Assessing the causal association of 1 400 blood metabolites with the risk of pancreatic cancer: a comprehensive Mendelian randomized study_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HUAN Yunfeng ¹ , YANG Jiwu ¹ , SHI Hongbo ¹ , ZHAO Pengju ¹ , CHENG Wei ¹ , LI Chuan ¹ ,  LIU Lixin ²

1. Department of General Surgery Ⅱ, The First Affiliated Hospital of Dali University, Dali, Yunnan 671000, P. R. China;
2. Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650000, P. R. China;

Corresponding author：

LIU Lixin, Email: Liulixin0660@163.com

Keywords：

pancreatic cancer; blood metabolite; Mendelian randomization; causality; genome-wide association study

DOI：

10.7507/1007-9424.202505070

Video：

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Objective To systematically evaluate the causal relationship between blood metabolites and pancreatic cancer (PC) risk using Mendelian randomization (MR). Methods We conducted a two-sample MR analysis using genetic instruments for 8 299 blood metabolites derived from a European genome-wide association study (GWAS) and PC outcome data from the GWAS Catalog. The primary analysis employed inverse-variance weighted (IVW) regression, with sensitivity analyses including MR-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity was assessed using Cochran’s Q test, pleiotropy was evaluated via MR-Egger intercept tests, and outliers were identified using MR-PRESSO. Robustness was confirmed through leave-one-out analyses. For metabolites showing significant associations (P<0.05), we performed independent replication using the same European PC GWAS cohort, followed by meta-analysis of all results. Reverse causation was excluded using Steiger directionality tests and bidirectional MR, while genetic confounding was assessed via linkage disequilibrium score regression (LDSC). Results After multi-stage screening, 26 blood metabolites demonstrated statistically significant associations with PC risk (P<0.05), comprising 18 annotated metabolites (12 lipids, 3 amino acids, 2 coenzymes/vitamins, 1 nucleotide, and 1 peptide), 3 metabolite ratios, and 5 unannotated metabolites. Replication analysis confirmed 6 of these 26 metabolites in the independent European PC GWAS cohort. Crucially, meta-analysis of all 26 metabolites yielded consistent significant associations (P<0.05 for all), with 1-palmitoleoylglycerol (16:1) exhibiting the strongest protective effect [OR=0.76, 95%CI (0.68, 0.85), P<1.0×10^-⁵]. LDSC analysis revealed no significant genetic confounding for 25/26 metabolites (P>0.05), except for myristate (14:0), Rg=1.534, Se=0.571, P=0.007), where genetic correlation potentially influenced MR estimates. Pathway analysis further implicated dysregulation of lipid metabolism as a key mechanism, with 1-palmitoleoylglycerol emerging as a high-priority biomarker candidate for PC risk stratification. Conclusions This study provides causal evidence within the European population that some blood metabolites are associated with PC risk, identifying 1-palmitoleoylglycerol as a novel protective biomarker and highlighting targeting lipid metabolic pathways as a promising therapeutic strategy for pancreatic cancer.

