stimulates the enzyme aromatase in fat cells[140]. Aromatase facilitates conversion of androgens to estrogens, increasing local estrogen levels[141]. Higher estrogen in turn promotes the proliferation of estrogen-sensitive cells and can create a tumor-friendly environment, especially in hormone-responsive tissues like the breast[142]. In obese women, this PGE2-aromatase pathway has been shown to drive chronic breast inflammation and is linked to higher risk of esrogen-dependent breast cancer[139]. Thus, an LA-rich diet via PGE2 effectively amplifies estrogen signaling, uniting inflammatory and hormonal risk factors for carcinogenesis[143].

Hyperinsulinemia is another hormonal disturbance tied to high-LA diets that magnifies chronic inflammation[4]. Chronically elevated insulin and IGF-1 promote the production of pro-inflammatory cytokines and activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in many tissues[144]. In insulin-resistant states, adipose tissue often becomes inflamed and secretes excess leptin, a pro-inflammatory adipokine, while reducing adiponectin, an anti-inflammatory hormone[145]. High leptin levels, commonly observed in individuals consuming western diets rich in omega-6, directly stimulate immune cells and endothelial cells to produce inflammatory mediators[146]. Leptin can also crosstalk with estrogen signaling compounding risks in breast and endometrial cancers. Meanwhile, low adiponectin removes an important brake on pro-tumor processes since adiponectin normally enhances insulin sensitivity and has anti-inflammatory effects[147]. Additionally, experimental evidence indicates that LA modulates appetite-regulating hormones, potentially exacerbating metabolic dysregulation. In a randomized crossover trial, consumption of an LA-rich meal (e.g., 35 g LA) significantly increased plasma ghrelin by 15% and resistin by 20% compared to an oleic acid-rich meal of identical caloric content (P < 0.05), effects associated with heightened hunger and impaired glucose homeostasis[38]. These hormonal shifts suggest that LA may promote overeating and insulin resistance, further amplifying an inflammatory milieu conducive to tumorigenesis.

Overall, hormonal imbalances induced by an LA-rich diet, including elevated estrogen, insulin/IGF-1, and leptin, converge to sustain a state of smoldering chronic inflammation and cell proliferation[148]. This state not only encourages initiation of tumors through DNA damage and proliferative signaling but also promotes their progression by supplying growth factors and angiogenic signals[149]. Notably, LA may even act directly on tumor cells. A recent preclinical study demonstrated that LA binds a fatty acid-binding protein in triple-negative breast cancer, activating the mTOR complex 1 growth pathway and markedly accelerating tumor growth in mice. This finding sheds light on how dietary fats can selectively drive aggressive cancer subtypes via cell-intrinsic hormone-like signaling[20].

PENTADECANOIC ACID HELPS REVERSE LA-INDUCED SUCCINATE BUILD-UP

Pentadecanoic acid (C15:0), an odd-chain saturated fatty acid enriched in ruminant fat, has emerged as a potential countermeasure to the pseudohypoxic cascade initiated by excess LA[150]. At the mitochondrial level, LA overload slows[4]. Pentadecanoic acid directly activates AMPK, thereby inducing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-driven mitochondrial biogenesis and restoring SDH transcription. Reduced succinate reverses inhibition of prolyl-4-hydroxylases, enzymes that normally tag HIF-1α for ubiquitin-mediated degradation[151].

Pentadecanoic acid supplementation shortens HIF-1α protein half-life[151]. This biochemical correction blocks downstream transcription of vascular endothelial growth factor and glucose transporter type 1, curtailing the angiogenic and glycolytic shift characteristic of the Warburg phenotype[150]. Furthermore, AMPK activation independently suppresses mTOR complex 1, a kinase that collaborates with HIF-1α to promote anabolic growth. Thus, pentadecanoic acid exerts a dual check on metabolic reprogramming: It restores oxidative flux through SDH and dampens HIF-1α/mTOR signaling that favors aerobic glycolysis[152].

Systemic inflammation fueled by succinate is thus addressed concurrently. Succinate engages the succinate receptor 1 on macrophages, driving IL-1β release[91]. Historically, saturated fats were viewed homogenously; however, odd-chain saturated fatty acids behave differently from their even-chain counterparts. Their β-oxidation yields propionyl-CoA, a gluconeogenic substrate that spares tricarboxylic-acid intermediates and may further ease mitochondrial crowding[153].

In this context, pragmatic dosing of 100-200 mg pentadecanoic acid per day (roughly one gram of full-fat dairy fat or a single commercial capsule) appears sufficient to normalize plasma levels without displacing essential nutrients[154]. While pentadecanoic acid cannot fully neutralize a diet delivering > 6% of calories from LA, it offers a mechanistically coherent adjunct, via AMPK-SDH restoration, HIF-1α destabilization, and microbiota modulation, to mitigate succinate-driven oncogenic and inflammatory signaling[155].

