Objective  To screen the core genes of ferroptosis and analyze the prognosis of pancreatic ductal adenocarcinoma (PDAC).

Methods  Based on the Gene Expression Omnibus (GEO) database, the GSE71989 data set was selected, and the differentially expressed genes (DEGs) were screened by limma package and ferroptosis data set. The Metascape database was used for enrichment analysis, the String database was used to establish a protein-protein interaction network (PPI), and the matthews correlation coefficient (MCC) algorithm was used to screen for prognostic related core genes. The Kaplan Meier plotter, R, GEPIA2 and TIMER databases were used to analyze and verify the prognosis of the selected core genes. The CMap database was used to screen potential therapeutic drugs for PDAC.

Results  A total of 2 038 DEGs were screened, of which 1 552 genes were up-regulated and 486 genes were down-regulated. Intersecting with the ferroptosis data set, 66 common DEGs were obtained. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the enrichment pathways of ferroptosis-related genes included ferroptosis pathway, interleukin-17 (IL-17) signaling pathway, chemical carcinogenesis-reactive oxygen species pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and hypoxia inducible factor-1 (HIF-1) signaling pathway. The pre-core targets: NADPH oxidase 4 (NOX4), caveolin-1 (CAV1), hypoxia inducible factor 1 subunit alpha (HIF1A), peroxisome proliferator activated receptor gamma (PPARG), interleukin-6 (IL-6), prostaglandin-endoperoxide synthase 2 (PTGS2) were obtained by MCC algorithm. The verification analysis suggested that the core genes were highly expressed genes, closely related to the overall survival rate of patients and had diagnostic value (P<0.05). Immune infiltration showed a significant positive correlation (P<0.05) between NOX4, HIF1A, IL-6 genes and macrophage and neutrophil infiltration levels. The NOX4, CAV1 and H1F1A genes were significantly positively correlated with CD8+ and DC cell infiltration levels (P<0.05). The selected small molecule drugs include HU-211, ispinesib, and ursolic acid, all of which have a strong correlation with PDAC.

Conclusion  The ferroptosis-related genes (NOX4, CAV1, HIF1A, PPARG, IL-6, PTGS2) screened based on the integrated database have a high diagnostic value for PDAC and may be a prognostic diagnostic indicator.

1.Islam S, Kitagawa T, Baron B, et al. ITGA2, LAMB3, and LAMC2 may be the potential therapeutic targets in pancreatic ductal adenocarcinoma: an integrated bioinformatics analysis[J]. Sci Rep, 2021, 11(1): 10563. DOI: 10.1038/s41598-021-90077-x.

2.Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, et al. Pancreatic cancer: advances and challenges[J]. Cell, 2023, 186(8): 1729-1754. DOI: 10.1016/j.cell.2023.02.014.

3.Maitra A, Hruban RH. Pancreatic cancer[J]. Annu Rev Pathol, 2008, 3: 157-188. DOI: 10.1146/annurev.pathmechdis.3.121806.154305.

4.Zhang W, Gong M, Zhang W, et al. Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling[J]. Cell Death Dis, 2022, 13(7): 630. DOI: 10.1038/s41419-022-05082-3.

5.徐昰栋, 刘子梅, 陈宁, 等. CCR10通过NRF2抑制结直肠癌细胞铁死亡的机制研究[J]. 中国实验诊断学, 2024, 28(3): 326-334. [Xu SD, Liu ZM, Chen N, et al. Study on the mechanism of CCR10 inhibiting ferroptosis of colorectal cancer cells through NRF2[J]. Chinese Journal of Laboratory Diagnosis, 2024, 28(3): 326-334.] DOI: 10.3969/j.issn.1007-4287.2024.03.015.

6.Liu J, Kang R, Tang D. The art of war: ferroptosis and pancreatic cancer[J]. Front Pharmacol, 2021, 12: 773909. DOI: 10.3389/fphar.2021.773909.

7.轩晨礒, 牛旭东, 淳雨婕, 等. 空间转录组技术在消化系统肿瘤研究中的应用进展[J]. 中国癌症防治杂志, 2023, 15(6): 702-710. [Xuan CY, Niu XD, Chun YJ, et al. Research progress of spatial transcriptomics technology in digestive system tumors[J]. Chinese Journal of Oncology Prevention and Treatment, 2023, 15(6): 702-710.] DOI: 10.3969/j.issn.1674‐5671.2023.06.18.

8.Cheng G, Lanza-Jacoby S. Metformin decreases growth of pancreatic cancer cells by decreasing reactive oxygen species: role of NOX4[J]. Biochem Biophys Res Commun, 2015, 465(1): 41-46. DOI: 10.1016/j.bbrc.2015.07.118.

