{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T07:50:28Z","timestamp":1794037828131,"version":"4.8.0"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sig Transduct Target Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Metabolic syndrome, characterized by metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM), poses a significant threat to patients\u2019 health worldwide; however, efficient treatment is currently unavailable. Here, we show that oral administration of sodium nitrate (NaNO\n                    <jats:sub>3<\/jats:sub>\n                    ) greatly attenuates the development and advancement of MASLD-like and T2DM-like phenotypes in mice induced by choline-deficient high-fat, western, or methionine\/choline-deficient diet. NaNO\n                    <jats:sub>3<\/jats:sub>\n                    attenuates metabolic turbulence by rebalancing CD206\n                    <jats:sup>+<\/jats:sup>\n                    \/CD11C\n                    <jats:sup>+<\/jats:sup>\n                    polarization (anti-inflammatory\/pro-inflammatory) and the function of bone marrow-derived macrophages (MoMFs). Using metabolic disorder animal models and bone marrow-reconstituted mice with mutated gene function in\n                    <jats:italic>Slc17a5<\/jats:italic>\n                    , which encodes sialin, we demonstrate that NaNO\n                    <jats:sub>3<\/jats:sub>\n                    protects against metabolic disorders through the actions of sialin in MoMFs. NaNO\n                    <jats:sub>3<\/jats:sub>\n                    can directly regulate MoMFs polarization and function in vitro and in mice, in which nitric oxide production from oral and enteral symbiotic bacteria is essentially abolished. At the molecular level, sialin, via the inhibition of the key transcription factor Rel, inhibits cathepsin L (CtsL) expression and thereby activates the Nrf2 pathway to modulate macrophage homeostasis and ameliorate metabolic abnormalities. Interestingly, the sialin-CtsL-Nrf2 pathway is downregulated in human macrophages from metabolic dysfunction-associated steatohepatitis (MASH) patients. Overall, we demonstrate the prophylactic and therapeutic effects of NaNO\n                    <jats:sub>3<\/jats:sub>\n                    on metabolic syndrome and reveal a new macrophage rebalancing strategy involving NaNO\n                    <jats:sub>3<\/jats:sub>\n                    through a novel sialin pathway. Our research indicates that NaNO\n                    <jats:sub>3<\/jats:sub>\n                    may be a pharmaceutical agent for managing and alleviating metabolic turbulence in humans.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02418-1","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T23:04:32Z","timestamp":1759359872000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sodium nitrate protects against metabolic syndrome by sialin-mediated macrophage rebalance"],"prefix":"10.1038","volume":"10","author":[{"given":"Shaorong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaning","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haozhe","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyue","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4718-6821","authenticated-orcid":false,"given":"Zhongtao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7122-6547","authenticated-orcid":false,"given":"Renhong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3274-5889","authenticated-orcid":false,"given":"Mo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4269-2450","authenticated-orcid":false,"given":"Guozhi","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3404-5173","authenticated-orcid":false,"given":"Dong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7066-2654","authenticated-orcid":false,"given":"Songlin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"2418_CR1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","volume":"15","author":"Z Younossi","year":"2018","unstructured":"Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11\u201320 (2018).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2418_CR2","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.1016\/S0140-6736(20)32511-3","volume":"397","author":"EE Powell","year":"2021","unstructured":"Powell, E. E., Wong, V. W. & Rinella, M. Non-alcoholic fatty liver disease. Lancet 397, 2212\u20132224 (2021).","journal-title":"Lancet"},{"key":"2418_CR3","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","volume":"79","author":"ME Rinella","year":"2023","unstructured":"Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 79, 1542\u20131556 (2023).","journal-title":"J. Hepatol."