Both fasting and ketogenic diets can enhance fatty acid utilization and ketone body production. AMPK–MNK–eIF4E signaling and 5′UTR-dependent selective translation participate in this nutritional adaptation and influence the ability of pancreatic cancer to adapt to a ketogenic metabolic environment.

Keywords: fasting; ketogenic diet; translatome; AMPK; MNK; eIF4E; PPARα; HMGCS2; β-hydroxybutyrate; pancreatic cancer

1 Metabolic Switching Induced by Fasting and Ketogenesis

(1) Enhanced Fatty Acid Mobilization and Oxidation

In the fed state, insulin promotes glucose utilization, glycogen synthesis, and lipid storage. After entering the fasting state, insulin levels decline, hepatic glycogen is gradually depleted, adipose-tissue lipolysis increases, and free fatty acids are released into the circulation. After the liver takes up fatty acids, mitochondrial β-oxidation increases, producing acetyl-CoA and reducing equivalents such as NADH and FADH₂.

(2) Enhanced Hepatic Ketone Body Production

A portion of the acetyl-CoA generated through fatty acid β-oxidation enters the mitochondrial ketogenesis pathway in hepatocytes. HMGCS2 catalyzes the formation of HMG-CoA from acetoacetyl-CoA and acetyl-CoA, and HMGCL subsequently cleaves HMG-CoA to generate acetoacetate. Acetoacetate can be reduced to β-hydroxybutyrate (BHB) or undergo spontaneous decarboxylation to form acetone. After BHB and acetoacetate are released into the circulation, they can be taken up and oxidized by extrahepatic tissues such as the brain and skeletal muscle.

1.2 Metabolic Differences between Ketogenic Diets and Fasting

Fasting is accompanied by reductions in total energy intake and the intake of multiple classes of nutrients, whereas a ketogenic diet generally maintains energy intake and promotes ketogenesis by markedly restricting carbohydrates and increasing the proportion of energy supplied by fat. Both conditions increase fatty acid utilization and hepatic ketone body production, but they differ substantially in nutrient intake, hormonal status, and sources of fatty acids.

2 Fasting-Induced Global Translation Suppression and Translatome Remodeling

2.1 From mRNA Abundance to Translational Efficiency

(1) mRNA Abundance Does Not Correspond Directly to Protein Output

The transcriptome primarily reflects the types and abundance of mRNAs within cells, whereas the translatome focuses on which mRNAs are being effectively utilized by ribosomes. mRNAs with the same abundance can exhibit different translational activities because of differences in translation-initiation efficiency and ribosome recruitment. When nutritional conditions change rapidly, cells can also alter the translational efficiency of existing mRNAs to modify protein-synthesis programs before large-scale transcriptional remodeling occurs.

(2) Ribosome Occupancy Reflects the Translational State of mRNA

A polysome is formed when multiple ribosomes simultaneously bind to a single mRNA. Actively translated mRNAs are generally enriched in heavy-polysome fractions, whereas translationally suppressed mRNAs shift toward lighter ribosomal fractions. Comparing the ribosome occupancy of mRNAs under different nutritional conditions can distinguish changes in mRNA abundance from changes in translational efficiency.

2.2 Coexistence of Reduced Global Translation and Enhanced Selective Translation

(1) Fasting Reduces Global Protein Synthesis

Protein synthesis continuously consumes ATP, GTP, and amino acids. During fasting, global translation in the liver declines, ribosome occupancy decreases for many mRNAs, and energy-intensive protein-synthesis activity is restricted. This suppression is not uniform, however, and certain mRNAs involved in fatty acid utilization and ketone body production can maintain relatively high translational efficiency.

(2) The P-eIF4E-Dependent Translational Program Is Selective

After 24 h of fasting, 445 genes showed significant translational upregulation in the livers of wild-type mice, whereas these changes could not be properly established when eIF4E Ser209 phosphorylation was impaired. The associated genes were primarily involved in lipolysis, fatty acid utilization, and ketone body production, with PPARα and HMGCS2 representing characteristic metabolic nodes.

3 Fatty Acid Sensing and AMPK–MNK–eIF4E Regulation

3.1 Fatty Acids Function as Both Metabolic Substrates and Nutrient Signals

(1) Fatty Acids Support Mitochondrial Energy Metabolism

After long-chain fatty acids such as palmitic acid, oleic acid, and linoleic acid enter hepatocytes, they can undergo fatty acid activation, mitochondrial transport, and β-oxidation to generate acetyl-CoA. The increased fatty acid supply during fasting provides important substrates for mitochondrial energy production and hepatic ketone body synthesis.

