[CORE-RSTB2023] Johnson RJ et al. (2023). The fructose survival hypothesis for obesity. Philosophical Transactions of the Royal Society B, 378(1885). Published 24 July 2023. doi: 10.1098/rstb.2022.0230
Keystone paper proposing that activation of the fructose survival pathway—via diet or endogenous triggers—initiates the metabolic switch underlying obesity and related diseases. Integrates molecular, evolutionary, and clinical evidence into a unified “energy-conservation” framework that informs all subsequent sections of this bibliography.

I) Mechanism & Core Biochemistry

Foundational work on fructokinase (KHK), ATP depletion → AMP → uric acid, mitochondrial suppression, and NO loss.

[MECH-M1993] Mayes PA (1993). Intermediary metabolism of fructose. Am J Clin Nutr. 58(5 Suppl):754S–765S. doi: 10.1093/ajcn/58.5.754S
Classic overview of hepatic fructose handling and unique entry points.

[MECH-T2010] Tappy L, Lê K-A (2010). Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev. 90(1):23–46. doi: 10.1152/physrev.00019.2009
Comprehensive review of fructose’s distinct metabolic effects vs glucose.

[MECH-J2007] Johnson RJ et al. (2007). Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 86(4):899–906. doi: 10.1093/ajcn/86.4.899
Frames fructose/uric-acid signaling as an upstream driver across diseases.

[MECH-N2005] Nakagawa T et al. (2005). Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol. 1(2):80–86. doi: 10.1038/ncpneph0019
Early articulation linking fructose → uric acid → metabolic syndrome.

[MECH-L2012] Lanaspa MA et al. (2012). Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One. 7(10):e47948. doi: 10.1371/journal.pone.0047948
Shows uric acid amplifies KHK activity, creating a feed-forward loop.

[MECH-S2009] Stanhope KL, Havel PJ (2009). Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 119(5):1322–1334. doi: 10.1172/JCI37385
Human trial showing fructose → DNL ↑ and insulin sensitivity ↓.

[MECH-S2019] Softic S, Cohen DE, Kahn CR (2019). Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig Dis Sci. 61(5):1282–93. doi: 10.1007/s10620-016-4054-0
Highlights fructose-driven DNL as a keystone of NAFLD pathophysiology.

II) Endogenous Fructose & Internal Triggers

Polyol pathway (aldose reductase → sorbitol → fructose) and triggers: glycemic spikes, salt/osmolality, dehydration, alcohol, hypoxia, stress.

[ENDO-L2013] Lanaspa MA et al. (2013). Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun. 4:2434. doi: 10.1038/ncomms3434
Direct evidence that internal fructose production drives metabolic syndrome.

[ENDO-AH2021] Andres-Hernando A et al. (2021). High salt intake causes leptin resistance and obesity by stimulating endogenous fructose production and metabolism. PNAS. 118(22):e2018147118. doi: 10.1073/pnas.1713837115
Shows Na⁺/osmolality → polyol pathway → obesity and leptin resistance.

[ENDO-H2017] Hwang JJ et al. (2017). The human brain produces fructose from glucose. JCI Insight. 2(4):e90508. doi: 10.1172/jci.insight.90508
Demonstrates in vivo conversion of glucose → fructose in the human brain.

[ENDO-J2020] Johnson RJ et al. (2020). Cerebral fructose metabolism as a potential mechanism driving Alzheimer’s disease. Front Aging Neurosci. 12:560865. doi: 10.3389/fnagi.2020.560865
Proposes cerebral fructose metabolism as a unifying driver of AD pathology.

[ENDO-P2017] Park TJ et al. (2017). Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science. 356(6335):307–311. doi: 10.1126/science.aab3896
Adaptive endogenous fructose use under hypoxia.

III) Nature & Historical Context

Natural adaptations that leverage the fructose program (seasonal fattening, hypoxia tolerance, rapid sugar oxidation) and the human transition from scarcity to excess.

[NAT-B2002] Bairlein F (2002). How to get fat: nutritional mechanisms of seasonal fat accumulation in migratory songbirds. Naturwissenschaften. 89:1–10. doi: 10.1007/s00114-001-0279-6
Seasonal fattening as adaptive transient fructose metabolism.

[NAT-P2017] Park TJ et al. (2017). Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science. 356(6335):307–311. doi: 10.1126/science.aab3896
Endogenous fructose use under hypoxia.

[NAT-J2020] Johnson RJ et al. (2020). Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts. J Intern Med. 287(3):252–262. doi: 10.1111/joim.12993
Fructose metabolism as a universal survival mechanism.

[NAT-W2007] Welch KC, Suarez RK (2007). Sugar flux and metabolic flexibility in hummingbirds. Proc R Soc B. 274(1610):1169–1174. doi: 10.1098/rspb.2006.0047
Extraordinary sugar throughput and switchability.