},{"key":"2418_CR4","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/s41575-020-00381-6","volume":"18","author":"DQ Huang","year":"2021","unstructured":"Huang, D. Q., El-Serag, H. B. & Loomba, R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 18, 223\u2013238 (2021).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2418_CR5","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/nri.2017.11","volume":"17","author":"O Krenkel","year":"2017","unstructured":"Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306\u2013321 (2017).","journal-title":"Nat. Rev. Immunol."},{"key":"2418_CR6","doi-asserted-by":"publisher","first-page":"4259","DOI":"10.1016\/j.cell.2022.10.007","volume":"185","author":"MD Park","year":"2022","unstructured":"Park, M. D., Silvin, A., Ginhoux, F. & Merad, M. Macrophages in health and disease. Cell 185, 4259\u20134279 (2022).","journal-title":"Cell"},{"key":"2418_CR7","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/s41575-018-0082-x","volume":"16","author":"K Kazankov","year":"2019","unstructured":"Kazankov, K. et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat. Rev. Gastroenterol. Hepatol. 16, 145\u2013159 (2019).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2418_CR8","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1002\/hep.30506","volume":"70","author":"J Cai","year":"2019","unstructured":"Cai, J., Zhang, X. J. & Li, H. The role of innate immune cells in nonalcoholic steatohepatitis. Hepatology 70, 1026\u20131037 (2019).","journal-title":"Hepatology"},{"key":"2418_CR9","doi-asserted-by":"publisher","first-page":"9872","DOI":"10.3390\/nu7125505","volume":"7","author":"P Song","year":"2015","unstructured":"Song, P., Wu, L. & Guan, W. Dietary nitrates, nitrites, and nitrosamines intake and the risk of gastric cancer: a meta-analysis. Nutrients 7, 9872\u20139895 (2015).","journal-title":"Nutrients"},{"key":"2418_CR10","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.niox.2015.04.006","volume":"48","author":"PE James","year":"2015","unstructured":"James, P. E., Willis, G. R., Allen, J. D., Winyard, P. G. & Jones, A. M. Nitrate pharmacokinetics: taking note of the difference. Nitric Oxide 48, 44\u201350 (2015).","journal-title":"Nitric Oxide"},{"key":"2418_CR11","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/nrd2466","volume":"7","author":"JO Lundberg","year":"2008","unstructured":"Lundberg, J. O., Weitzberg, E. & Gladwin, M. T. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug Discov. 7, 156\u2013167 (2008).","journal-title":"Nat. Rev. Drug Discov."},{"key":"2418_CR12","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1111\/bph.14484","volume":"176","author":"AW DeMartino","year":"2019","unstructured":"DeMartino, A. W., Kim-Shapiro, D. B., Patel, R. P. & Gladwin, M. T. Nitrite and nitrate chemical biology and signalling. Br. J. Pharmacol. 176, 228\u2013245 (2019).","journal-title":"Br. J. Pharmacol."},{"key":"2418_CR13","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1016\/j.scib.2023.03.043","volume":"68","author":"W Pan","year":"2023","unstructured":"Pan, W. et al. Nanonitrator: novel enhancer of inorganic nitrate\u2019s protective effects, predicated on swarm learning approach. Sci. Bull. 68, 838\u2013850 (2023).","journal-title":"Sci. Bull."},{"key":"2418_CR14","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.freeradbiomed.2012.12.015","volume":"57","author":"L Jin","year":"2013","unstructured":"Jin, L. et al. Active secretion and protective effect of salivary nitrate against stress in human volunteers and rats. Free Radic. Biol. Med. 57, 61\u201367 (2013).","journal-title":"Free Radic. Biol. Med."},{"key":"2418_CR15","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.634115","volume":"12","author":"S Li","year":"2021","unstructured":"Li, S. et al. Dietary inorganic nitrate protects hepatic ischemia-reperfusion injury through NRF2-mediated antioxidative stress. Front. Pharmacol. 12, 634115 (2021).","journal-title":"Front. Pharmacol."},{"key":"2418_CR16","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1007\/s11427-017-9207-x","volume":"61","author":"H Wang","year":"2018","unstructured":"Wang, H. et al. Inorganic nitrate alleviates the senescence-related decline in liver function. Sci. China Life Sci. 61, 24\u201334 (2018).","journal-title":"Sci. China Life Sci."