1.	任佳栋, 洪蕴, 刘彬, 等. 1990–2021年全球和中国胰腺癌的疾病负担分析及其未来趋势预测. 中国普外基础与临床杂志, 2025, 32(6): 722-730.
2.	Tarasiuk A, Mackiewicz T, Małecka-Panas E, et al. Biomarkers for early detection of pancreatic cancer - miRNAs as a potential diagnostic and therapeutic tool?. Cancer Biol Ther, 2021, 22(5-6): 347-356.
3.	He J, Ahuja N, Makary MA, et al. 2 564 resected periampullary adenocarcinomas at a single institution: trends over three decades. HPB (Oxford), 2014, 16(1): 83-90.
4.	Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 2011, 144(5): 646-674.
5.	Christofk HR, Vander Heiden MG, Harris MH, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 2008, 452(7184): 230-233.
6.	Whitehouse S, Cooper RH, Randle PJ. Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem J, 1974, 141(3): 761-774.
7.	Mayers JR, Wu C, Clish CB, et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med, 2014, 20(10): 1193-1198.
8.	Shu X, Zheng W, Yu D, et al. Prospective metabolomics study identifies potential novel blood metabolites associated with pancreatic cancer risk. Int J Cancer, 2018, 143(9): 2161-2167.
9.	Fahrmann JF, Bantis LE, Capello M, et al. A plasma-derived protein-metabolite multiplexed panel for early-stage pancreatic cancer. J Natl Cancer Inst, 2019, 111(4): 372-379.
10.	Stolzenberg-Solomon R, Derkach A, Moore S, et al. Associations between metabolites and pancreatic cancer risk in a large prospective epidemiological study. Gut, 2020, 69(11): 2008-2015.
11.	Richmond RC, Davey Smith G. Mendelian randomization: concepts and scope. Cold Spring Harb Perspect Med, 2022, 12(1): a040501. doi: 10.1101/cshperspect.a040501.
12.	Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet, 2023, 55(1): 44-53.
13.	Sakaue S, Kanai M, Tanigawa Y, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet, 2021, 53(10): 1415-1424.
14.	Yang J, Yan B, Zhao B, et al. Assessing the causal effects of human serum metabolites on 5 major psychiatric disorders. Schizophr Bull, 2020, 46(4): 804-813.
15.	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
16.	Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol, 2013, 178(7): 1177-1184.
17.	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
18.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
19.	Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
20.	Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet, 2018, 27(R2): R195-R208.
21.	Greco M FD, Minelli C, Sheehan NA, et al. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med, 2015, 34(21): 2926-2940.
22.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
23.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
24.	Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081. doi: 10.1371/journal.pgen.1007081.
25.	Zhou W, Nielsen JB, Fritsche LG, et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet, 2018, 50(9): 1335-1341.
26.	O’Connor LJ, Price AL. Distinguishing genetic correlation from causation across 52 diseases and complex traits. Nat Genet, 2018, 50(12): 1728-1734.
27.	Pinho AV, Chantrill L, Rooman I. Chronic pancreatitis: a path to pancreatic cancer. Cancer Lett, 2014, 345(2): 203-209.
28.	Michaud DS, Vrieling A, Jiao L, et al. Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan). Cancer Causes Control, 2010, 21(8): 1213-1225.
29.	Bosetti C, Lucenteforte E, Silverman DT, et al. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Ann Oncol, 2012, 23(7): 1880-1888.
30.	Yuan C, Babic A, Khalaf N, et al. Diabetes, weight change, and pancreatic cancer risk. JAMA Oncol, 2020, 6(10): e202948. doi: 10.1001/jamaoncol.2020.2948.