(2) Linoleic Acid Participates in AMPK Activation

Fatty acids can also participate in nutrient-signal regulation. Linoleic acid is a representative example that can interact with the AMPK γ subunit and enhance AMPK activity. Under this nutritional condition, AMPK inhibition reduces fatty acid-induced MNK and eIF4E phosphorylation, thereby linking fatty acid availability to translational regulation.

3.2 AMPK Connects Nutrient Sensing with MNK–eIF4E Signaling

(1) AMPK Coordinates Energy Metabolism and Biosynthetic Activity

AMP-activated protein kinase (AMPK) is an important cellular energy-sensing kinase. When energy stress increases, AMPK promotes energy-producing processes such as fatty acid oxidation while inhibiting certain energy-consuming biosynthetic activities. Under fasting and specific fatty acid-stimulation conditions, AMPK also participates in the regulation of MNK phosphorylation.

(2) MNK Controls eIF4E Ser209 Phosphorylation

MAP kinase-interacting kinases 1/2 (MNK1/2) are important upstream kinases of eIF4E Ser209. AMPK can promote MNK1 phosphorylation, further connecting fatty acid sensing to eIF4E-mediated translational control. This AMPK–MNK connection is currently supported primarily in the contexts of fasting and fatty acid stimulation and should not be extended to a classical linear signaling pathway that universally exists in all cell types.

4 eIF4E Phosphorylation and Selective mRNA Translation

4.1 eIF4E Ser209 Phosphorylation Alters Translational Selectivity

(1) eIF4E Participates in Cap-Dependent Translation Initiation

Eukaryotic translation initiation factor 4E (eIF4E) recognizes the 5′ cap structure of mRNA and forms the eIF4F translation-initiation complex together with components such as eIF4G and eIF4A, promoting mRNA recruitment to ribosomes. Different mRNAs vary in their dependence on eIF4F assembly and cap-dependent translation initiation, allowing changes in eIF4E activity to produce transcript-specific translational effects.

(2) Ser209 Phosphorylation Regulates Selective Translation

Fasting enhances eIF4E Ser209 phosphorylation, but P-eIF4E does not universally increase the translation of all mRNAs and instead primarily affects a group of mRNAs with specific regulatory features. These include certain transcripts associated with lipid metabolism and ketone body production; when Ser209 phosphorylation is blocked, the enhanced translation of these mRNAs is suppressed, accompanied by reduced production of the corresponding metabolic proteins and decreased ketogenic capacity.

4.2 The 5′UTR Confers Distinct Translational Responses on mRNAs

(1) PRTE Participates in Selective Translation

The 5′ untranslated region (5′UTR) of mRNA contains cis-regulatory elements that can influence translation initiation. The 5′UTRs of certain P-eIF4E-sensitive mRNAs contain a pyrimidine-rich translational element (PRTE), making their translational efficiency more sensitive to the phosphorylation state of eIF4E.

(2) PPARα Is a Representative Regulatory Example

The PPARα 5′UTR contains a functionally relevant PRTE. When this regulatory region is altered, fasting-induced enhancement of PPARα translation is substantially weakened, whereas the total amount of PPARα mRNA does not necessarily decrease correspondingly, indicating that PPARα is regulated not only transcriptionally but also at the translational level through a 5′UTR-dependent mechanism.

5 PPARα- and HMGCS2-Mediated Adaptation to Ketogenesis

5.1 PPARα Regulates Fatty Acid Oxidation and Ketogenic Programs

(1) PPARα Is an Important Transcriptional Regulator of Fasting Adaptation

Peroxisome proliferator-activated receptor alpha (PPARα) is an important nuclear receptor involved in lipid metabolism. Following activation, PPARα promotes fatty acid uptake, mitochondrial and peroxisomal fatty acid oxidation, and the expression of multiple genes involved in ketone body production.

(2) PPARα Is Also Regulated at the Translational Level

Changes in PPARα protein levels during fasting cannot be fully explained by its mRNA abundance. P-eIF4E and the PPARα 5′UTR participate in regulating its translational efficiency, increasing PPARα protein output and further affecting genetic programs associated with fatty acid oxidation and ketone body production.

5.2 HMGCS2 Directly Participates in Ketone Body Production

(1) HMGCS2 Is a Key Enzyme in Ketone Body Synthesis

3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) is localized in hepatocyte mitochondria and catalyzes the formation of HMG-CoA from acetoacetyl-CoA and acetyl-CoA, making it an important regulatory node in ketone body production. PPARα primarily regulates the expression of genes associated with fatty acid oxidation and ketogenesis, whereas HMGCS2 participates directly in ketone body synthesis.