MICROBIOME REGRESSION

In addition to acute dysbiosis, long-term dietary patterns high in fat and low in complex carbohydrates can cause a regression of gut microbiome diversity[156]. Microbiota-accessible carbohydrates found in dietary fiber have a crucial involvement in shaping the microbial ecosystem and are notably reduced in the western diet compared to traditional diets[157]. Studies in mice have shown that chronic low-microbiota-accessible carbohydrate diets lead to a progressive loss of microbial species across generations. Notably, after several generations on a fiber-deprived diet, some bacterial taxa become extinct and cannot be recovered even if fiber is later reintroduced. This illustrates that dietary habits can induce microbial extinctions that permanently erode the symbiotic functions microbes provide[158].

Such microbiome regression has multiple implications for cancer[159]. A less diverse microbiota often means reduced production of beneficial metabolites like SCFAs, which normally help regulate inflammation, reinforce the intestinal barrier, and even induce cancer cell differentiation or apoptosis in the colon[160]. A fiber-starved microbiome may also resort to digesting the host’s mucus layer for nutrients, thinning this protective barrier[161]. An eroded mucus layer allows closer contact between bacteria and the epithelium, increasing the likelihood of inflammation and DNA-damaging agents reaching colonic cells[162]. Additionally, a loss of beneficial organisms can enable the expansion of harmful ones that produce carcinogenic compounds, such as certain Bacteroides species generating secondary bile acids or Enterococcus producing genotoxins[163]. Epidemiologically, reduced gut microbial diversity has been associated with colorectal cancer and with risk factors like obesity[164]. Thus, the western high-LA, low-fiber dietary pattern effectively impoverishes the gut ecosystem removing important anti-cancer checks and balances that traditional fiber-rich diets supported[146].

Beyond the gut, systemic immunity may suffer from microbiome regression. The education of the immune system by commensal microbes training regulatory T-cells to prevent excessive inflammation is compromised when diversity is lost[165]. Inflammatory tone throughout the body can rise as a result, contributing to the kind of chronic, low-grade inflammation that predisposes tissues to cancer. The concept of “terrain” in oncology encompasses the microbiome as a vital component of the host environment[166]. A regressed microbiome is a degraded terrain, one that fails to metabolize dietary components in a health-promoting way and instead generates pro-carcinogenic signals[167]. Therefore, preserving or restoring microbiome diversity is likely essential in counteracting the cancer-promoting effects of high-LA diets[166]. Collectively, these mechanisms illustrate how excess LA exposure perturbs multiple biological systems, fostering an internal environment conducive to cancer. The convergence of oxidative stress, autophagy and mitophagy impairment, inflammation, and microbiome dysfunction defines a pathological metabolic terrain[168].

KETOGENIC LOW-CARBOHYDRATE DIETS IN A COMPROMISED GUT TERRAIN

Ketogenic or other low-carbohydrate diets are sometimes proposed as therapeutic interventions for cancer or metabolic diseases[169]. These diets typically involve high fat intake, often > 70% of calories, and minimal carbohydrates, shifting the body’s metabolism toward fat oxidation and ketone production[170]. While such diets can reduce blood glucose and insulin levels, potentially unfavorable to tumor growth, they may present underappreciated drawbacks when implemented in individuals with LA-induced dysbiosis or other pre-existing gut issues[24]. One concern is that strict carbohydrate restriction usually entails a drastic reduction in dietary fiber, the primary fuel for commensal gut microbes[171].

In a recent controlled trial, healthy adults on a 12-week ketogenic diet with < 8% of calories from carbohydrates experienced a significant decrease in beneficial gut bacteria, notably Bifidobacteria, compared to those on a higher-carbohydrate diet[172]. Obligate anaerobes such as Bifidobacterium spp. ferment resistant oligosaccharides into butyrate and concurrently synthesize B-complex vitamins[173]. These metabolites, in turn, strengthen tight-junction integrity and thus preserve epithelial barrier function, a mechanism historically prioritized in mucosal immunology research[174]. The keto diet group’s fiber intake dropped to roughly 15 g/day (about half of recommended levels), explaining the loss of these microbes. Such changes in the microbiome could negate some metabolic benefits of the diet and even introduce new risks. Indeed, the same study noted that the keto diet led to unfavorable lipid changes (elevations in LDL cholesterol and apolipoprotein-B (apoB) and reduced the participants’ glucose tolerance upon re-introducing carbs[172]. These effects underscore that a diet effective for short-term weight loss or blood sugar control might concurrently impair other aspects of physiology.

During the eight-week ketogenic intervention, median fiber intake collapsed to approximately 15 g/day, barely 50% of the 28-30 g/day benchmark set by the National Academies, thereby starving vital obligate anaerobe microbiota of fermentable substrates and diminishing butyrate-producing taxa such as Faecalibacterium prausnitzii by nearly 40%. Historically, such contractions in microbial diversity have been linked to impaired epithelial integrity and muted SCFA signaling. Furthermore, the same cohort experienced a 12% surge in LDL cholesterol and an 11% rise in apoB; upon reintroducing carbohydrates, their two-hour oral-glucose-tolerance area under the curve increased by 18%. In this context, a regimen effective for rapid weight loss or transient glycemic control can simultaneously undermine lipid homeostasis and gut-microbial resilience, highlighting the trade-offs embedded in highly restrictive dietary paradigms.