31.	Xiao S, Zhou L. Gastric cancer: Metabolic and metabolomics perspectives (review). Int J Oncol, 2017, 51(1): 5-17.
32.	Gupta S, Roy A, Dwarakanath BS. Metabolic cooperation and competition in the tumor microenvironment: implications for therapy. Front Oncol, 2017, 7: 68. doi: 10.3389/fonc.2017.00068.
33.	Ventura R, Mordec K, Waszczuk J, et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine, 2015, 2(8): 808-824.
34.	Harayama T, Riezman H. Understanding the diversity of membrane lipid composition. Nat Rev Mol Cell Biol, 2018, 19(5): 281-296.
35.	Wang T, Fahrmann JF, Lee H, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab, 2018, 27(1): 136-150. e135.
36.	Igal RA. Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis, 2010, 31(9): 1509-1515.
37.	Ntambi JM. Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol. J Lipid Res, 1999, 40(9): 1549-1558.
38.	Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J, 2014, 61(7): B4890.
39.	Yi J, Zhu J, Wu J, et al. Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc Natl Acad Sci U S A, 2020, 117(49): 31189-31197.
40.	Katoh Y, Yaguchi T, Kubo A, et al. Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody. J Immunother Cancer, 2022, 10(7): e004616. doi: 10.1136/jitc-2022-004616.
41.	Ko PJ, Dixon SJ. Protein palmitoylation and cancer. EMBO Rep, 2018, 19(10): e46666. doi: 10.15252/embr.201846666.
42.	Fhu CW, Ali A. Protein lipidation by palmitoylation and myristoylation in cancer. Front Cell Dev Biol, 2021, 9: 673647. doi: 10.3389/fcell.2021.673647.
43.	Wang H, Xu X, Wang J, et al. The role of N-myristoyltransferase 1 in tumour development. Ann Med, 2023, 55(1): 1422-1430.
44.	Mackey JR, Lai J, Chauhan U, et al. N-myristoyltransferase proteins in breast cancer: prognostic relevance and validation as a new drug target. Breast Cancer Res Treat, 2021, 186(1): 79-87.
45.	Zhao L, Zhang C, Luo X, et al. CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis. J Hepatol, 2018, 69(3): 705-717.
46.	Pedram A, Razandi M, Deschenes RJ, et al. DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors. Mol Biol Cell, 2012, 23(1): 188-199.
47.	Sun R, Xu H, Liu F, et al. Unveiling the intricate causal nexus between pancreatic cancer and peripheral metabolites through a comprehensive bidirectional two-sample Mendelian randomization analysis. Front Mol Biosci, 2023, 10: 1279157. doi: 10.3389/fmolb.2023.1279157.
48.	Xie G, Lu L, Qiu Y, et al. Plasma metabolite biomarkers for the detection of pancreatic cancer. J Proteome Res, 2015, 14(2): 1195-1202.
49.	Sivanand S, Vander Heiden MG. Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell, 2020, 37(2): 147-156.
50.	Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care, 2018, 21(1): 64-70.
51.	Peng H, Wang Y, Luo W. Multifaceted role of branched-chain amino acid metabolism in cancer. Oncogene, 2020, 39(44): 6747-6756.
52.	Silva LS, Poschet G, Nonnenmacher Y, et al. Branched-chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype. EMBO Rep, 2017, 18(12): 2172-2185.
53.	Ikeda K, Kinoshita M, Kayama H, et al. Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Rep, 2017, 21(7): 1824-1838.
54.	Otsuru T, Kobayashi S, Wada H, et al. Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein. Cancer Sci, 2019, 110(3): 985-996.
55.	De Falco P, Lazzarino G, Felice F, et al. Hindering NAT8L expression in hepatocellular carcinoma increases cytosolic aspartate delivery that fosters pentose phosphate pathway and purine biosynthesis promoting cell proliferation. Redox Biol, 2023, 59: 102585. doi: 10.1016/j.redox.2022.102585.
