{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:06:48Z","timestamp":1784700408944,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005725","name":"National Plan for Science, Technology and Innovation","doi-asserted-by":"publisher","award":["2023ZD0508500"],"award-info":[{"award-number":["2023ZD0508500"]}],"id":[{"id":"10.13039\/501100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005725","name":"National Plan for Science, Technology and Innovation","doi-asserted-by":"publisher","award":["2023ZD0508504"],"award-info":[{"award-number":["2023ZD0508504"]}],"id":[{"id":"10.13039\/501100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007128","name":"Natural Science Foundation of Shaanxi Province","doi-asserted-by":"publisher","award":["2023-JC-YB-742"],"award-info":[{"award-number":["2023-JC-YB-742"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007128","name":"Natural Science Foundation of Shaanxi Province","doi-asserted-by":"publisher","award":["2024JC-YBQN-0911"],"award-info":[{"award-number":["2024JC-YBQN-0911"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015401","name":"Key Research and Development Projects of Shaanxi Province","doi-asserted-by":"publisher","award":["2023-ZDLSF-40"],"award-info":[{"award-number":["2023-ZDLSF-40"]}],"id":[{"id":"10.13039\/501100015401","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007547","name":"Fourth Military Medical University","doi-asserted-by":"publisher","award":["2023LC2320"],"award-info":[{"award-number":["2023LC2320"]}],"id":[{"id":"10.13039\/501100007547","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007547","name":"Fourth Military Medical University","doi-asserted-by":"publisher","award":["2024LC2441"],"award-info":[{"award-number":["2024LC2441"]}],"id":[{"id":"10.13039\/501100007547","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Liver fibrosis is an important predictor of mortality in patients with type 2 diabetes mellitus (T2DM). Current clinical practice relies on total 25-hydroxyvitamin D, which does not distinguish between its two main circulating isoforms, 25(OH)D2 and 25(OH)D3, although these metabolites may differ in their associations with liver fibrosis and long-term prognosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed two independent T2DM cohorts: hospitalized Chinese patients with T2DM (\n                      <jats:italic>n<\/jats:italic>\n                      = 1,978) and US adults with T2DM from the National Health and Nutrition Examination Survey (NHANES) 2007\u20132018 (\n                      <jats:italic>n<\/jats:italic>\n                      = 4,616). Serum 25(OH)D2 and 25(OH)D3 were quantified by liquid chromatography\u2013tandem mass spectrometry (LC\u2013MS\/MS). Isoform-specific associations with advanced fibrosis, defined by the NAFLD Fibrosis Score (NFS) and Fibrosis-4 index (FIB-4), were examined using multivariable logistic regression and restricted cubic spline (RCS) analyses. In NHANES, multivariable Cox proportional-hazards models were used to evaluate all-cause, cardiovascular, and diabetes-related mortality according to vitamin D status.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In both cohorts, lower serum 25(OH)D3 was non-linearly associated with a higher risk of advanced liver fibrosis. By contrast, 25(OH)D2 showed no protective association; in NHANES, the highest tertile was associated with a higher risk of NFS-defined fibrosis (OR = 1.41,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.003). RCS analyses suggested cohort-specific apparent inflection regions for 25(OH)D3 at 11.88 ng\/mL in the Chinese cohort and 23.86 ng\/mL in NHANES; these exploratory estimates were not intended as clinical cut-offs. In longitudinal NHANES analyses, lower 25(OH)D3 was associated with higher cause-specific mortality among participants with advanced fibrosis; however, estimates within the FIB-4 high-risk stratum were based on sparse events and were therefore regarded as exploratory and interpreted with caution. Bioinformatic analysis implicated the AGE\u2013RAGE and PI3K\u2013Akt signaling pathways as candidate mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Lower serum 25(OH)D3, but not 25(OH)D2, was associated with advanced liver fibrosis in T2DM after multivariable adjustment. Among participants with advanced fibrosis, lower 25(OH)D3 was also associated with higher cardiovascular mortality, although cause-specific estimates based on sparse events were exploratory. These findings may support further investigation of isoform-specific 25(OH)D3 assessment for risk stratification in this population.