Excluding fermentable carbohydrates in a chronically inflamed, dysbiotic intestine can impede microbial restitution[175]. Key commensals, Bifidobacterium adolescentis, Faecalibacterium prausnitzii, and other butyrogenic strains, catabolize soluble fibers and resistant starches into SCFAs increasing colonic butyrate concentrations[176]. These metabolites tighten epithelial junctions and temper NF-κB signaling; when the requisite substrates fall below approximately 20 g/day, obligate anaerobic microbiota contract, whereas mucin-degrading opportunists, Ruminococcus gnavus in particular, whose relative abundance can rise three-fold under fiber scarcity, expand[177]. This dysbiotic shift elevates LPS concentrations, thereby amplifying Toll-like receptor 4 signaling and aggravating the mitochondrial bioenergetic deficits characteristic of metabolic dysfunction[178]. The resulting barrier dysfunction magnifies endotoxin translocation and systemic cytokines, thereby intensifying precisely the inflammatory environments ketogenic therapy aims to quell[179]. These consequences argue for a nuanced approach in which targeted, fermentable carbohydrates are reintroduced to rehabilitate microbiota without abolishing the metabolic benefits of controlled ketosis.

Imposing a low carbohydrate regimen on an already dysbiotic intestine is intrinsically double-edged[180]. Transient glucose deprivation can curb glycolytic tumor clones, yet it also deprives beneficial commensals of fermentable substrates[181]. Historically, oncologic nutrition prized substrate restriction; however, contemporary microbiome studies show that indiscriminate carbohydrate removal can deepen barrier erosion and raise circulating IL-6 by 20%-30%[171]. Thus, while extreme carbohydrate restriction may ease hyperglycemic stress, it leaves the underlying ecological disequilibrium unchanged or even exacerbated. The next section details such terrain-oriented strategies, integrating diet, circadian timing, and exercise to rehabilitate gut-immune homeostasis.

TERRAIN RESTORATION HYPOTHESIS: LOW LA DIET WITH PHASED CARBOHYDRATE REINTRODUCTION

The “terrain-restoration” framework is presently hypothetical, a mechanistic model extrapolated from pre-clinical work, small proof-of-concept human studies, and ecological observations. No randomized-controlled trials have yet tested whether the combined strategy of LA minimization, staged carbohydrate re-introduction, microbiota rehabilitation, and mitochondrial supports can reduce cancer incidence or improve oncologic outcomes in humans[39,122]. Accordingly, all clinical recommendations derived from this model should be considered exploratory and implemented, if at all, within ethically approved research protocols or personalized nutrition plans that include rigorous monitoring for unintended metabolic effects[171].

Addressing the deleterious effects of excess LA requires a multifaceted strategy aimed at restoring metabolic balance and reducing chronic inflammation (Figure 4). Specifically, reducing intake of industrial seed oils, soybean, corn, safflower, and sunflower, which collectively supply ≥ 80% of dietary LA in western populations, and substituting them with low-LA lipids such as butter, ghee, beef tallow, or lauric-rich coconut oils, gradually normalizes adipose fatty-acid composition[182]. In controlled feeding trials, a shift from > 6% to 2%-3% of energy as LA lowers plasma F₂-isoprostanes by approximately 20% within 12 weeks. Historically, such reductions have also encouraged recolonization by butyrate-producing microbiota, thereby dampening mucosal cytokine output and fortifying the intestinal barrier[171]. However, this dietary shift is proposed as a hypothesis, as its effectiveness in preventing or treating cancer lacks validation from clinical trials[122].

Figure 4 Four-phase dietary-lifestyle protocol for re-establishing a cancer-resistant metabolic terrain sequential dietary-lifestyle program aimed at restoring a cancer-resistant internal terrain: (1) Strict linoleic acid minimization; (2) Low-residue carbohydrate repletion; (3) Graded fermentable-fiber restoration to repopulate butyrogenic taxa; and (4) Adjunctive metabolic supports (intermittent fasting, pentadecanoic acid, exercise). Quantitative targets reference published human or animal data where available.

Emerging technologies, such as conversational-artificial intelligence (AI) platforms, could theoretically assist by parsing ingredient lists, identifying hidden LA sources and suggesting accessible low-LA alternatives[183]. These tools aim to bridge the gap between nutrition research and everyday food choices, potentially empowering users to reduce inadvertent LA intake without sacrificing convenience[184]. Nevertheless, their practical impact on dietary habits and health outcomes remains untested, rendering their role in this hypothesis speculative and in need of rigorous evaluation.

