Ovarian cancer is a highly lethal malignancy, with treatment efficacy frequently compromised by the development of cisplatin resistance. This study investigates the molecular mechanisms driving cisplatin resistance, focusing on interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), a key interferon-stimulated gene. Through comprehensive transcriptome profiling, we systematically compared gene expression patterns between cisplatin-sensitive and cisplatin-resistant ovarian cancer cells, identifying a consistent upregulation of IFIT1 in resistant cells. Functional assays provided evidence that IFIT1 plays a central role in mediating cisplatin resistance. Mechanistically, IFIT1 was found to be associated with activation of inflammatory signaling pathways, suggesting its involvement in resistance-related immune regulation. Clinically, elevated IFIT1 expression significantly correlated with an unfavorable prognosis in ovarian cancer patients. Moreover, we demonstrated that hypoxia-inducible factor-1 alpha transcriptionally regulates IFIT1, linking its expression to hypoxia response. Overall, these findings identify IFIT1 as a key driver of cisplatin resistance in ovarian cancer, shedding light on its clinical significance and the regulatory networks underpinning therapy resistance. IFIT1 holds promise both as a prognostic indicator and as a target for therapeutic intervention. However, its clinical translation will depend on rigorous validation and in-depth exploration.

1. Ebell MH, Culp MB, Radke TJ. A systematic review of symptoms for the diagnosis of ovarian cancer. Am J Prev Med. 2016;50(3):384-394. doi: 10.1016/j.amepre.2015.09.023

2. Yang L, Xie HJ, Li YY, Wang X, Liu XX, Mai J. Molecular mechanisms of platinumbased chemotherapy resistance in ovarian cancer (review). Oncol Rep. 2022;47(4):82 doi: 10.3892/or.2022.8293

3. Li H, Luo F, Jiang X, et al. CircITGB6 promotes ovarian cancer cisplatin resistance by resetting tumor-associated macrophage polarization toward the M2 phenotype. J Immunother Cancer. 2022;10(3):e004029. doi: 10.1136/jitc-2021-004029

4. Wang D, Tang X, Ruan J, et al. HSP90AB1 as the druggable target of maggot extract reverses cisplatin resistance in ovarian cancer. Oxid Med Cell Longev. 2023;2023:9335440. doi: 10.1155/2023/9335440

5. Hasan AA, Kalinina E, Nuzhina J, Volodina Y, Shtil A, Tatarskiy V. Potentiation of cisplatin cytotoxicity in resistant ovarian cancer SKOV3/Cisplatin cells by quercetin pre-treatment. Int J Mol Sci. 2023;24(13):10960. doi: 10.3390/ijms241310960

6. Amoroso MR, Matassa DS, Agliarulo I, et al. Stress-adaptive response in ovarian cancer drug resistance: Role of TRAP1 in oxidative metabolism-driven inflammation. Adv Protein Chem Struct Biol. 2017;108:163-198. doi: 10.1016/bs.apcsb.2017.01.004

7. Ding Y, Zhuang S, Li Y, Yu X, Lu M, Ding N. Hypoxia-induced HIF1α dependent COX2 promotes ovarian cancer progress. J Bioenerg Biomembr. 2021;53(4):441-448. doi: 10.1007/s10863-021-09900-9

8. Wendel JR, Wang X, Hawkins SM. The endometriotic tumor microenvironment in ovarian cancer. Cancers (Basel). 2018;10(8):261. doi: 10.3390/cancers10080261

9. Chen Z, Han F, Du Y, Shi H, Zhou W. Hypoxic microenvironment in cancer: Molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023;8(1):70. doi: 10.1038/s41392-023-01332-8

10. Chun J. Isoalantolactone suppresses glycolysis and resensitizes cisplatin-based chemotherapy in cisplatin-resistant ovarian cancer cells. Int J Mol Sci. 2023;24(15):12397. doi: 10.3390/ijms241512397

11. Anestakis D, Petanidis S, Kalyvas S, et al. Mechanisms and applications of interleukins in cancer immunotherapy. Int J Mol Sci. 2015;16(1):1691-1710. doi: 10.3390/ijms16011691

12. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-899. doi: 10.1016/j.cell.2010.01.025

13. Zhao H, Wu L, Yan G, et al. Inflammation and tumor progression: Signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021;6(1):263. doi: 10.1038/s41392-021-00658-5

14. Korbecki J, Siminska D, Gassowska-Dobrowolska M, et al. Chronic and cycling hypoxia: Drivers of cancer chronic inflammation through HIF-1 and NF-κB Activation: A review of the molecular mechanisms. Int J Mol Sci. 2021;22(19):10701. doi: 10.3390/ijms221910701

15. Sanhueza C, Araos J, Naranjo L, et al. Modulation of intracellular pH in human ovarian cancer. Curr Mol Med. 2016;16(1):23-32. doi: 10.2174/1566524016666151222143437