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1820737","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:54:06Z","timestamp":1784699646000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Serum 25(OH)D3 and advanced liver fibrosis in type 2 diabetes: a Chinese hospital cohort with NHANES validation and mortality follow-up"],"prefix":"10.3389","volume":"13","author":[{"given":"Guohong","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaoqian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duolin","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meitong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaowei","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenghui","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Health Management, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"101372","DOI":"10.1016\/j.gendis.2024.101372","article-title":"Transcription factors, metabolic dysfunction-associated fatty liver disease, and therapeutic implications","volume":"12","author":"Hu","year":"2025","journal-title":"Genes Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2138","DOI":"10.1136\/gutjnl-2023-330110","article-title":"Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: an updated systematic review and meta-analysis","volume":"72","author":"En Li Cho","year":"2023","journal-title":"Gut."},{"key":"B4","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/s41575-021-00448-y","article-title":"The complex link between NAFLD and type 2 diabetes mellitus\u2014mechanisms and treatments","volume":"19","author":"Byrne","year":"2022","journal-title":"Nat Rev Gastroenterol Hepatol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1007\/s12072-023-10625-7","article-title":"The impact of an increased Fibrosis-4 index and the severity of hepatic steatosis on mortality in individuals living with diabetes","volume":"18","author":"Ma","year":"2024","journal-title":"Hepatol Int."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1111\/liv.14780","article-title":"Impact of liver fibrosis score on prognosis in patients with previous myocardial infarction: a prospective cohort study","volume":"41","author":"Cao","year":"2021","journal-title":"Liver Int."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2209","DOI":"10.1007\/s11739-023-03394-6","article-title":"Fibrosis-4 index is closely associated with clinical outcomes in acute cardioembolic stroke patients with nonvalvular atrial fibrillation","volume":"18","author":"Yang","year":"2023","journal-title":"Intern Emerg Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.cgh.2022.05.015","article-title":"Poor diagnostic efficacy of noninvasive tests for advanced fibrosis in obese or younger than 60 diabetic NAFLD patients","volume":"21","author":"Ito","year":"2023","journal-title":"Clinicl Gastroenterol Hepatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1152\/physrev.00014.2015","article-title":"Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects","volume":"96","author":"Christakos","year":"2016","journal-title":"Physiol Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"9016","DOI":"10.3390\/ijms23169016","article-title":"Role of vitamin D in liver disease and complications of advanced chronic liver disease","volume":"23","author":"Ravaioli","year":"2022","journal-title":"IJMS."},{"key":"B11","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/j.jceh.2019.03.001","article-title":"Impact of vitamin D status in chronic liver disease","volume":"9","author":"Khan","year":"2019","journal-title":"J Clin Exp Hepatol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1186\/s12967-023-04367-1","article-title":"Mitochondrial metabolic dysfunction and non-alcoholic fatty liver disease: new insights from pathogenic mechanisms to clinically targeted therapy","volume":"21","author":"Zheng","year":"2023","journal-title":"J Transl Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1093\/ajcn\/nqaa295","article-title":"Vitamin D in human serum and adipose tissue after supplementation","volume":"113","author":"Best","year":"2021","journal-title":"Am J Clin Nutr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"100133","DOI":"10.1016\/j.advnut.2023.09.016","article-title":"Comparison of the effect of daily vitamin D2 and vitamin D3 supplementation on serum 25-hydroxyvitamin D concentration (total 25(OH)D, 25(OH)D2, and 25(OH)D3) and importance of body mass index: a systematic review and meta-analysis","volume":"15","author":"van den Heuvel","year":"2024","journal-title":"Adv Nutr."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1002\/mas.21768","article-title":"Analysis of vitamin D metabolic markers by mass spectrometry: recent progress regarding the \u201cgold standard\u201d method and integration into clinical practice","volume":"42","author":"Alexandridou","year":"2023","journal-title":"Mass Spectrom Rev."},{"key":"B16","unstructured":"Hyattsville, MD\n          CDC\/NCHS\n          National Health and Nutrition Examination Survey (NHANES): Vitamin D Laboratory Methods, 2007\u20132018 Survey Cycles"},{"key":"B17","doi-asserted-by":"publisher","first-page":"D1328","DOI":"10.1093\/nar\/gkae883","article-title":"Comparative Toxicogenomics database's 20th anniversary: update 2025","volume":"53","author":"Davis","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"117737","DOI":"10.1016\/j.biopha.2024.117737","article-title":"An anti-RAGE chimeric antibody alleviates CCl4-induced liver fibrosis via RAGE\/NF-kB pathway in mice","volume":"181","author":"Liu","year":"2024","journal-title":"Biomed Pharmacother."