Complementing these AI-guided dietary refinements, activation of intrinsic quality-control pathways directly repairs the organelle damage left behind by prior LA overload, thereby extending metabolic restoration from the pantry to the cellular level[185]. Autophagy and its mitochondria-specific branch, mitophagy, are AMPK- and Unc-51-like autophagy activating kinase 1 (ULK1)-coordinated clearance systems that sequester dysfunctional cellular components, particularly depolarized mitochondria, into double-membrane autophagosomes for lysosomal degradation, a principle first elucidated by Christian de Duve over five decades ago[186].

By recycling these damaged organelles and releasing substrates that elevate the NAD⁺/NADH ratio, the pathways boost ETC flux, complex I activity can rise approximately 30% in PTEN-induced putative kinase 1/Parkin-activated hepatocytes, thereby re-establishing the metabolic flexibility required for efficient glucose oxidation[187]. Intermittent fasting can activate AMPK-sirtuin 1 signaling, thereby recruiting ULK1 to initiate autophagy and mitophagy[188]. In murine hepatocytes, a single 24 hours fast doubles microtubule-associated protein 1 Light chain 3 (LC3), form II (LC2-II) flux and boosts PTEN-induced putative kinase 1/Parkin recruitment, accelerating clearance of damaged mitochondria and ubiquitinated protein aggregates; these turnover interrupts the feed-forward loop of mitochondrial ROS and NF-κB-driven inflammation[189]. While promising in preclinical models, where fasting has shown benefits against tumor progression, these effects require confirmation in human studies[110].

In preclinical studies, intermittent fasting has reduced tumor progression and sensitized cancers to chemotherapy, partly by creating a less favorable metabolic environment for cancer cells[190]. Coupling these approaches with mitochondrial support, such as supplementing carnitine and coenzyme Q₁₀ to sustain complex III electron flow[191,192], α-lipoic acid and pyrroloquinoline quinone as redox recyclers[193], NAD⁺ precursors to elevate the NAD⁺/NADH ratio[194], plus low-dose uncouplers first trialed in the 1970s, synergistically fortifies mitochondrial resilience when layered onto intermittent fasting or exercise-induced autophagy/mitophagy.

Regular physical exercise is perhaps the most powerful mitochondrial therapy as it enhances mitochondrial biogenesis and efficiency, lowers insulin resistance, and reduces systemic chronic inflammation. Thus, an exercise program is an integral part of terrain restoration, helping to correct the sedentary, overfed state that magnifies LA’s harms. In this context, exercise is a crucial component, though its specific contribution to cancer risk reduction in a low-LA framework remains to be quantified.

MICROBIAL AND METABOLIC OPTIMIZATION STRATEGIES

PGC-1α serves as a pivotal catalyst in mitochondrial biogenesis, a fundamental process for sustaining cellular energy homeostasis[195]. By coordinating with transcription factors such as nuclear respiratory factor 1 and nuclear respiratory factor, PGC-1α drives the expression of genes vital for mitochondrial DNA replication and transcription, including transcription factor A, mitochondrial[196]. This orchestrated transcriptional activity increases mitochondrial mass, often doubling the mitochondrial DNA content in metabolically active cells, and enhances oxidative phosphorylation efficiency, thereby boosting ATP synthesis. Historically, mitochondrial biogenesis has been recognized as a key adaptive response to metabolic demands, underscoring PGC-1α’s role in maintaining cellular vitality under stress[197].

Furthermore, converging evidence indicates that PGC-1α not only orchestrates mitochondrial biogenesis but also modulates autophagy, particularly mitophagy, thereby reinforcing cellular quality-control networks that can influence oncogenesis[198]. Experimental activation of PGC-1α across several models elevates the transcripts and proteins of canonical autophagy mediators, including beclin 1 and light chain 3, form II, and up-regulates mitophagy receptors such as B-cell lymphoma 2/adenovirus E1B 19 kDa interacting protein 3 and NIP3-like protein X, driving the formation of autophagosomes that target depolarized mitochondria[199-201]. By facilitating the selective removal of dysfunctional organelles, PGC-1α limits mitochondrial ROS production, preserves mitochondrial DNA integrity and sustains oxidative phosphorylation efficiency[202,203].

In mouse models of melanoma, breast and prostate cancer, enforced PGC-1α expression mitigates the Warburg-type metabolic shift and suppresses tumor growth or metastasis, whereas genetic or epigenetic silencing of PGC-1α has the opposite effect. Nevertheless, the impact of PGC-1α is tissue-specific; in cholangiocarcinoma and certain hematological malignancies, high PGC-1α may instead facilitate invasion, underscoring a context-dependent role[204]. Taken together, the coordinated induction of mitochondrial renewal and targeted clearance by PGC-1α offers a mechanism that, in many but not all settings, counteracts oncogenic metabolic reprogramming and supports tumor suppression.

