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AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis

Cell Death & Differentiation volume 32, pages 488–505 (2025)Cite this article

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Abstract

Emerging evidence suggests that signaling pathways can be spatially regulated to ensure rapid and efficient responses to dynamically changing local cues. Ferroptosis is a recently defined form of lipid peroxidation-driven cell death. Although the molecular mechanisms underlying ferroptosis are emerging, spatial aspects of its signaling remain largely unexplored. By analyzing a public database, we found that a mitochondrial chaperone protein, glucose-regulated protein 75 (GRP75), may have a previously undefined role in regulating ferroptosis. This was subsequently validated. Interestingly, under ferroptotic conditions, GRP75 translocated from mitochondria to mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and the cytosol. Further mechanistic studies revealed a highly spatial regulation of GRP75-mediated antiferroptotic signaling. Under ferroptotic conditions, lipid peroxidation predominantly accumulated at the ER, which activated protein kinase A (PKA) in a cAMP-dependent manner. In particular, a signaling microdomain, the outer mitochondrial membrane protein A-kinase anchor protein 1 (AKAP1)-anchored PKA, phosphorylated GRP75 at S148 in MAMs. This caused GRP75 to be sequestered outside the mitochondria, where it competed with Nrf2 for Keap1 binding through a conserved high-affinity RGD-binding motif, ETGE. Nrf2 was then stabilized and activated, leading to the transcriptional activation of a panel of antiferroptotic genes. Blockade of the PKA/GRP75 axis dramatically increased the responses of cancer cells to ferroptosis both in vivo and in vitro. Our identification a localized signaling cascade involved in protecting cancer cells from ferroptosis broadens our understanding of cellular defense mechanisms against ferroptosis and also provides a new target axis (AKAP1/PKA/GRP75) to improve the responses of cancer cells to ferroptosis.

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Fig. 1: GRP75 determines ferroptosis sensitivity of colon cancers.
Fig. 2: PKA activation is required for sequestering GRP75 at MAMs under ferroptosis.
Fig. 3: PKA phosphorylates GRP75 at MAMs.
Fig. 4: GRP75 is the substrate of PKA.
Fig. 5: GRP75 protects cells from ferroptosis by interacting with Keap1 to stabilize Nrf2 protein.
Fig. 6: GRP75 competes with Nrf2 in binding with Keap1 thought the high affinity ETGE motif.
Fig. 7: Genetic inhibition of GRP75 sensitizes cancer cells’ response to SAS-induced ferroptosis in CDX model.
Fig. 8: Chemical inhibition of GRP75 inhibits sensitizes cancer cells’ response to SAS-induced ferroptosis in PDX model.
Fig. 9: The model of local activation of AKAP1/PKA/GRP75 at MAMs in protecting cells from ferroptosis.

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Data reported in this paper will be shared by the lead contact upon request.

References

  1. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Zheng S, Guan XY. Ferroptosis: Promising approach for cancer and cancer immunotherapy. Cancer Lett. 2023;561:216152.

    Article  CAS  PubMed  Google Scholar 

  3. Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185:2401–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22:381–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Zhang R, Kang R, Tang D. Ferroptosis in gastrointestinal cancer: from mechanisms to implications. Cancer Lett. 2023;561:216147.

    Article  CAS  PubMed  Google Scholar 

  6. Dos Santos AF, Fazeli G, Xavier da Silva TN, Friedmann Angeli JP. Ferroptosis: mechanisms and implications for cancer development and therapy response. Trends Cell Biol. 2023;33:1062–76.

    Article  PubMed  Google Scholar 

  7. Xu H, Ye D, Ren M, Zhang H, Bi F. Ferroptosis in the tumor microenvironment: perspectives for immunotherapy. Trends Mol Med. 2021;27:856–67.

    Article  CAS  PubMed  Google Scholar 

  8. Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer. 2019;19:405–14.

    Article  CAS  PubMed  Google Scholar 

  9. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171:273–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Zhao Y, Li M, Yao X, Fei Y, Lin Z, Li Z, et al. HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications. Cell Rep. 2020;33:108487.