},{"key":"2418_CR17","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1073\/pnas.1809406115","volume":"116","author":"I Cordero-Herrera","year":"2019","unstructured":"Cordero-Herrera, I. et al. AMP-activated protein kinase activation and NADPH oxidase inhibition by inorganic nitrate and nitrite prevent liver steatosis. Proc. Natl. Acad. Sci. USA 116, 217\u2013226 (2019).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2418_CR18","doi-asserted-by":"publisher","first-page":"13434","DOI":"10.1073\/pnas.1116633109","volume":"109","author":"L Qin","year":"2012","unstructured":"Qin, L. et al. Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane. Proc. Natl. Acad. Sci. USA 109, 13434\u201313439 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2418_CR19","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/70585","volume":"23","author":"FW Verheijen","year":"1999","unstructured":"Verheijen, F. W. et al. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat. Genet. 23, 462\u2013465 (1999).","journal-title":"Nat. Genet."},{"key":"2418_CR20","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.1016\/j.immuni.2024.08.016","volume":"57","author":"W Guo","year":"2024","unstructured":"Guo, W. et al. Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease. Immunity 57, 2310\u20132327 e2316 (2024).","journal-title":"Immunity"},{"key":"2418_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41351-1","volume":"14","author":"Q Li","year":"2023","unstructured":"Li, Q. et al. Deficiency of endothelial sirtuin1 in mice stimulates skeletal muscle insulin sensitivity by modifying the secretome. Nat. Commun. 14, 5595 (2023).","journal-title":"Nat. Commun."},{"key":"2418_CR22","doi-asserted-by":"publisher","first-page":"3695","DOI":"10.1096\/fj.201700034R","volume":"31","author":"J Shi","year":"2017","unstructured":"Shi, J. et al. Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model. FASEB J. 31, 3695\u20133709 (2017).","journal-title":"FASEB J."},{"key":"2418_CR23","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.add3949","volume":"15","author":"S Wang","year":"2023","unstructured":"Wang, S. et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci. Transl. Med. 15, eadd3949 (2023).","journal-title":"Sci. Transl. Med."},{"key":"2418_CR24","doi-asserted-by":"publisher","first-page":"15355","DOI":"10.1523\/JNEUROSCI.3005-09.2009","volume":"29","author":"LM Prolo","year":"2009","unstructured":"Prolo, L. M., Vogel, H. & Reimer, R. J. The lysosomal sialic acid transporter sialin is required for normal CNS myelination. J. Neurosci. 29, 15355\u201315365 (2009).","journal-title":"J. Neurosci."},{"key":"2418_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10748-2","volume":"10","author":"Y Wu","year":"2019","unstructured":"Wu, Y. et al. Generating viable mice with heritable embryonically lethal mutations using the CRISPR-Cas9 system in two-cell embryos. Nat. Commun. 10, 2883 (2019).","journal-title":"Nat. Commun."},{"key":"2418_CR26","doi-asserted-by":"publisher","first-page":"698","DOI":"10.3390\/molecules25030698","volume":"25","author":"D Dana","year":"2020","unstructured":"Dana, D. & Pathak, S. K. A review of small molecule inhibitors and functional probes of human cathepsin L. Molecules 25, 698 (2020).","journal-title":"Molecules"},{"key":"2418_CR27","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.lfs.2019.02.040","volume":"221","author":"T Sato","year":"2019","unstructured":"Sato, T. et al. Cathepsin L-deficiency enhances liver regeneration after partial hepatectomy. Life Sci. 221, 293\u2013300 (2019).","journal-title":"Life Sci."},{"key":"2418_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11624","volume":"7","author":"EH Kobayashi","year":"2016","unstructured":"Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016).","journal-title":"Nat. Commun."},{"key":"2418_CR29","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/cod.14073","volume":"87","author":"R Vallion","year":"2022","unstructured":"Vallion, R. & Kerdine-Romer, S. Regulation of the immune response to contact sensitizers by Nrf2. Contact Dermat. 87, 13\u201319 (2022).","journal-title":"Contact Dermat."},{"key":"2418_CR30","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1177\/1947601911421925","volume":"2","author":"TD Gilmore","year":"2011","unstructured":"Gilmore, T. D. & Gerondakis, S. The c-Rel transcription factor in development and disease. Genes Cancer 2, 695\u2013711 (2011).","journal-title":"Genes Cancer"},{"key":"2418_CR31","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1038\/s42255-020-00306-2","volume":"2","author":"J Leslie","year":"2020","unstructured":"Leslie, J. et al. c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis. Nat. Metab. 2, 1350\u20131367 (2020).","journal-title":"Nat. Metab."