Reconstituting an optimized microbiota is the second therapeutic pillar. In colons overrun by facultative anaerobes, Enterobacteriaceae, Ruminococcus gnavus, and similar taxa, abrupt reintroduction of fermentable carbohydrates can spike colonic LPS and intensify colonic epithelial chronic inflammation[205]. Although low-carbohydrate regimens initially blunt this endotoxemia by starving the opportunists, prolonged fiber deprivation further depletes butyrate-producing commensals and ultimately worsens barrier dysfunction[206]. A staged “carbohydrate ladder” resolves the paradox while maintaining the low-LA template. Phase 1 supplies low-residue starches such as polished white rice (approximately 1 g fiber per cup) and clarified, pulp-free fruit juice to replenish glycogen without fueling LPS-producing blooms[207].

Once gastrointestinal complaints such as gas and bloating normalize, phase 2 introduces slowly digestible tubers, whole fruits, boiled potatoes, sweet potatoes, taro, followed by incremental additions of progressively increasing fermentable carbohydrates[208]. This graded expansion nurtures Faecalibacterium prausnitzii and Bifidobacterium adolescentis, restoring colonic butyrate while keeping LPS-driven metabolic stress in check[209]. Reversing dysbiosis dampens systemic inflammation: When LPS production falls; less endotoxin translocates via the portal vein to activate hepatic Kupffer cells or form crown-like macrophage clusters in adipose tissue[210].

To directly counteract the inflammatory and oxidative mediators from LA, certain pharmacological interventions can be employed. Low-dose aspirin, for instance, irreversibly inhibits COX-2, thereby reducing the production of PGE2 and other prostaglandins from AA[211]. In doing so, it may blunt the PGE2-driven aromatase and estrogen amplification loop in obesity-related cancers; indeed, observational studies suggest regular aspirin use is associated with reduced incidence or recurrence of colorectal and breast cancers, especially in overweight individuals with high inflammation[212,213]. Moreover, preclinical studies highlight LA’s distinct metabolic impact on adiposity. In animal models, diets high in LA (e.g., 20% of energy) induced significantly greater visceral fat accumulation, approximately 25% more by weight, compared to isocaloric diets rich in saturated fatty acids, despite equivalent energy intake[214]. This suggests that LA may preferentially promote lipid storage, potentially via upregulation of peroxisome proliferator-activated receptor gamm, thereby contributing to obesity-related cancer risk.

Pharmacologic attenuation of LA-derived eicosanoid signaling can be achieved with low-dose aspirin (75-100 mg/day), which acetylates the catalytic serine of COX-2 and suppresses PGE2 synthesis by approximately 50% within hours[215]. Historically deployed for cardiovascular prophylaxis, this COX-2 blockade also interrupts the PGE2-driven aromatase-estrogen feed-forward loop that fuels obesity-associated malignancies[216]; meta-analyses report a 15%-25% reduction in colorectal and breast-cancer incidence or recurrence among habitual aspirin users, particularly in individuals with elevated C-reactive protein[217]. Consequently, judicious aspirin therapy offers a mechanistically coherent adjunct for dampening LA-amplified inflammatory and hormonal stimuli in oncogenesis.

Meta-analyses spanning three decades reveal that supraphysiologic antioxidant regimens, ≥ 400 IU/day α-tocopherol coupled with 500 mg/day ascorbate, neither curb cancer incidence nor mortality and may, by quenching beneficial metabolic signaling ROS, blunt exercise-induced mitochondrial biogenesis[218]. Attention therefore is pivoting to mitochondria-targeted redox modulators such as plastoquinone analog SkQ1, and Szeto-Schiller peptide, which concentrate 500-1000-fold within the inner-mitochondrial membrane and directly shield cardiolipin and mitochondrial DNA from LA-amplified peroxidation at nanomolar doses[219]. Though still in early-phase trials, these precision agents offer a mechanistically coherent alternative to blanket antioxidant therapy, preserving physiologic ROS signaling while mitigating LA-driven mitochondrial injury[220].

Lifestyle and environmental interventions are essential for comprehensive terrain restoration, with optimal sleep hygiene serving as a vital component. Adhering to a consistent sleep regimen of 7-8 hours per night can reduce baseline cortisol concentrations by approximately 20%-30% and dampen sympathetic nervous system activity, thereby attenuating stress-induced gluconeogenesis and systemic inflammation, as indicated by lowered IL-6 Levels[221]. Historically, sleep optimization has been overshadowed by dietary and pharmacological approaches in metabolic health, yet its role in regulating neuroendocrine pathways is increasingly recognized[222]. Additionally, ensuring adequate intake of essential micronutrients, such as selenium, which supports thioredoxin reductase activity, and magnesium, crucial for ATP-dependent enzymatic processes, enhances antioxidant capacity and immune resilience, potentially mitigating oxidative stress linked to high-LA diets[223,224].