[NAT-G2023] Gershman A et al. (2023). Genomic insights into metabolic flux in hummingbirds. Genome Res. 33(5):703–714. doi: 10.1101/gr.276779.122
Genomic specialization for extreme sugar metabolism.

[HIST-B2004] Bray GA, Nielsen SJ, Popkin BM (2004). Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 79(4):537–543. doi: 10.1093/ajcn/79.4.537
Rise of HFCS as a turning point.

[HIST-Y1972] Yudkin J (1972). Pure, White and Deadly. London: Davis-Poynter. (Book)
Historical context connecting sugar and chronic disease.

[NAT-D2004] Dudley R (2004). Ethanol, fruit ripening, and the historical origins of human alcoholism in primate frugivory. Integr Comp Biol. 44(4):315–323. doi: 10.1093/icb/44.4.315
Ethanol as a seasonal signal—adjacent survival chemistry.

IV) Disease Manifestations

How the energy-failure fingerprint expresses as metabolic syndrome, CVD, neurodegeneration, and cancer.

IV-A) Metabolic Dysfunction — The Primary Fingerprint of the Fructose Pathway

Early manifestations: ATP depletion, uric acid generation, de novo lipogenesis, insulin resistance, hepatic lipid accumulation.

[DIS-J2013] Johnson RJ et al. (2013). Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 62(10):3307–3315. doi: 10.2337/db12-1814
Mechanistic and clinical synthesis: fructose/uric acid → diabetes/obesity.

[DIS-J2009] Johnson RJ et al. (2009). Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev. 30(2):96–116. doi: 10.1210/er.2008-0033
Model connecting fructose metabolism, uric acid, β-cell dysfunction, insulin resistance.

[DIS-SL2010] Sánchez-Lozada LG et al. (2010). Comparison of free fructose and glucose to sucrose in the ability to cause fatty liver. Eur J Nutr. 49(1):1–9. doi: 10.1007/s00394-009-0042-x
Fructose—more than glucose—drives hepatic steatosis.

[DIS-B2010] Bocarsly ME et al. (2010). High-fructose corn syrup causes characteristics of obesity in rats. Pharmacol Biochem Behav. 97(1):101–106. doi: 10.1016/j.pbb.2010.02.012
HFCS intake linked to obesity independent of calories.

[DIS-N2006] Nakagawa T et al. (2006). A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 290(3):F625–F631. doi: 10.1152/ajprenal.00140.2005
Uric acid mediates fructose-induced hypertension/insulin resistance.

[DIS-R2011] Roncal-Jimenez CA et al. (2011). Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake. Metabolism. 60(9):1259–1270. doi: 10.1016/j.metabol.2011.01.008
Fructose can trigger pathology independent of caloric surplus.

IV-B) Cardiovascular Disease — Fragile Vessels from Fragile Energy

[CVD-F2008] Feig DI, Kang D-H, Johnson RJ (2008). Uric Acid and Cardiovascular Risk. N Engl J Med. 359(17):1811–1821. doi: 10.1056/NEJMra0800885
Authoritative review linking uric acid to endothelial dysfunction and CVD.

[CVD-N2006] Nakagawa T et al. (2006). A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 290(3):F625–F631. doi: 10.1152/ajprenal.00140.2005
Mechanistic animal data for BP/insulin resistance.

[CVD-K2005] Khosla UM et al. (2005). Hyperuricemia induces endothelial dysfunction. Kidney Int. 67(5):1739–1742. doi: 10.1111/j.1523-1755.2005.00273.x
Elevated uric acid impairs endothelial function.

[CVD-FJ2008] Feig DI, Soletsky B, Johnson RJ (2008). Allopurinol lowers BP in adolescents with essential hypertension: randomized trial. JAMA. 300(8):924–932. doi: 10.1001/jama.300.8.924
Human RCT supports causal role of uric acid in BP.

[CVD-B2008] Brown CM et al. (2008). Fructose ingestion acutely elevates blood pressure in healthy young humans. Am J Physiol Regul Integr Comp Physiol. 294(3):R730–R737. doi: 10.1152/ajpregu.00680.2007
Acute hemodynamic response to fructose.

[CVD-KA2005] Kang D-H et al. (2005). Uric acid–induced C-reactive protein expression and NO suppression in vascular cells. J Am Soc Nephrol. 16(12):3553–3562. doi: 10.1681/ASN.2005050572
Links uric acid to vascular inflammation and NO loss.

[CVD-ZH2008] Zharikov S et al. (2008). Uric acid decreases NO and increases arginase in endothelial cells. Am J Physiol Cell Physiol. 295(5):C1183–C1190. doi: 10.1152/ajpcell.00075.2008
Mechanism for reduced NO bioavailability.