    Article  CAS  PubMed  Google Scholar 

  12. Tang B, Wang Y, Xu W, Zhu J, Weng Q, Chen W, et al. Macrophage xCT deficiency drives immune activation and boosts responses to immune checkpoint blockade in lung cancer. Cancer Lett. 2023;554:216021.

    Article  CAS  PubMed  Google Scholar 

  13. Kholodenko BN, Hancock JF, Kolch W. Signalling ballet in space and time. Nat Rev Mol Cell Biol. 2010;11:414–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Vasan K, Werner M, Chandel NS. Mitochondrial Metabolism as a Target for Cancer Therapy. Cell Metab. 2020;32:341–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Harrington JS, Ryter SW, Plataki M, Price DR, Choi AMK. Mitochondria in health, disease, and aging. Physiol Rev. 2023;103:2349–422.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593:586–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Gan B. Mitochondrial regulation of ferroptosis. J Cell Biol. 2021;220:e202105043.

  18. Fontana F, Limonta P. The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer. Free Radic Biol Med. 2021;176:203–21.

    Article  CAS  PubMed  Google Scholar 

  19. Zheng S, Wang X, Zhao D, Liu H, Hu Y. Calcium homeostasis and cancer: insights from endoplasmic reticulum-centered organelle communications. Trends Cell Biol. 2023;33:312–23.

    Article  CAS  PubMed  Google Scholar 

  20. He Q, Qu M, Shen T, Su J, Xu Y, Xu C, et al. Control of mitochondria-associated endoplasmic reticulum membranes by protein S-palmitoylation: Novel therapeutic targets for neurodegenerative diseases. Ageing Res Rev. 2023;87:101920.

    Article  CAS  PubMed  Google Scholar 

  21. Booth DM, Enyedi B, Geiszt M, Várnai P, Hajnóczky G. Redox Nanodomains Are Induced by and Control Calcium Signaling at the ER-Mitochondrial Interface. Mol cell. 2016;63:240–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. von Krusenstiern AN, Robson RN, Qian N, Qiu B, Hu F, Reznik E, et al. Identification of essential sites of lipid peroxidation in ferroptosis. Nat Chem Biol. 2023;19:719–30.

    Article  Google Scholar 

  23. Taskén K, Aandahl EM. Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev. 2004;84:137–67.

    Article  PubMed  Google Scholar 

  24. Taylor SS, Ilouz R, Zhang P, Kornev AP. Assembly of allosteric macromolecular switches: lessons from PKA. Nat Rev Mol Cell Biol. 2012;13:646–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Ramms DJ, Raimondi F, Arang N, Herberg FW, Taylor SS, Gutkind JS. Gαs-Protein Kinase A (PKA) Pathway Signalopathies: The Emerging Genetic Landscape and Therapeutic Potential of Human Diseases Driven by Aberrant Gαs-PKA Signaling. Pharmacol Rev. 2021;73:155–97.

    Article  CAS  PubMed  Google Scholar 

  26. Kritzer MD, Li J, Dodge-Kafka K, Kapiloff MS. AKAPs: the architectural underpinnings of local cAMP signaling. J Mol Cell Cardiol. 2012;52:351–8.

    Article  CAS  PubMed  Google Scholar 

  27. Aggarwal S, Gabrovsek L, Langeberg LK, Golkowski M, Ong SE, Smith FD, et al. Depletion of dAKAP1-protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility. J Biol Chem. 2019;294:3152–68.

    Article  CAS  PubMed  Google Scholar 

  28. Merrill RA, Strack S. Mitochondria: a kinase anchoring protein 1, a signaling platform for mitochondrial form and function. Int J Biochem Cell Biol. 2014;48:92–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Kim H, Scimia MC, Wilkinson D, Trelles RD, Wood MR, Bowtell D, et al. Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Mol Cell. 2011;44:532–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Pryde KR, Smith HL, Chau KY, Schapira AH. PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy. J Cell Biol. 2016;213:163–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Dagda RK, Gusdon AM, Pien I, Strack S, Green S, Li C, et al. Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson’s disease. Cell Death Differ. 2011;18:1914–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Yang HM, Kim J, Shin D, Kim JY, You J, Lee HC, et al. Resistin impairs mitochondrial homeostasis via cyclase-associated protein 1-mediated fission, leading to obesity-induced metabolic diseases. Metab: Clin Exp. 2023;138:155343.