},{"key":"2418_CR32","doi-asserted-by":"publisher","first-page":"7131","DOI":"10.1128\/jvi.68.11.7131-7138.1994","volume":"68","author":"S Sif","year":"1994","unstructured":"Sif, S. & Gilmore, T. D. Interaction of the v-Rel oncoprotein with cellular transcription factor Sp1. J. Virol. 68, 7131\u20137138 (1994).","journal-title":"J. Virol."},{"key":"2418_CR33","doi-asserted-by":"publisher","first-page":"19188","DOI":"10.1074\/jbc.M602059200","volume":"281","author":"J Liu","year":"2006","unstructured":"Liu, J. & Ma, X. Interferon regulatory factor 8 regulates RANTES gene transcription in cooperation with interferon regulatory factor-1, NF-kappaB, and PU.1. J. Biol. Chem. 281, 19188\u201319195 (2006).","journal-title":"J. Biol. Chem."},{"key":"2418_CR34","doi-asserted-by":"publisher","first-page":"2933","DOI":"10.1016\/j.molimm.2007.01.015","volume":"44","author":"H Cha-Molstad","year":"2007","unstructured":"Cha-Molstad, H., Young, D. P., Kushner, I. & Samols, D. The interaction of C-Rel with C\/EBPbeta enhances C\/EBPbeta binding to the C-reactive protein gene promoter. Mol. Immunol. 44, 2933\u20132942 (2007).","journal-title":"Mol. Immunol."},{"key":"2418_CR35","doi-asserted-by":"publisher","first-page":"e18670","DOI":"10.1371\/journal.pone.0018670","volume":"6","author":"L Loizou","year":"2011","unstructured":"Loizou, L., Andersen, K. G. & Betz, A. G. Foxp3 interacts with c-Rel to mediate NF-kappaB repression. PLoS One 6, e18670 (2011).","journal-title":"PLoS One"},{"key":"2418_CR36","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adc9653","volume":"15","author":"Y Xiao","year":"2023","unstructured":"Xiao, Y. et al. Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Sci. Transl. Med. 15, eadc9653 (2023).","journal-title":"Sci. Transl. Med."},{"key":"2418_CR37","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1136\/gutjnl-2019-318382","volume":"69","author":"O Krenkel","year":"2020","unstructured":"Krenkel, O. et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut 69, 551\u2013563 (2020).","journal-title":"Gut"},{"key":"2418_CR38","doi-asserted-by":"publisher","first-page":"E69","DOI":"10.1152\/ajpendo.00256.2024","volume":"328","author":"AP Sowton","year":"2025","unstructured":"Sowton, A. P. et al. Chronic inorganic nitrate supplementation does not improve metabolic health and worsens disease progression in mice with diet-induced obesity. Am. J. Physiol. Endocrinol. Metab. 328, E69\u2013E91 (2025).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2418_CR39","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/s00125-019-05040-3","volume":"63","author":"B Tramunt","year":"2020","unstructured":"Tramunt, B. et al. Sex differences in metabolic regulation and diabetes susceptibility. Diabetologia 63, 453\u2013461 (2020).","journal-title":"Diabetologia"},{"key":"2418_CR40","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/nature24265","volume":"550","author":"T Tukiainen","year":"2017","unstructured":"Tukiainen, T. et al. Landscape of X chromosome inactivation across human tissues. Nature 550, 244\u2013248 (2017).","journal-title":"Nature"},{"key":"2418_CR41","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/2042-6410-3-13","volume":"3","author":"K Karastergiou","year":"2012","unstructured":"Karastergiou, K., Smith, S. R., Greenberg, A. S. & Fried, S. K. Sex differences in human adipose tissues - the biology of pear shape. Biol. Sex. Differ. 3, 13 (2012).","journal-title":"Biol. Sex. Differ."},{"key":"2418_CR42","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.genm.2009.02.002","volume":"6","author":"EB Geer","year":"2009","unstructured":"Geer, E. B. & Shen, W. Gender differences in insulin resistance, body composition, and energy balance. Gend. Med. 6, 60\u201375 (2009).","journal-title":"Gend. Med."},{"key":"2418_CR43","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13293-015-0033-y","volume":"6","author":"F Mauvais-Jarvis","year":"2015","unstructured":"Mauvais-Jarvis, F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol. Sex. Differ. 6, 14 (2015).","journal-title":"Biol. Sex. Differ."},{"key":"2418_CR44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.138270","volume":"286","author":"JZ Gong","year":"2025","unstructured":"Gong, J. Z. et al. Cathepsin L of Fasciola hepatica meliorates colitis by altering the gut microbiome and inflammatory macrophages. Int. J. Biol. Macromol. 286, 138270 (2025).","journal-title":"Int. J. Biol. Macromol."