56.	Sullivan LB, Gui DY, Hosios AM, et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell, 2015, 162(3): 552-563.
57.	Xu L, Chen J, Jia L, et al. SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. J Cell Mol Med, 2020, 24(24): 14392-14404.
58.	Infantino V, Dituri F, Convertini P, et al. Epigenetic upregulation and functional role of the mitochondrial aspartate/glutamate carrier isoform 1 in hepatocellular carcinoma. Biochim Biophys Acta Mol Basis Dis, 2019, 1865(1): 38-47.
59.	Alkan HF, Walter KE, Luengo A, et al. Cytosolic aspartate availability determines cell survival when glutamine is limiting. Cell Metab, 2018, 28(5): 706-720. e706.
60.	Sullivan LB, Luengo A, Danai LV, et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat Cell Biol, 2018, 20(7): 782-788.
61.	Krall AS, Xu S, Graeber TG, et al. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat Commun, 2016, 7: 11457. oi: 10.1038/ncomms11457.
62.	Krall AS, Mullen PJ, Surjono F, et al. Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth. Cell Metab, 2021, 33(5): 1013-1026. e1016.
63.	Stocker R, Yamamoto Y, McDonagh AF, et al. Bilirubin is an antioxidant of possible physiological importance. Science, 1987, 235(4792): 1043-1046.
64.	Vítek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol, 2012, 3: 55. doi: 10.3389/fphar.2012.00055.
65.	Riphagen IJ, Deetman PE, Bakker SJ, et al. Bilirubin and progression of nephropathy in type 2 diabetes: a post hoc analysis of RENAAL with independent replication in IDNT. Diabetes, 2014, 63(8): 2845-2853.
66.	Gào X, Brenner H, Holleczek B, et al. Urinary 8-isoprostane levels and occurrence of lung, colorectal, prostate, breast and overall cancer: Results from a large, population-based cohort study with 14 years of follow-up. Free Radic Biol Med, 2018, 123: 20-26.
67.	Wen CP, Zhang F, Liang D, et al. The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling. Clin Cancer Res, 2015, 21(1): 193-200.
68.	Horsfall LJ, Rait G, Walters K, et al. Serum bilirubin and risk of respiratory disease and death. JAMA, 2011, 305(7): 691-697.
69.	Inoguchi T, Nohara Y, Nojiri C, et al. Association of serum bilirubin levels with risk of cancer development and total death. Sci Rep, 2021, 11(1): 13224. doi: 10.1038/s41598-021-92442-2.
70.	Vitek L, Hubacek JA, Pajak A, et al. Association between plasma bilirubin and mortality. Ann Hepatol, 2019, 18(2): 379-385.
71.	Wang S, Zhu X, Xiong L, et al. Toll-like receptor 4 knockout alleviates paraquat-induced cardiomyocyte contractile dysfunction through an autophagy-dependent mechanism. Toxicol Lett, 2016, 257: 11-22.
72.	Zhang W, Lin H, He X, et al. Gut microbiota-derived phenylacetylglutamine mitigates neuroinflammation induced by intracerebral hemorrhage in mice. J Stroke Cerebrovasc Dis, 2025, 34(8): 108357. doi: 10.1016/j.jstrokecerebrovasdis.2025.108357.
73.	Fu H, Kong B, Zhu J, et al. Phenylacetylglutamine increases the susceptibility of ventricular arrhythmias in heart failure mice by exacerbated activation of the TLR4/AKT/mTOR signaling pathway. Int Immunopharmacol, 2023, 116: 109795. doi: 10.1016/j.intimp.2023.109795.
74.	Yang H, Wang B, Wang T, et al. Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis. PLoS One, 2014, 9(10): e109980. doi: 10.1371/journal.pone.0109980.
75.	Zhang H, Zhang S. The expression of Foxp3 and TLR4 in cervical cancer: association with immune escape and clinical pathology. Arch Gynecol Obstet, 2017, 295(3): 705-712.
76.	Orlacchio A, Mazzone P. The role of toll-like receptors (TLRs) mediated inflammation in pancreatic cancer pathophysiology. Int J Mol Sci, 2021, 22(23): 12743. doi: 10.3390/ijms222312743.