(2) HMGCS2 Is a Fasting-Associated Selective Translation Target

The increase in HMGCS2 protein during fasting contains a substantial translational regulatory component. When eIF4E Ser209 phosphorylation is blocked, HMGCS2 protein output declines, accompanied by reduced hepatic ketone body production.

5.3 Ketogenic Diets Engage Partially Overlapping Translational Programs

(1) A High-Fat, Low-Carbohydrate Environment Increases the Demand for Ketogenesis

A ketogenic diet markedly restricts carbohydrates and increases the proportion of energy supplied by fat, causing the liver to continuously maintain relatively high levels of fatty acid oxidation and ketone body production. Its nutritional background differs from complete fasting, but the two states partially overlap in translational programs associated with fatty acid utilization and ketogenesis.

(2) P-eIF4E Participates in Metabolic Adaptation under Ketogenic Conditions

When eIF4E Ser209 phosphorylation is blocked, ketogenic diet-induced ketone body production is also weakened. P-eIF4E-dependent selective translation participates not only in complete fasting but also in hepatic metabolic adaptation under high-fat, low-carbohydrate conditions.

6 Translational Adaptation and Metabolic Vulnerabilities in Pancreatic Cancer

6.1 Metabolic Plasticity and Ketone Body Utilization in Pancreatic Cancer

(1) Tumor Dependence on Energy Substrates Is Heterogeneous

Tumor cells differ substantially in their dependence on substrates such as glucose, fatty acids, glutamine, and ketone bodies. When glucose availability decreases, tumors with strong metabolic plasticity can still maintain their energy and biosynthetic requirements through fatty acid oxidation, mitochondrial respiration, and the utilization of alternative substrates.

(2) Certain Pancreatic Cancers Possess Ketone Body-Related Metabolic Capacity

In certain pancreatic cancer models, HMGCL–BHB-associated metabolism can participate in tumor metabolic adaptation and progression, indicating that elevated ketone body levels do not necessarily produce antitumor effects. The extent to which different tumors utilize ketone bodies is influenced by factors such as metabolic-enzyme expression, mitochondrial function, and the nutritional environment.

6.2 Translatome Remodeling Supports Tumor Adaptation to Nutritional Changes

(1) Substrate Switching Requires Reconfiguration of Metabolic Proteins

A ketogenic diet reduces the proportion of glucose-derived substrates and increases systemic fatty acid utilization and circulating ketone body levels. Tumor cells must adjust substrate transport, lipid metabolism, and mitochondrial function accordingly to adapt to the altered nutritional environment.

(2) Selective Translation Provides Rapid Regulation of Protein Output

Compared with reconstructing a complete transcriptional program, regulating the translational efficiency of existing mRNAs can alter protein output more rapidly. P-eIF4E-dependent selective translation allows certain metabolic mRNAs to maintain relatively high translational efficiency after changes in nutritional status, providing a protein basis for lipid utilization, mitochondrial metabolism, and other adaptive processes.

6.3 MNK–eIF4E Intervention Exploits Metabolic Dependence under Ketogenic Conditions

(1) Tomivosertib Inhibits MNK1/2-Mediated eIF4E Phosphorylation

Tomivosertib (eFT508) is an MNK1/2 inhibitor that reduces eIF4E Ser209 phosphorylation and restricts P-eIF4E-dependent selective translation. Its principal effect is not the direct inhibition of fatty acid oxidation or ketone body production but the restriction of the cell’s ability to adjust protein output according to the nutritional environment.

(2) Pancreatic Cancer Models Show Effects of Combined Intervention

In T3M4 and AsPC1 pancreatic cancer xenograft models, a ketogenic diet combined with Tomivosertib restricted tumor growth more effectively than the nutritional intervention alone and was accompanied by changes in tumor translational programs.

(3) Clinical Translation Requires Further Validation

Direct evidence for the antitumor effects of combining a ketogenic diet with MNK–eIF4E intervention currently derives primarily from cellular and animal models, and its clinical efficacy and applicable patient populations require further investigation.

7 Products

7.1 Products for Fatty Acid and Ketone Body Metabolism Research

7.2 Products for AMPK–MNK–eIF4E Translational Regulation Research

7.3 Products for Fatty Acid Oxidation and Mitochondrial Metabolism Research

7.4 Products for Evaluating Nutritional Switching and Metabolic Phenotypes

Major Abbreviations

References

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