},{"key":"2418_CR45","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1186\/s13071-023-06051-1","volume":"16","author":"RD Liu","year":"2023","unstructured":"Liu, R. D. et al. Trichinella spiralis cathepsin L induces macrophage M1 polarization via the NF-kappaB pathway and enhances the ADCC killing of newborn larvae. Parasit. Vectors 16, 433 (2023).","journal-title":"Parasit. Vectors"},{"key":"2418_CR46","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e29273","volume":"10","author":"Z Zhang","year":"2024","unstructured":"Zhang, Z., Wang, J., Shi, Y., Wang, B. & Wang, D. Cathepsin L promotes oesophageal squamous cell carcinoma development and may be associated with tumour-associated macrophages. Heliyon 10, e29273 (2024).","journal-title":"Heliyon"},{"key":"2418_CR47","doi-asserted-by":"publisher","first-page":"9926","DOI":"10.1073\/pnas.91.21.9926","volume":"91","author":"P Moi","year":"1994","unstructured":"Moi, P., Chan, K., Asunis, I., Cao, A. & Kan, Y. W. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2\/AP1 repeat of the beta-globin locus control region. Proc. Natl. Acad. Sci. USA 91, 9926\u20139930 (1994).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2418_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08680-6","volume":"10","author":"P Wang","year":"2019","unstructured":"Wang, P. et al. Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis. Nat. Commun. 10, 755 (2019).","journal-title":"Nat. Commun."},{"key":"2418_CR49","doi-asserted-by":"publisher","first-page":"967193","DOI":"10.3389\/fimmu.2022.967193","volume":"13","author":"L Wang","year":"2022","unstructured":"Wang, L. & He, C. Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front. Immunol. 13, 967193 (2022).","journal-title":"Front. Immunol."},{"key":"2418_CR50","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/S0140-6736(08)61246-5","volume":"373","author":"A Garber","year":"2009","unstructured":"Garber, A. et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 373, 473\u2013481 (2009).","journal-title":"Lancet"},{"key":"2418_CR51","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1177\/0022034516673019","volume":"95","author":"XM Qu","year":"2016","unstructured":"Qu, X. M. et al. From nitrate to nitric oxide: the role of salivary glands and oral bacteria. J. Dent. Res. 95, 1452\u20131456 (2016).","journal-title":"J. Dent. Res."},{"key":"2418_CR52","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","volume":"630","author":"J Abramson","year":"2024","unstructured":"Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493\u2013500 (2024).","journal-title":"Nature"},{"key":"2418_CR53","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1093\/bioinformatics\/btu097","volume":"30","author":"BG Pierce","year":"2014","unstructured":"Pierce, B. G. et al. ZDOCK server: interactive docking prediction of protein-protein complexes and symmetric multimers. Bioinformatics 30, 1771\u20131773 (2014).","journal-title":"Bioinformatics"},{"key":"2418_CR54","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1002\/pro.3235","volume":"27","author":"TD Goddard","year":"2018","unstructured":"Goddard, T. D. et al. UCSF ChimeraX: meeting modern challenges in visualization and analysis. Protein Sci. 27, 14\u201325 (2018).","journal-title":"Protein Sci."},{"key":"2418_CR55","doi-asserted-by":"publisher","first-page":"3786","DOI":"10.1016\/j.celrep.2018.12.006","volume":"25","author":"G Sun","year":"2018","unstructured":"Sun, G. et al. OX40 regulates both innate and adaptive immunity and promotes nonalcoholic steatohepatitis. Cell Rep. 25, 3786\u20133799 e3784 (2018).","journal-title":"Cell Rep."},{"key":"2418_CR56","doi-asserted-by":"publisher","first-page":"e0570","DOI":"10.1097\/HC9.0000000000000570","volume":"8","author":"KG Jackson","year":"2024","unstructured":"Jackson, K. G. et al. Sphingosine kinase 2 (SphK2) depletion alters redox metabolism and enhances inflammation in a diet-induced MASH mouse model. Hepatol. Commun. 8, e0570 (2024).","journal-title":"Hepatol. Commun."}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02418-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02418-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02418-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T23:04:34Z","timestamp":1759359874000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02418-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,2]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2418"],"URL":"https:\/\/doi.org\/10.1038\/s41392-025-02418-1","relation":{},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,2]]},"assertion":[{"value":"7 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 October 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"323"}}