1. 任佳栋, 洪蕴, 刘彬, 等. 1990–2021年全球和中国胰腺癌的疾病负担分析及其未来趋势预测. 中国普外基础与临床杂志, 2025, 32(6): 722-730.
2. Tarasiuk A, Mackiewicz T, Małecka-Panas E, et al. Biomarkers for early detection of pancreatic cancer - miRNAs as a potential diagnostic and therapeutic tool?. Cancer Biol Ther, 2021, 22(5-6): 347-356.
3. He J, Ahuja N, Makary MA, et al. 2 564 resected periampullary adenocarcinomas at a single institution: trends over three decades. HPB (Oxford), 2014, 16(1): 83-90.
4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 2011, 144(5): 646-674.
5. Christofk HR, Vander Heiden MG, Harris MH, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 2008, 452(7184): 230-233.
6. Whitehouse S, Cooper RH, Randle PJ. Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem J, 1974, 141(3): 761-774.
7. Mayers JR, Wu C, Clish CB, et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med, 2014, 20(10): 1193-1198.
8. Shu X, Zheng W, Yu D, et al. Prospective metabolomics study identifies potential novel blood metabolites associated with pancreatic cancer risk. Int J Cancer, 2018, 143(9): 2161-2167.
9. Fahrmann JF, Bantis LE, Capello M, et al. A plasma-derived protein-metabolite multiplexed panel for early-stage pancreatic cancer. J Natl Cancer Inst, 2019, 111(4): 372-379.
10. Stolzenberg-Solomon R, Derkach A, Moore S, et al. Associations between metabolites and pancreatic cancer risk in a large prospective epidemiological study. Gut, 2020, 69(11): 2008-2015.
11. Richmond RC, Davey Smith G. Mendelian randomization: concepts and scope. Cold Spring Harb Perspect Med, 2022, 12(1): a040501. doi: 10.1101/cshperspect.a040501.
12. Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet, 2023, 55(1): 44-53.
13. Sakaue S, Kanai M, Tanigawa Y, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet, 2021, 53(10): 1415-1424.
14. Yang J, Yan B, Zhao B, et al. Assessing the causal effects of human serum metabolites on 5 major psychiatric disorders. Schizophr Bull, 2020, 46(4): 804-813.
15. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
16. Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol, 2013, 178(7): 1177-1184.
17. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
18. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
19. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
20. Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet, 2018, 27(R2): R195-R208.
21. Greco M FD, Minelli C, Sheehan NA, et al. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med, 2015, 34(21): 2926-2940.
22. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
23. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
24. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081. doi: 10.1371/journal.pgen.1007081.
25. Zhou W, Nielsen JB, Fritsche LG, et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet, 2018, 50(9): 1335-1341.
26. O’Connor LJ, Price AL. Distinguishing genetic correlation from causation across 52 diseases and complex traits. Nat Genet, 2018, 50(12): 1728-1734.
27. Pinho AV, Chantrill L, Rooman I. Chronic pancreatitis: a path to pancreatic cancer. Cancer Lett, 2014, 345(2): 203-209.
28. Michaud DS, Vrieling A, Jiao L, et al. Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan). Cancer Causes Control, 2010, 21(8): 1213-1225.
29. Bosetti C, Lucenteforte E, Silverman DT, et al. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Ann Oncol, 2012, 23(7): 1880-1888.
30. Yuan C, Babic A, Khalaf N, et al. Diabetes, weight change, and pancreatic cancer risk. JAMA Oncol, 2020, 6(10): e202948. doi: 10.1001/jamaoncol.2020.2948.
31. Xiao S, Zhou L. Gastric cancer: Metabolic and metabolomics perspectives (review). Int J Oncol, 2017, 51(1): 5-17.
32. Gupta S, Roy A, Dwarakanath BS. Metabolic cooperation and competition in the tumor microenvironment: implications for therapy. Front Oncol, 2017, 7: 68. doi: 10.3389/fonc.2017.00068.
33. Ventura R, Mordec K, Waszczuk J, et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine, 2015, 2(8): 808-824.
34. Harayama T, Riezman H. Understanding the diversity of membrane lipid composition. Nat Rev Mol Cell Biol, 2018, 19(5): 281-296.
35. Wang T, Fahrmann JF, Lee H, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab, 2018, 27(1): 136-150. e135.
36. Igal RA. Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis, 2010, 31(9): 1509-1515.
37. Ntambi JM. Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol. J Lipid Res, 1999, 40(9): 1549-1558.
38. Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J, 2014, 61(7): B4890.
39. Yi J, Zhu J, Wu J, et al. Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc Natl Acad Sci U S A, 2020, 117(49): 31189-31197.
40. Katoh Y, Yaguchi T, Kubo A, et al. Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody. J Immunother Cancer, 2022, 10(7): e004616. doi: 10.1136/jitc-2022-004616.
41. Ko PJ, Dixon SJ. Protein palmitoylation and cancer. EMBO Rep, 2018, 19(10): e46666. doi: 10.15252/embr.201846666.
42. Fhu CW, Ali A. Protein lipidation by palmitoylation and myristoylation in cancer. Front Cell Dev Biol, 2021, 9: 673647. doi: 10.3389/fcell.2021.673647.
43. Wang H, Xu X, Wang J, et al. The role of N-myristoyltransferase 1 in tumour development. Ann Med, 2023, 55(1): 1422-1430.
44. Mackey JR, Lai J, Chauhan U, et al. N-myristoyltransferase proteins in breast cancer: prognostic relevance and validation as a new drug target. Breast Cancer Res Treat, 2021, 186(1): 79-87.