Equally important, reducing exposure to environmental stressors complements these physiological interventions[225]. Abstinence from tobacco smoking and minimization of contact with xenobiotics, such as polychlorinated biphenyls, curtail ROS production and lipid peroxidation, which are exacerbated in high-LA metabolic states[226]. These measures align with established oncopreventive strategies that have long emphasized environmental detoxification[227]. Consequently, the therapeutic framework to counter an LA-driven cancer risk profile is multifaceted. It includes targeted dietary adjustments, metabolic reprogramming through time-restricted feeding protocols, and microbiota optimization. These approaches offer a hypothetical means to counter LA-related cancer risk, but its efficacy and safety must be substantiated through human research[39]. Table 4 outlines these candidate interventions, highlighting proposed human doses, primary molecular targets, expected biomarker shifts, and the current level of supporting evidence across preclinical and early clinical studies[8,42,150,228-238].

Table 4 Candidate strategies to mitigate linoleic acid-driven metabolic stress: Doses, biomarkers, and evidence landscape.

Intervention	Proposed human dose	Primary target	Expected biomarker change	Evidence level	Ref.
Dietary LA reduction	≤ 3% total kcal	Lipid peroxidation	F2-isoprostanes decreased 20% in 12 weeks	RCT-pilot	[42,228,274]
Pentadecanoic acid (C15:0)	100-200 mg/day	AMPK/SDH restoration	Succinate decreased 30% (rodent)	Preclinical	[150,229,230]
Low-dose aspirin	75-100 mg/day	COX-2/PGE2 axis	Serum PGE2 decreased 50% in 24 hours	Observational + RCT-CV	[231-234]
Intermittent fasting	16:8 daily	Autophagy induction	LC3-II flux rose 2 × (mouse)	Early human	[235-238]

LA: Linoleic acid; AMPK: AMP-activated protein kinase; SDH: Succinate dehydrogenase; COX-2: Cyclo-oxygenase-2; PGE2: Prostaglandin E2; RCT: Randomized controlled trial; CV: Cardiovascular.

LIMITATIONS

Although mechanistic data indicate a potential link between excessive intake of LA and oncogenesis, it is crucial to acknowledge the significant limitations and nuances inherent in this relationship[4]. Epidemiological studies in human populations have yielded inconsistent results regarding the association between high LA intake and cancer risk. For instance, a meta-analysis of 10 cohort studies found no significant association between LA intake and breast cancer risk[31]. Conversely, some investigations suggest an inverse correlation between LA intake and specific cancer incidences, such as prostate cancer[239]. These divergent findings underscore the importance of contextual factors in modulating LA’s impact on cancer risk.

Specifically, the balance between omega-6 and omega-3 fatty acids, overall dietary quality, and individual metabolic profiles may influence the relationship between LA intake and oncogenesis[240]. Furthermore, many observational studies are susceptible to confounding variables, such as dietary substitution effects and healthy-user biases[241]. For example, individuals who replace saturated fats with vegetable oils rich in LA may also adopt other health-promoting behaviors, potentially obscuring any adverse effects of LA on cancer risk[242]. Moreover, the substantial increase in LA consumption over recent decades, driven historically by dietary guidelines prioritizing reduced saturated fat intake, has coincided with other significant lifestyle modifications, including higher intake of refined sugars, reduced physical activity, and increased exposure to environmental toxins[243-245]. Consequently, isolating the specific contribution of LA to the rising incidence of cancer presents a considerable challenge.

The majority of mechanistic insights linking LA to carcinogenesis are derived from animal models or in vitro cell culture studies. In these experiments, rodent diets are often formulated with extreme fatty acid compositions, such as high LA to omega-3 ratios which may not accurately reflect typical human dietary patterns where ratios are generally lower[246]. While rodents fed diets exceptionally high in LA do exhibit increased tumor development in certain experimental models, these studies frequently employ potent chemical carcinogens, such as 7,12-dimethylbenz(a)anthracen, or utilize genetically predisposed strains, like the APC(Min/+) mouse limiting their relevance to human dietary patterns[18,247].

Additionally, the levels of LA used in these experiments often surpass those commonly encountered in human diets, with some studies administering diets containing up to 10% LA by weight, compared to typical human intakes of 5%-10% of total energy[4]. Therefore, the relevance of these findings to moderate alterations in human dietary LA intake remains uncertain. Furthermore, certain processes implicated in LA-induced carcinogenesis, such as succinate accumulation or pseudohypoxia, are primarily inferred from general metabolic principles and observations in rare hereditary syndromes, such as hereditary leiomyomatosis and renal cell cancer, which involves mutations in the fumarate hydratase gene[248]. Direct evidence of these phenomena in individuals consuming high-LA diets is lacking. Human metabolism exhibits considerable adaptability, and it is plausible that homeostatic mechanisms, such as the upregulation of antioxidant enzymes like superoxide dismutas, may mitigate some of the adverse effects associated with excessive LA intake in vivo[249].

