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author：

Lin, H. (Lin, H..) [1] | Zhu, S. (Zhu, S..) [2] | Chen, Y. (Chen, Y..) [3] | Lu, J. (Lu, J..) [4] | Xie, C. (Xie, C..) [5] | Liao, C. (Liao, C..) [6] | Huang, X. (Huang, X..) [7] | Li, G. (Li, G..) [8] | Wu, Y. (Wu, Y..) [9] | Li, Z. (Li, Z..) [10] | Hu, J. (Hu, J..) [11] | Lin, X. (Lin, X..) [12] | Tian, Y. (Tian, Y..) [13] | Li, Q. (Li, Q..) [14] | Wang, Z. (Wang, Z..) [15] | Chen, S. (Chen, S..) [16]

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Scopus

Abstract：

Aims:　Current　therapeutic　strategies　for　pancreatic　ductal　adenocarcinoma　(PDAC)　have　limited　efficacy　in　increasing　patient　survival　rates,　largely　due　to　ferroptosis　resistance　and　immunosuppression.　The　aim　of　this　study　is　to　identify　molecular　mechanisms　associated　with　ferroptosis　resistance　and　immunosuppression　in　PDAC　tumour　cells.　Methods:　Circular　RNA　sequencing　(circRNA-seq)　was　performed　on　clinical　samples　to　identify　potential　circRNAs　that　mediate　ferroptosis　resistance.　C11-BODIPY　staining,　FerroOrange　staining,　the　glutathione　ratio,　malondialdehyde　quantification,　and　transmission　electron　microscopy　were　employed　to　assess　ferroptosis.　RNA　pulldown,　mass　spectrometry,　RNA　immunoprecipitation,　and　coimmunoprecipitation　assays　were　conducted　to　investigate　the　molecular　mechanisms　involved.　A　HuNSG　mouse　xenograft　tumour　model　was　utilized　to　validate　therapeutic　agents.　Results:　A　circRNA　derived　from　TRIP12　(cTRIP12)　was　identified　in　PDAC　samples　resistant　to　ferroptosis.　cTRIP12　knockdown　increased　the　sensitivity　of　PDAC　cells　to　ferroptosis　and　immunotherapy.　Subsequent　mechanistic　studies　revealed　that　cTRIP12　specifically　binds　to　the　O-linked　N-acetylglucosamine　transferase　(OGT)　protein　and　increases　intracellular　O-GlcNAcylation　levels,　leading　to　increased　protein　levels　of　ferritin　heavy　chain　(FTH)　and　PD-L1　in　tumour　cells.　Notably,　high　cTRIP12　expression　suppressed　ferroptosis　sensitivity　and　increased　immune　resistance　in　PDAC　cells　by　functioning　as　a　protein　scaffold　through　its　interaction　with　OGT　and　protein　kinase　R-like　endoplasmic　reticulum　kinase　(PERK).　cTRIP12　inhibition　induced　ferroptosis　in　PDAC　cells　by　reducing　FTH　and　PD-L1　expression　and　synergistically　increased　the　immunotherapy　efficacy.　In　vivo　animal　experiments　confirmed　that　the　triple　therapy　consisting　of　GSK2656157,　erastin,　and　anti-CTLA-4　effectively　suppressed　the　progression　of　PDAC　in　tumours　with　high　cTRIP12　expression.　Conclusion:　We　elucidated　the　molecular　mechanisms　underlying　the　simultaneous　occurrence　of　ferroptosis　resistance　and　immune　suppression　in　PDAC　patients.　Our　study　provides　a　novel　therapeutic　strategy　that　could　promote　ferroptosis　in　tumour　cells　and　increase　immunotherapy　efficacy.　©　2025　The　Authors

Keyword：

Circular RNA Ferroptosis Immunotherapy O-GlcNAcylation Pancreatic ductal adenocarcinoma

Community：

  • [ 1 ] [Lin H.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 2 ] [Lin H.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 3 ] [Zhu S.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 4 ] [Zhu S.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 5 ] [Chen Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 6 ] [Chen Y.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 7 ] [Lu J.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 8 ] [Lu J.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 9 ] [Xie C.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 10 ] [Xie C.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 11 ] [Liao C.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 12 ] [Liao C.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 13 ] [Liao C.]Fuzhou University, Fuzhou, 350001, China
  • [ 14 ] [Huang X.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 15 ] [Huang X.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 16 ] [Huang X.]Fuzhou University, Fuzhou, 350001, China
  • [ 17 ] [Li G.]Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
  • [ 18 ] [Wu Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 19 ] [Wu Y.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 20 ] [Li Z.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 21 ] [Li Z.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 22 ] [Hu J.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 23 ] [Lin X.]Fuzhou University, Fuzhou, 350001, China
  • [ 24 ] [Tian Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 25 ] [Tian Y.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 26 ] [Tian Y.]Fuzhou University, Fuzhou, 350001, China
  • [ 27 ] [Li Q.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 28 ] [Li Q.]Fuzhou University, Fuzhou, 350001, China
  • [ 29 ] [Li Q.]Fujian Provincial Institute of Clinical Geriatrics, Fuzhou, 350001, China
  • [ 30 ] [Li Q.]Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China
  • [ 31 ] [Li Q.]Fujian Provincial Center for Geriatrics, Fuzhou, 350001, China
  • [ 32 ] [Wang Z.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 33 ] [Wang Z.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 34 ] [Wang Z.]Fuzhou University, Fuzhou, 350001, China
  • [ 35 ] [Chen S.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 36 ] [Chen S.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 37 ] [Chen S.]Fuzhou University, Fuzhou, 350001, China
  • [ 38 ] [Chen S.]Fujian Provincial Institute of Clinical Geriatrics, Fuzhou, 350001, China
  • [ 39 ] [Chen S.]Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China
  • [ 40 ] [Chen S.]Fujian Provincial Center for Geriatrics, Fuzhou, 350001, China

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Drug Resistance Updates

ISSN： 1368-7646

Year： 2025

Volume： 81

1 5 . 8 0 0

JCR@2023

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