},{"key":"B19","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.jhep.2023.11.005","article-title":"Redox-sensitive high-mobility group box-1 isoforms contribute to liver fibrosis progression and resolution in mice","volume":"80","author":"Ge","year":"2024","journal-title":"J Hepatol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"117263","DOI":"10.1016\/j.ejmech.2025.117263","article-title":"A comparative study on the antioxidant and antiglycation properties of different vitamin D forms","volume":"285","author":"Pawlukianiec","year":"2025","journal-title":"Eur J Med Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1186\/s13643-022-02129-6","article-title":"Assessment of the quality and content of clinical practice guidelines (CPGs) for vitamin D and for immigrants using the AGREE-II instrument: a protocol for systematic review","volume":"11","author":"Yousef","year":"2022","journal-title":"Syst Rev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"156058","DOI":"10.1016\/j.metabol.2024.156058","article-title":"1,25-Dihydroxyvitamin D3 protects against placental inflammation by suppressing NLRP3-mediated IL-1\u03b2 production via Nrf2 signalling pathway in preeclampsia","volume":"162","author":"Liu","year":"2025","journal-title":"Metabolism."},{"key":"B23","doi-asserted-by":"publisher","first-page":"20561","DOI":"10.1021\/acs.jmedchem.5c01753","article-title":"Design, synthesis, and evaluation of antifibrotic activity of nonsteroidal VDR agonists featuring 1,6-naphthol as a CD-ring surrogate","volume":"68","author":"Gao","year":"2025","journal-title":"J Med Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"102203","DOI":"10.1016\/j.redox.2021.102203","article-title":"1,25-dihydroxyvitamin D3 attenuates IL-1\u03b2 secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes","volume":"48","author":"Nakajo","year":"2021","journal-title":"Redox Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3390\/cells13030239","article-title":"Novel vitamin D3 hydroxymetabolites require involvement of the vitamin d receptor or retinoic acid-related orphan receptors for their antifibrogenic activities in human fibroblasts","volume":"13","author":"Janjetovic","year":"2024","journal-title":"Cells."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1002\/jcsm.12754","article-title":"Risk stratification using sarcopenia status among subjects with metabolic dysfunction\u2014associated fatty liver disease","volume":"12","author":"Chun","year":"2021","journal-title":"J Cachexia Sarcopenia Muscle."},{"key":"B27","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1007\/s11154-022-09736-7","article-title":"Vitamin D deficiency and cardiometabolic risk factors in adolescents: systematic review and meta-analysis","volume":"23","author":"Daniel","year":"2022","journal-title":"Rev Endocr Metab Disord."},{"key":"B28","doi-asserted-by":"publisher","first-page":"6682","DOI":"10.1039\/D0FO03230A","article-title":"Molecular mechanisms from insulin-mimetic effect of vitamin D: treatment alternative in Type 2 diabetes mellitus","volume":"12","author":"Torres Dominguez","year":"2021","journal-title":"Food Funct."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3602","DOI":"10.1080\/10408398.2021.1990850","article-title":"High prevalence of vitamin D deficiency in Asia: a systematic review and meta-analysis","volume":"63","author":"Jiang","year":"2023","journal-title":"Crit Rev Food Sci Nutr."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3436","DOI":"10.1016\/j.clnu.2020.11.019","article-title":"Differences and determinants of vitamin D deficiency among UK biobank participants: a cross-ethnic and socioeconomic study","volume":"40","author":"Sutherland","year":"2021","journal-title":"Clin Nutr."},{"key":"B31","doi-asserted-by":"publisher","first-page":"101654","DOI":"10.1016\/j.eclinm.2022.101654","article-title":"Association between vitamin D deficiency and the risk of prevalent type 2 diabetes and incident prediabetes: a prospective cohort study using data from the irish longitudinal study on ageing (TILDA)","volume":"53","author":"McCarthy","year":"2022","journal-title":"eClinicMed."},{"key":"B32","doi-asserted-by":"publisher","first-page":"117250","DOI":"10.1016\/j.ejmech.2025.117250","article-title":"Design, synthesis, and anti-liver fibrosis activity of novel non-steroidal vitamin D receptor agonists based on open-ring steroid scaffold","volume":"286","author":"Gao","year":"2025","journal-title":"Eur J Med Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"115596","DOI":"10.1016\/j.ejmech.2023.115596","article-title":"Design, synthesis and anti-hepatic fibrosis activity of novel diphenyl vitamin D receptor agonists","volume":"258","author":"Xing","year":"2023","journal-title":"Eur J Med Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1017\/S0029665123002185","article-title":"Vitamin D intake and status in Ireland: a narrative review","volume":"82","author":"Scully","year":"2023","journal-title":"Proc Nutr Soc."}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1820737\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:54:08Z","timestamp":1784699648000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1820737\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":34,"alternative-id":["10.3389\/fnut.2026.1820737"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2026.1820737","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]},"article-number":"1820737"}}