16. De Valliere C, Cosin-Roger J, Simmen S, et al. Hypoxia positively regulates the expression of pH-sensing g-protein-coupled receptor OGR1 (GPR68). Cell Mol Gastroenterol Hepatol. 2016;2(6):796-810. doi: 10.1016/j.jcmgh.2016.06.003

17. Jordan KR, Sikora MJ, Slansky JE, et al. The capacity of the ovarian cancer tumor microenvironment to integrate inflammation signaling conveys a shorter disease-free interval. Clin Cancer Res. 2020;26(23):6362-6373. doi: 10.1158/1078-0432.ccr-20-1762

18. Diamond MS. IFIT1: A dual sensor and effector molecule that detects non-2’-O methylated viral RNA and inhibits its translation. Cytokine Growth Factor Rev. 2014;25(5): 543-550. doi: 10.1016/j.cytogfr.2014.05.002

19. Mears HV, Emmott E, Chaudhry Y, Hosmillo M, Goodfellow IG, Sweeney TR. Ifit1 regulates norovirus infection and enhances the interferon response in murine macrophage-like cells. Wellcome Open Res. 2019;4:82. doi: 10.12688/wellcomeopenres.15223.1

20. Ye S, Pang H, Gu YY, et al. Protein interaction for an interferon-inducible systemic lupus associated gene, IFIT1. Rheumatology (Oxford). 2003;42(10):1155-1163. doi: 10.1093/rheumatology/keg315

21. Li J, Lin TY, Chen L, et al. miR-19 regulates the expression of interferon-induced genes and MHC class I genes in human cancer cells. Int J Med Sci. 2020;17(7):953-964. doi: 10.7150/ijms.44377

22. Roby JA, Clarke BD, Khromykh AA. Loop de loop: Viral RNA evades IFIT1 targeting. Trends Microbiol. 2014;22(4): 171-173. doi: 10.1016/j.tim.2014.02.014

23. Franco JH, Chattopadhyay S, Pan ZK. How different pathologies are affected by IFIT expression. Viruses. 2023;15(2):342. doi: 10.3390/v15020342

24. Pingale KD, Kanade GD, Karpe YA. Hepatitis E virus polymerase binds to IFIT1 to protect the viral RNA from IFIT1-mediated translation inhibition. J Gen Virol. 2019;100(3):471-483. doi: 10.1099/jgv.0.001229

25. Zhou X, Michal JJ, Zhang L, et al. Interferon induced IFIT family genes in host antiviral defense. Int J Biol Sci. 2013;9(2):200-208. doi: 10.7150/ijbs.5613

26. Weiss CM, Trobaugh DW, Sun C, et al. The interferon-induced exonuclease ISG20 exerts antiviral activity through upregulation of Type I interferon response proteins. mSphere. 2018;3(5):e00209-e00218. doi: 10.1128/mSphere.00209-18

27. Zhao F, Liu A, Gong X, et al. Hypoxia-induced RNASEH2A limits activation of cGAS-STING signaling in HCC and predicts poor prognosis. Tumori. 2022;108(1):63-76. doi: 10.1177/03008916211026019

28. Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: Drivers of tumour metastasis. Nat Rev Cancer. 2014;14(6):430-439. doi: 10.1038/nrc3726

29. He Y, Jiang S, Cui Y, et al. Induction of IFIT1/IFIT3 and inhibition of Bcl-2 orchestrate the treatment of myeloma and leukemia via pyroptosis. Cancer Lett. 2024;588: 216797. doi: 10.1016/j.canlet.2024.216797

30. Gao Y, Zou T, Xu P, et al. Fusobacterium nucleatum stimulates cell proliferation and promotes PD-L1 expression via IFIT1-related signal in colorectal cancer. Neoplasia. 2023;35:100850. doi: 10.1016/j.neo.2022.100850

31. Liu YJ, Li JP, Han M, et al. IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC). J Transl Med. 2024;22(1):580. doi: 10.1186/s12967-024-05389-z

32. Schmitt M, Gallistl J, Schuler-Toprak S, et al. Anti-tumoral effect of chemerin on ovarian cancer cell lines mediated by activation of interferon alpha response. Cancers (Basel). 2022;14(17):4108. doi: 10.3390/cancers14174108

33. Mishra P, Singh U, Pandey CM, Mishra P, Pandey G. Application of student’s t-test, analysis of variance, and covariance. Ann Card Anaesth. 2019;22(4):407-411. doi: 10.4103/aca.ACA_94_19

34. Matassa DS, Amoroso MR, Lu H, et al. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ. 2016;23(9):1542-1554. doi: 10.1038/cdd.2016.39

35. Koti M, Siu A, Clement I, et al. A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer. Br J Cancer. 2015;112(7):1215-1222. doi: 10.1038/bjc.2015.81