[CVD-PP2010] Perez-Pozo SE et al. (2010). Excessive fructose intake induces features of metabolic syndrome in healthy men: role of uric acid in the hypertensive response. Int J Obes (Lond). 34(3):454–461. doi: 10.1038/ijo.2009.259
Human intervention: BP rise tracks with uric acid.

IV-C) Neurodegeneration — The Brain on Fragile Energy

[NEURO-J2023] Johnson RJ et al. (2023). Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism? Am J Clin Nutr. 117(3):455–466. doi: 10.1016/j.ajcnut.2023.01.002
Synthesis proposing intracerebral fructose/uric-acid signaling in AD.

[NEURO-H2017] Hwang JJ et al. (2017). The human brain produces fructose from glucose. JCI Insight. 2(4):e90508. doi: 10.1172/jci.insight.90508
Direct human evidence for brain polyol pathway.

[NEURO-J2020] Johnson RJ et al. (2020). Cerebral fructose metabolism as a potential mechanism driving Alzheimer’s disease. Front Aging Neurosci. 12:560865. doi: 10.3389/fnagi.2020.560865
Hypothesis detailing how overactive brain fructose metabolism may drive AD.

[NEURO-O2017] Oppelt SA, Zhang W, Tolan DR (2017). Specific regions of the brain are capable of fructose metabolism. Brain Res. 1657:312–322. doi: 10.1016/j.brainres.2016.12.022
Maps brain areas expressing fructose-handling machinery.

[NEURO-P2013] Page KA et al. (2013). Effects of fructose vs glucose on regional cerebral blood flow in appetite/reward regions. JAMA. 309(1):63–70. doi: 10.1001/jama.2012.116975
Human fMRI: distinct responses to fructose vs glucose.

[NEURO-L2015] Luo S et al. (2015). Differential effects of fructose versus glucose on brain/appetitive responses. PNAS. 112(20):6509–6514. doi: 10.1073/pnas.1503358112
Fructose heightens reactivity to food cues—link to foraging drive.

[NEURO-X2016] Xu J et al. (2016). Elevation of brain glucose and polyol-pathway intermediates with brain-copper deficiency in AD. Sci Rep. 6:27524. doi: 10.1038/srep27524
AD brain shows increased polyol intermediates—consistent with endogenous fructose.

[NEURO-S2016] Shao X et al. (2016). Uric acid induces cognitive dysfunction via hippocampal inflammation. J Neurosci. 36(43):10990–11005. doi: 10.1523/JNEUROSCI.1480-16.2016
Mechanistic bridge from uric acid to cognition.

VI) Cancer — Metabolic Reprogramming & Fructose Pathway

[CANC-N2020] Nakagawa T et al. (2020). Fructose contributes to the Warburg effect for cancer growth. Cancer Metab. 8:16. doi: 10.1186/s40170-020-00222-9
Positions KHK, ATP depletion, and F1P signaling in cancer rewiring.

[CANC-C2025] Chen X, Yang M, Wang L, Tu J, Yuan X (2025). Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications. Int J Med Sci. 22(11):2852–2876. doi: 10.7150/ijms.108549
Comprehensive review of fructose metabolism in tumors.

[CANC-L2016] Li X et al. (2016). A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. Nat Cell Biol. 18(5):561–571. doi: 10.1038/ncb3338
KHK-A predominance supports tumor growth via altered fructose handling.

[CANC-B2018] Bu P et al. (2018). Aldolase B–mediated fructose metabolism drives metabolic reprogramming of colon cancer liver metastasis. Cell Metab. 27(6):1249–1264.e4. doi: 10.1016/j.cmet.2018.04.003
Fructose catabolism fuels metastatic colon tumors.

[CANC-C2016] Chen WL et al. (2016). Enhanced fructose utilization mediated by SLC2A5 is a unique metabolic feature of AML. Cancer Cell. 30(5):779–791. doi: 10.1016/j.ccell.2016.09.006
GLUT5-driven fructose use is targetable in AML.

[CANC-W2018] Weng Y et al. (2018). Fructose fuels lung adenocarcinoma through GLUT5. Cell Death Dis. 9(5):557. doi: 10.1038/s41419-018-0630-x
GLUT5 uptake confers growth advantage in lung adenocarcinoma.

[CANC-L2010] Liu H et al. (2010). Fructose induces transketolase flux to promote pancreatic cancer growth. Cancer Res. 70(15):6368–6376. doi: 10.1158/0008-5472.CAN-09-4615
Fructose shunted into non-oxidative PPP for anabolism.

[CANC-G2019] Goncalves MD et al. (2019). High-fructose corn syrup enhances intestinal tumor growth in mice. Science. 363(6433):1345–1349. doi: 10.1126/science.aat8515
HFCS boosts tumor growth via F1P/lipogenesis—weight gain independent.

