Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis

Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis Juan Cubillos-Ruiz, Deepika Awasthi, Erin McMinn, Camilla Salvagno, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7983397/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Dendritic cells (DCs) orchestrate adaptive immune responses to pathogens and tumors, yet how dietary lipids influence DC metabolism and function remains largely unexplored. Here we show that dietary polyunsaturated fatty acids (PUFAs) govern DC activity via Nuclear factor erythroid 2–like 2 (Nrf2)–dependent control of ferroptosis. In mice, an n-6 PUFA–enriched diet suppressed DC Nrf2 signaling, depleted glutathione, and induced lipid peroxidation and ferroptosis, thereby compromising antigen presentation. By contrast, dietary n-3 PUFAs enhanced Nrf2 signaling and redox homeostasis, preserving DC integrity and T cell priming. Pharmacologic Nrf2 activation or ferroptosis inhibition restored the function of DCs from n-6 PUFA–fed mice. Notably, adoptive immunotherapy with DCs conditioned by a diet rich in n-3 PUFAs—but not n-6 PUFAs—elicited durable, T cell–dependent control of metastatic ovarian cancer. These findings identify dietary PUFAs as key modulators of the Nrf2–glutathione–ferroptosis axis in DCs and reveal a redox-sensitive metabolic checkpoint that can be leveraged to improve cancer immunotherapy. Biological sciences/Immunology/Antigen processing and presentation/Antigen-presenting cells Biological sciences/Immunology/Tumour immunology Full Text Additional Declarations Yes there is potential Competing Interest. J.R.C.-R. holds patents on the use of immune modulators for ovarian cancer therapy. J.R.C.-R is a scientific consultant for Autoimmunity Biologic Solutions, Inc., and holds stock options in Vescor Therapeutics. Supplementary Files SuppTable1.docx Supplemental Table 1 SuppTable2.docx Supplemental Table 2 Suppltable3Fattyacidprofiles.xlsx Supplemental Table 3 SuppTable4DEGUpdown.xlsx Supplemental Table 4 SuppFigs.pdf Supplemental Figures 1-7 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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