    Article  CAS  PubMed  Google Scholar 

  33. Lee AS. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer. 2014;14:263–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Maio N, Rouault TA. Outlining the Complex Pathway of Mammalian Fe-S Cluster Biogenesis. Trends Biochem Sci. 2020;45:411–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Dai Y, Li F, Jiao Y, Wang G, Zhan T, Xia Y, et al. Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming. Cell Death Discov. 2021;7:140.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Zhao Q, Luo T, Gao F, Fu Y, Li B, Shao X, et al. GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity. Diabetes. 2022;71:233–48.

    Article  CAS  PubMed  Google Scholar 

  37. Hayashi T, Rizzuto R, Hajnoczky G, Su TP. MAM: more than just a housekeeper. Trends cell Biol. 2009;19:81–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Thoudam T, Chanda D, Lee JY, Jung MK, Sinam IS, Kim BG, et al. Enhanced Ca(2+)-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease. Nat Commun. 2023;14:1703.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Feng S, Huang Q, Deng J, Jia W, Gong J, Xie D, et al. DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer. Cancer Lett. 2022;532:215588.

    Article  CAS  PubMed  Google Scholar 

  40. Liao Y, Liu Y, Shao Z, Xia X, Deng Y, Cai J, et al. A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance. Oncogene. 2021;40:4291–306.

    Article  CAS  PubMed  Google Scholar 

  41. Liu X, Lin W, Shi X, Davies RG, Wagstaff KM, Tao T, et al. PKA-site phosphorylation of importin13 regulates its subcellular localization and nuclear transport function. Biochemical J. 2018;475:2699–712.

    Article  CAS  Google Scholar 

  42. Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatol (Baltim, Md). 2016;63:173–84.

    Article  CAS  Google Scholar 

  43. Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23:101107.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, et al. Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol cell. 2009;34:663–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Zhang JZ, Lu TW, Stolerman LM, Tenner B, Yang JR, Zhang JF, et al. Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling. Cell. 2020;182:1531–44.e1515.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Haushalter KJ, Schilling JM, Song Y, Sastri M, Perkins GA, Strack S, et al. Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα. Am J Physiol Heart Circulatory Physiol. 2019;317:H1231–h1242.

    Article  CAS  Google Scholar 

  47. Carroll WL, Evensen NA. Targeting a major hub of cell fate decisions - the mitochondrial-associated membrane. Haematologica. 2019;104:419–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. D’Eletto M, Rossin F, Occhigrossi L, Farrace MG, Faccenda D, Desai R, et al. Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75. Cell Rep. 2018;25:3573–81.e3574.

    Article  PubMed  Google Scholar 

  49. Liu Y, Ma X, Fujioka H, Liu J, Chen S, Zhu X. DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1. Proc Natl Acad Sci USA. 2019;116:25322–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Zhang Z, Zhou H, Gu W, Wei Y, Mou S, Wang Y, et al. CGI1746 targets σ(1)R to modulate ferroptosis through mitochondria-associated membranes. Nat Chem. Biol. 2024;20:699–709.

  51. Li Y, Cao Y, Xiao J, Shang J, Tan Q, Ping F, et al. Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury. Cell Death Differ. 2020;27:2635–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Lee H, Zandkarimi F, Zhang Y, Meena JK, Kim J, Zhuang L, et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol. 2020;22:225–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Yi J, Zhu J, Wu J, Thompson CB, Jiang X. Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc Natl Acad Sci USA. 2020;117:31189–97.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Wadhwa R, Colgin L, Yaguchi T, Taira K, Reddel RR, Kaul SC. Rhodacyanine dye MKT-077 inhibits in vitro telomerase assay but has no detectable effects on telomerase activity in vivo. Cancer Res. 2002;62:4434–8.

    CAS  PubMed  Google Scholar 

  55. Propper DJ, Braybrooke JP, Taylor DJ, Lodi R, Styles P, Cramer JA, et al. Phase I trial of the selective mitochondrial toxin MKT077 in chemo-resistant solid tumours. Ann Oncol : Off J Eur Soc Med Oncol. 1999;10:923–7.