45. Zhao L, Zhang C, Luo X, et al. CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis. J Hepatol, 2018, 69(3): 705-717.
46. Pedram A, Razandi M, Deschenes RJ, et al. DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors. Mol Biol Cell, 2012, 23(1): 188-199.
47. Sun R, Xu H, Liu F, et al. Unveiling the intricate causal nexus between pancreatic cancer and peripheral metabolites through a comprehensive bidirectional two-sample Mendelian randomization analysis. Front Mol Biosci, 2023, 10: 1279157. doi: 10.3389/fmolb.2023.1279157.
48. Xie G, Lu L, Qiu Y, et al. Plasma metabolite biomarkers for the detection of pancreatic cancer. J Proteome Res, 2015, 14(2): 1195-1202.
49. Sivanand S, Vander Heiden MG. Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell, 2020, 37(2): 147-156.
50. Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care, 2018, 21(1): 64-70.
51. Peng H, Wang Y, Luo W. Multifaceted role of branched-chain amino acid metabolism in cancer. Oncogene, 2020, 39(44): 6747-6756.
52. Silva LS, Poschet G, Nonnenmacher Y, et al. Branched-chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype. EMBO Rep, 2017, 18(12): 2172-2185.
53. Ikeda K, Kinoshita M, Kayama H, et al. Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Rep, 2017, 21(7): 1824-1838.
54. Otsuru T, Kobayashi S, Wada H, et al. Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein. Cancer Sci, 2019, 110(3): 985-996.
55. De Falco P, Lazzarino G, Felice F, et al. Hindering NAT8L expression in hepatocellular carcinoma increases cytosolic aspartate delivery that fosters pentose phosphate pathway and purine biosynthesis promoting cell proliferation. Redox Biol, 2023, 59: 102585. doi: 10.1016/j.redox.2022.102585.
56. Sullivan LB, Gui DY, Hosios AM, et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell, 2015, 162(3): 552-563.
57. Xu L, Chen J, Jia L, et al. SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. J Cell Mol Med, 2020, 24(24): 14392-14404.
58. Infantino V, Dituri F, Convertini P, et al. Epigenetic upregulation and functional role of the mitochondrial aspartate/glutamate carrier isoform 1 in hepatocellular carcinoma. Biochim Biophys Acta Mol Basis Dis, 2019, 1865(1): 38-47.
59. Alkan HF, Walter KE, Luengo A, et al. Cytosolic aspartate availability determines cell survival when glutamine is limiting. Cell Metab, 2018, 28(5): 706-720. e706.
60. Sullivan LB, Luengo A, Danai LV, et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat Cell Biol, 2018, 20(7): 782-788.
61. Krall AS, Xu S, Graeber TG, et al. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat Commun, 2016, 7: 11457. oi: 10.1038/ncomms11457.
62. Krall AS, Mullen PJ, Surjono F, et al. Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth. Cell Metab, 2021, 33(5): 1013-1026. e1016.
63. Stocker R, Yamamoto Y, McDonagh AF, et al. Bilirubin is an antioxidant of possible physiological importance. Science, 1987, 235(4792): 1043-1046.
64. Vítek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol, 2012, 3: 55. doi: 10.3389/fphar.2012.00055.
65. Riphagen IJ, Deetman PE, Bakker SJ, et al. Bilirubin and progression of nephropathy in type 2 diabetes: a post hoc analysis of RENAAL with independent replication in IDNT. Diabetes, 2014, 63(8): 2845-2853.
66. Gào X, Brenner H, Holleczek B, et al. Urinary 8-isoprostane levels and occurrence of lung, colorectal, prostate, breast and overall cancer: Results from a large, population-based cohort study with 14 years of follow-up. Free Radic Biol Med, 2018, 123: 20-26.
67. Wen CP, Zhang F, Liang D, et al. The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling. Clin Cancer Res, 2015, 21(1): 193-200.
68. Horsfall LJ, Rait G, Walters K, et al. Serum bilirubin and risk of respiratory disease and death. JAMA, 2011, 305(7): 691-697.
69. Inoguchi T, Nohara Y, Nojiri C, et al. Association of serum bilirubin levels with risk of cancer development and total death. Sci Rep, 2021, 11(1): 13224. doi: 10.1038/s41598-021-92442-2.
70. Vitek L, Hubacek JA, Pajak A, et al. Association between plasma bilirubin and mortality. Ann Hepatol, 2019, 18(2): 379-385.
71. Wang S, Zhu X, Xiong L, et al. Toll-like receptor 4 knockout alleviates paraquat-induced cardiomyocyte contractile dysfunction through an autophagy-dependent mechanism. Toxicol Lett, 2016, 257: 11-22.
72. Zhang W, Lin H, He X, et al. Gut microbiota-derived phenylacetylglutamine mitigates neuroinflammation induced by intracerebral hemorrhage in mice. J Stroke Cerebrovasc Dis, 2025, 34(8): 108357. doi: 10.1016/j.jstrokecerebrovasdis.2025.108357.
73. Fu H, Kong B, Zhu J, et al. Phenylacetylglutamine increases the susceptibility of ventricular arrhythmias in heart failure mice by exacerbated activation of the TLR4/AKT/mTOR signaling pathway. Int Immunopharmacol, 2023, 116: 109795. doi: 10.1016/j.intimp.2023.109795.
74. Yang H, Wang B, Wang T, et al. Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis. PLoS One, 2014, 9(10): e109980. doi: 10.1371/journal.pone.0109980.
75. Zhang H, Zhang S. The expression of Foxp3 and TLR4 in cervical cancer: association with immune escape and clinical pathology. Arch Gynecol Obstet, 2017, 295(3): 705-712.
76. Orlacchio A, Mazzone P. The role of toll-like receptors (TLRs) mediated inflammation in pancreatic cancer pathophysiology. Int J Mol Sci, 2021, 22(23): 12743. doi: 10.3390/ijms222312743.

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