9.Li H, Peng C, Zhu C, et al. Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner[J]. Clin Epigenetics, 2021, 13(1): 18. DOI: 10.1186/s13148-021-01016-6.

10.李丽, 曾普华, 杨仁义, 等. 基于PPARG/FABP4/GPX4通路研究淫羊藿苷诱导HepG2肝癌细胞铁死亡的作用机制[J]. 中国中药杂志, 2024, 49(5): 1295-1309. [Li L, Zeng PH, Yang RY, et al. Study on mechanism of icariin-induced ferroptosis in HepG2 hepatoma carcinoma cells through PPARG/FABP4/GPX4 pathway[J]. China Journal of Chinese Materia Medica, 2024, 49(5): 1295-1309.] DOI: 10.19540/j.cnki.cjcmm. 20231212.703.

11.Yamashita M, Kumazoe M, Onda H, et al. PPAR/PDK4 pathway is involved in the anticancer effects of cGMP in pancreatic cancer[J]. Biochem Biophys Res Commun, 2023, 672: 154-160. DOI: 10.1016/j.bbrc.2023.06.043.

12.Lesina M, Wörmann SM, Neuhöfer P, et al. Interleukin-6 in inflammatory and malignant diseases of the pancreas[J]. Semin Immunol, 2014, 26(1): 80-87. DOI: 10.1016/j.smim.2014.01.002.

13.Pop VV, Seicean A, Lupan I, et al. IL-6 roles-molecular pathway and clinical implication in pancreatic cancer-a systemic review[J]. Immunol Lett, 2017, 181: 45-50. DOI: 10.1016/j.imlet.2016.11.010.

14.Van Duijneveldt G, Griffin MDW, Putoczki TL. Emerging roles for the IL-6 family of cytokines in pancreatic cancer[J]. Clin Sci (Lond), 2020, 134(16): 2091-2115. DOI: 10.1042/CS20191211.

15.Badgley MA, Kremer DM, Maurer HC, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice[J]. Science, 2020, 368(6486): 85-89. DOI: 10.1126/science.aaw9872.

16.Tao P, Jiang Y, Wang H, et al. CYP2J2-produced epoxyeicosatrienoic acids contribute to the ferroptosis resistance of pancreatic ductal adenocarcinoma in a PPARγ-dependent manner[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2021, 46(9): 932-941. DOI: 10.11817/j.issn.1672-7347.2021.210413.

17.Zhang Y, Chandra V, Riquelme Sanchez E, et al. Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer[J]. J Exp Med, 2020, 217(12): e20190354. DOI: 10.1084/jem.20190354.

18.He Z, Wang J, Zhu C, et al. Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis[J]. Cancer Lett, 2022, 548: 215751. DOI: 10.1016/j.canlet.2022.215751.

19.Jeong HO, Lee H, Kim H, et al. Cellular plasticity and immune microenvironment of malignant pleural effusion are associated with EGFR-TKI resistance in non-small-cell lung carcinoma[J]. iScience, 2022, 25(11): 105358. DOI: 10.1016/j.isci.2022.105358.

20.Huang H, Benzonana LL, Zhao H, et al. Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination[J]. Br J Cancer, 2014, 111(7): 1338-1349. DOI: 10.1038/bjc.2014.426.

21.Chen X, Wu Q, You L, et al. Propofol attenuates pancreatic cancer malignant potential via inhibition of NMDA receptor[J]. Eur J Pharmacol, 2017, 795: 150-159. DOI: 10.1016/j.ejphar.2016.12.017.

22.Chen J, Zhao CC, Chen FR, et al. KIF4A regulates the progression of pancreatic ductal adenocarcinoma through proliferation and invasion[J]. Biomed Res Int, 2021, 2021: 8249293. DOI: 10.1155/2021/8249293.

23.Murase Y, Ono H, Ogawa K, et al. Inhibitor library screening identifies ispinesib as a new potential chemotherapeutic agent for pancreatic cancers[J]. Cancer Sci, 2021, 112(11): 4641-4654. DOI: 10.1111/cas.15134.

24.López-Hortas L, Pérez-Larrán P, González-Muñoz MJ, et al. Recent developments on the extraction and application of ursolic acid. A review[J]. Food Res Int, 2018, 103: 130-149. DOI: 10.1016/j.foodres.2017.10.028.

25.Lin JH, Chen SY, Lu CC, et al. Ursolic acid promotes apoptosis, autophagy, and chemosensitivity in gemcitabine‐resistant human pancreatic cancer cells[J]. Phytother Res, 2020, 34(8): 2053-2066. DOI: 10.1002/ptr.6669.