    Article  CAS  Google Scholar 

  56. Britten CD, Rowinsky EK, Baker SD, Weiss GR, Smith L, Stephenson J, et al. A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077. Clin Cancer Res. 2000;6:42–9.

    CAS  PubMed  Google Scholar 

  57. Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the Hallmarks of Cancer. Cancer cell. 2018;34:21–43.

    Article  CAS  PubMed  Google Scholar 

  58. Liu H, Zhao D, Li H, Zhang W, Lin Q, Wang X, et al. Blocking iASPP/Nrf2/M-CSF axis improves anti-cancer effect of chemotherapy-induced senescence by attenuating M2 polarization. Cell death Dis. 2022;13:166.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Anandhan A, Dodson M, Shakya A, Chen J, Liu P, Wei Y, et al. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Sci Adv. 2023;9:eade9585.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Suzuki T, Yamamoto M. Molecular basis of the Keap1-Nrf2 system. Free Radic Biol Med. 2015;88:93–100.

  61. Lignitto L, LeBoeuf SE, Homer H, Jiang S, Askenazi M, Karakousi TR, et al. Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1. Cell. 2019;178:316–29.e318.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Wieckowski MR, Giorgi C, Lebiedzinska M, Duszynski J, Pinton P. Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat Protoc. 2009;4:1582–90.

    Article  CAS  PubMed  Google Scholar 

  63. Zheng S, Wang X, Liu H, Zhao D, Lin Q, Jiang Q, et al. iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers. Cell Death Differ. 2023;30:327–40.

    Article  CAS  PubMed  Google Scholar 

  64. Afshar N, Black BE, Paschal BM. Retrotranslocation of the chaperone calreticulin from the endoplasmic reticulum lumen to the cytosol. Mol Cell Biol. 2005;25:8844–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72.

    Article  CAS  PubMed  Google Scholar 

  66. Zhao W, Zhao S, Li L, Huang X, Xing S, Zhang Y, et al. Sparse deconvolution improves the resolution of live-cell super-resolution fluorescence microscopy. Nat Biotechnol. 2022;40:606–17.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work was funded by National Nature Science Foundation (No. 82025027, 82150115, 32000517 and 82303023), the National Key R & D Program of China (2022YFA1105200), China Postdoctoral Science Foundation (No. 2022TQ0093, 2020M680045, 2021T140161 and 2023M730871), the Nature Science Foundation of Heilongjiang Province (No. LH2023C070 and YQ2021C024), the Postdoc Foundation of Heilongjiang Province (No. LBH-Z22176), and the Open fund for Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases (No. NCD-2023-1-04), Henan Province science and technology research and development plan joint fund (NO. 225200810019).

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  1. These authors contributed equally: Hao Liu, Shanliang Zheng.

Authors and Affiliations

  1. School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China

    Hao Liu, Shanliang Zheng, Junren Dai, Yanan Zhao, Fan Yang, Zhiyuan Xiang, Wenxin Zhang, Xingwen Wang, Yafan Gong, Ning Zhang & Ying Hu

  2. Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou, Henan Province, 450000, China

    Hao Liu, Zhiyuan Xiang, Wenxin Zhang, Yafan Gong & Ying Hu

  3. BGI-SHENZHEN, Shenzhen, Guangdong Province, 518083, China

    Guixue Hou

  4. The third affiliated hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150040, China

    Li Li

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Contributions

YH designed the experiments and wrote the paper. HL, SZ, GH, JR, YZ, FY, ZX, WZ, XW, YG, and NZ performed the experiments and analyzed the data. LL collected human colon cancer specimens.

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Correspondence to Ying Hu.

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The study for human colon cancer samples has been approved by the Research Ethics Committee of Harbin Medical University, China. All animal procedures were performed according to protocols approved by the Rules for Animal Experiments published by the Chinese Government (Beijing, China) and approved by the Research Ethics Committee of Harbin Institute of Technology, China.

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Liu, H., Zheng, S., Hou, G. et al. AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis. Cell Death Differ 32, 488–505 (2025). https://doi.org/10.1038/s41418-024-01414-2

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