[CANC-D2009] Diggle CP et al. (2009). Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J Histochem Cytochem. 57(8):763–774. doi: 10.1369/jhc.2009.953190
Maps KHK expression relevant to tumor contexts.

[CANC-W1956a] Warburg O. (1956). On the origin of cancer cells. Science. 123:309–314. doi: 10.1126/science.123.3191.309

[CANC-W1956b] Warburg O. (1956). On respiratory impairment in cancer cells. Science. 124:269–270. doi: 10.1126/science.124.3215.269
Anchor context: aerobic glycolysis as a hallmark.

V) Interventions & Therapeutics

Ketohexokinase (KHK) inhibition, uric-acid modulation, and nutraceutical/lifestyle levers that down-shift the fructose pathway.

[INT-S2023] Saxena AR et al. (2023). A phase 2a, randomized, double-blind trial of PF-06835919 in NAFLD + T2D. Diabetes Obes Metab. 25(4):992–1001. doi: 10.1111/dom.14946
First human proof-of-concept that KHK inhibition lowers hepatic fat and uric acid.

[INT-K2021] Kazierad DJ et al. (2021). Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers. Med. 2(7):800–813.e3. doi: 10.1016/j.medj.2021.04.007
Independent phase-2 confirmation of hepatic/inflammatory improvement.

[INT-F2025] Fukuda T et al. (2025). LY3522348, a new ketohexokinase inhibitor: first-in-human study. Diabetes Ther. 16(7):1399–1415. doi: 10.1007/s13300-025-01752-5
Establishes safety, PK, and target engagement for LY3522348.

[INT-SH2020] Shepherd EL et al. (2021). Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis. JHEP Rep. 3(2):100217. doi: 10.1016/j.jhepr.2020.100217
Preclinical mechanistic evidence of anti-fibrotic, anti-steatotic effects.

[INT-AH2017] Andres-Hernando A et al. (2017). Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice. Nat Commun. 8:14181. doi: 10.1038/ncomms14181
KHK deletion prevents ischemic/oxidative renal injury.

[INT-J2023] Johnson RJ et al. (2023). Uric acid and chronic kidney disease: still more to do. Kidney Int Rep. 8(2):229–239. doi: 10.1016/j.ekir.2022.11.016
Reviews uric-acid lowering strategies aligned with fructose-pathway modulation.

[INT-LE2016] Le MT et al. (2016). Bioactivity-guided identification of botanical inhibitors of ketohexokinase. PLoS One. 11(6):e0157458. doi: 10.1371/journal.pone.0157458
Identifies luteolin among strongest natural KHK-C inhibitors.

[INT-ALT2019] Nutrients (2019). Altilix® (artichoke + luteolin) RCT — improved hepatic fat and insulin sensitivity. Nutrients. 11:2580. doi: 10.3390/nu11112580
Nutraceutical endpoints mirroring pharmaceutical KHK inhibition.

[INT-ALT2023] Terzo S et al. (2023). Mediation analysis of Altilix®: visceral-fat reduction links to BP and liver-fat improvement. Nutrients. 15(2):462. doi: 10.3390/nu15020462
Mechanistic confirmation of nutraceutical efficacy.

[INT-OST2023] García-Arroyo FE et al. (2023). Osthole prevents heart damage via fructokinase suppression. Antioxidants (Basel). 12(5):1023. doi: 10.3390/antiox12051023
Cardioprotection via natural KHK pathway inhibition.

[INT-SCHW2017] Schwarz JM et al. (2017). Effects of dietary fructose restriction on liver fat, de novo lipogenesis, and insulin kinetics in children with obesity. Gastroenterology. 153(3):743–752. doi: 10.1053/j.gastro.2017.05.043
Rapid reversal of hepatic DNL via sugar restriction.

[INT-EF1994] Bonthron DT et al. (1994). Molecular basis of essential fructosuria: cloning and mutational analysis of human KHK. Hum Mol Genet. 3(9):1627–1631. doi: 10.1093/hmg/3.9.1627
Defines benign KHK loss-of-function; human safety model for KHK inhibition.

[INT-EF2003] Asipu A et al. (2003). Properties of normal and mutant recombinant human ketohexokinases and implications for essential fructosuria. Diabetes. 52(9):2426–2432. doi: 10.2337/diabetes.52.9.2426
Confirms metabolic innocuity of KHK-deficient variants.

[INT-EF2009] Trinh CH et al. (2009). Structures of alternatively spliced isoforms of human KHK. Acta Crystallogr D Biol Crystallogr. 65(Pt 3):201–211. doi: 10.1107/S0907444908041115
Structural basis aligning with benign essential fructosuria.