Another limitation of the LA-cancer hypothesis is that LA is not uniformly associated with adverse effects[250]. Given its fundamental physiological importance, completely eliminating LA from the diet is neither feasible nor advisable[251]. Instead, the objective of dietary interventions is to achieve a balanced intake that optimizes health outcomes while mitigating potential risks[252]. The optimal level of dietary LA for human health remains a subject of ongoing scientific debate. Historically, large-scale population trials, such as the Minnesota Coronary Experiment conducted in the 1960s and 1970s, have demonstrated that replacing saturated fatty acids with LA-rich vegetable oils can reduce LDL cholesterol concentrations by approximately 10%-15%, a well-established risk factor for CVD[38]. However, recent re-analyses of these trials have suggested that excessive LA intake may, under certain metabolic conditions like insulin resistance, promote the oxidation of LDL particles and exacerbate systemic inflammation, potentially offsetting cardiovascular benefits[45].

From an oncological perspective, there is a notable absence of long-term RCTs that have specifically evaluated whether reducing dietary LA intake can decrease cancer incidence or mortality rates. Consequently, proposed therapeutic strategies, such as modifying dietary fat composition to lower LA levels or inducing autophagy to mitigate LA-induced cellular stress, are primarily grounded in scientific rationale derived from mechanistic studies and preclinical models, including mouse xenografts[253]. However, robust clinical trial data in human populations remain limited, highlighting the need for further investigation to validate these approaches.

Furthermore, individual responses to dietary LA are likely to vary due to genetic heterogeneity[254]. For instance, polymorphisms in genes encoding enzymes involved in fatty acid metabolism, such as fatty acid desaturase 1, could alter the efficiency of LA conversion to AA, a downstream metabolite implicated in inflammatory pathways. This genetic variability may influence an individual’s susceptibility to LA-induced metabolic dysregulation, complicating uniform dietary recommendations[255]. Additionally, cancer’s multifactorial etiology, driven by factors like somatic mutations (e.g., TP53) and immune evasion, extends beyond diet, cautioning against overemphasis on LA[256]. Finally, it is important to acknowledge that focusing exclusively on a single nutrient like LA may oversimplify the multifactorial etiology of cancer. Cancer development is a complex process driven by an interplay of factors, including somatic genetic mutations, immune system evasion, and tissue-specific microenvironmental influences, such as hypoxia in solid tumors, that extend beyond dietary contributions alone[257].

While the LA-cancer hypothesis offers a unifying framework for exploring the potential role of dietary fats in oncogenesis, it must be integrated with other well-established preventive measures. These include avoiding tobacco use, controlling oncogenic infections such as human papillomaviru, and maintaining a healthy body weight through balanced nutrition and regular physical activity. In summary, more research, particularly prospective studies in human populations, is essential to determine the extent to which reducing LA intake and implementing terrain-focused therapeutic strategies will translate into measurable reductions in cancer risk or improvements in clinical outcomes. Recognizing these limitations ensures that recommendations are formulated with appropriate scientific caution and reinforces the importance of a holistic, multifactorial approach to cancer prevention and treatment. Prospective human studies will be helpful to quantify LA’s role in cancer risk, ensuring recommendations are evidence-based and integrated into a holistic prevention strategy.

PRACTICAL CHALLENGES FOR HUMAN APPLICATION

Although reducing dietary LA and restoring a balanced “terrain” is mechanistically compelling, translating these insights into everyday life is non-trivial.

Ubiquity of seed-oil LA in the modern food system

LA-rich oils are deeply embedded in global supply chains, from restaurant fryers to processed foods and ostensibly “healthy” snacks, making meaningful reduction difficult without substantial label scrutiny or home cooking. Even motivated participants in controlled feeding trials struggled to keep LA < 3% of energy, and biochemical markers (e.g., plasma 9- and 13-HODE) only fell when the research team provided all meals[42]. Long biological half-lives add to the lag: Adipose LA turns over slowly, so tissue re-equilibration may take many months even after intake falls[6].

Measurement and compliance hurdles

Self-reported food frequency questionnaires underestimate hidden oils, while objective biomarkers (erythrocyte or adipose fatty-acid profiling) remain costly and are rarely available in clinical practice. Digital solutions, barcode-scanning apps and large-language-model (LLM) chatbots that flag high-LA ingredients, are emerging, but real-world adherence data are sparse[182,183].

Dietary trade-offs and metabolic side-effects

Strategies that cut LA often rely on high-fat or ketogenic templates. Recent randomized data show that a well-formulated ketogenic diet can still impair glucose tolerance, elevate apoB, and erode gut-microbiota diversity within 12 weeks, even under close supervision[171]. Achieving low-LA intake and adequate fermentable-fiber supply therefore demands careful menu design, potentially raising cost and complexity.

Socio-economic and cultural barriers

Low-LA cooking fats (e.g., ghee, pasture-raised butter, extra-virgin olive oil) are often more expensive or culturally unfamiliar. Public-health messaging has, for decades, endorsed vegetable oils to lower LDL-C; reversing this narrative will require coordinated clinician education, clearer front-of-pack labeling, and policy incentives for food manufacturers.

Research design constraints

Because virtually all industrialized populations consume LA well above ancestral levels, identifying “true” low-LA control groups is challenging. Future trials may need inpatient feeding, isotopic tracers, or recruitment of populations with traditional dietary patterns to disentangle LA effects from other lifestyle variables.

LEVERAGING LLM TOOLS TO OVERCOME INGREDIENTIDENTIFICATION BARRIERS

Despite growing public interest in lowering dietary LA, many consumers remain unaware that stealth vegetable-oil ingredients such as “high-oleic canola”, “vegetable shortening”, “textured soy protein” are embedded in > 70% of packaged foods. LLM platforms and AI-powered chatbots are now emerging as scalable aides that can: (1) Parse complex ingredient panels in real time; (2) Flag probable high-LA additives; and (3) Suggest lower-LA substitutes within a user’s price and taste constraints. In proof-of-concept studies, AI nutrition assistants have already reduced the time needed to identify hidden fats and allergens by 40%-60%, boosted label-reading accuracy, and increased users’ confidence in making grocery swaps[182]. Furthermore, consumer-facing chatbots that integrate barcode scanners with LLM-driven nutrient databases have improved adherence to heart-healthy and weight-loss diets in randomized usability trials[183]. These early successes suggest that embedding LA-screening algorithms into ubiquitous smartphone apps could democratize the identification-and-replacement step that currently limits population-level reduction of seed-oil exposure. Key hurdles, such as hallucinated ingredient matches, data-privacy safeguards, and equitable access for low-resource users, will need iterative refinement, but the technology offers a promising, action-oriented adjunct to the dietary strategies outlined above. Together, these practical obstacles underscore that efficacy does not guarantee feasibility. Successful human application will require multi-level interventions, consumer tools, food-industry reformulation, and pragmatic clinical protocols, to complement the biochemical rationale outlined earlier.

CONCLUSION

The parallel rise of industrial seed oil consumption and cancer rates over the last century warrants investigation into the potential role of modern dietary patterns in modulating cancer risk. While preclinical studies indicate that excess LA intake may promote a pro-tumorigenic environment through mechanisms such as increased oxidative stress through lipid peroxidation, chronic low-grade inflammation, and disruptions in mitochondrial function, it is essential to acknowledge that cancer is a multifactorial disease. LA-rich diets may contribute to cellular dysfunction, including mitochondrial destabilization, impaired autophagy, and shifts in hormonal signaling and gut microbiota composition, which could collectively foster a terrain more conducive to tumor development. This perspective does not negate the established roles of known carcinogens, such as tobacco smoke or ultraviolet radiation, but underscores that dietary factors, as modifiable components, may influence the host environment in ways that either suppress or promote the growth of incipient cancers.

Understanding the potential impact of LA on cancer biology opens new avenues for research into preventive and therapeutic strategies. Current dietary guidelines, which have historically prioritized reductions in total fat or saturated fat intake, could benefit from further research to determine the optimal balance of omega-6 to omega-3 fatty acids and to evaluate the long-term health implications of highly processed seed oils. Furthermore, epidemiological studies are needed to clarify the association between LA intake and cancer risk in human populations, as existing evidence is predominantly derived from animal models and in vitro studies. For individuals diagnosed with cancer or at elevated risk, personalized nutritional interventions, such as reducing LA intake while ensuring sufficient micronutrients and omega-3 fatty acids, could be explored as adjuncts to standard oncological care, pending clinical validation.

Additionally, approaches such as intermittent fasting, pharmacological autophagy enhancers, and gut microbiome restoration protocols represent a shift from targeting tumor cells alone to strengthening the host environment. This terrain-centric paradigm posits that when the body’s biochemistry is rebalanced, such as oxidative damage controlled, inflammation quieted, and metabolism optimized directs cancer cells from thriving. However, it is important to recognize that much of the evidence supporting this approach remains preclinical or observational, and rigorous clinical trials are required to substantiate its efficacy in human populations.

In conclusion, the marked increase in fatty acid consumption, driven by the widespread adoption of industrial seed oils over the past century could hypothetically play a role in shaping a metabolic environment that influences cancer risk, though definitive causal relationships remain unestablished. Re-aligning our diets more closely with evolutionary conditions (minimizing refined seed oils and emphasizing whole foods rich in fiber and omega-3s) and addressing the downstream effects of excess LA hold promise for reducing cancer incidence in future generations. Interdisciplinary research integrating nutrition science, oncology, and microbiology will be essential to elucidate the precise role of LA in cancer pathogenesis and to develop evidence-based interventions for prevention and treatment. The challenge moving forward is to translate these insights into public health policies and clinical practices that prioritize cancer-preventive lifestyles alongside early detection and advanced therapeutic modalities.