{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:01:40Z","timestamp":1790053300837,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2025ZD0551806"],"award-info":[{"award-number":["2025ZD0551806"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270846"],"award-info":[{"award-number":["82270846"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82270846"],"award-info":[{"award-number":["82270846"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Sichuan Science and Technology Program","award":["2026YFHZ0379"],"award-info":[{"award-number":["2026YFHZ0379"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Cholesterol sulfate (CS) is a multifunctional signaling molecule implicated in diverse physiological and pathological processes. Its clinical translation as a biomarker is hindered by the lack of established reference intervals, unclear disease-specific alterations, and undefined relationships with routine laboratory parameters. This study aimed to establish a serum CS reference range for Chinese populations, evaluate its associations with various diseases and clinical laboratory parameters, and define its clinical diagnostic utility. Methods: A total of 642 subjects were enrolled, comprising 372 healthy controls and 270 patients with one of six diseases: Alzheimer\u2019s disease, osteoporosis, obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), or Crohn\u2019s disease. Serum CS concentrations were quantified using LC-MS\/MS. Reference intervals were established using non-parametric methods. Univariate analyses included Spearman\u2019s rank correlation, Mann\u2013Whitney U test, and receiver operating characteristic (ROC) curve analysis; multivariate analysis employed a gamma-family generalized linear model (GLM) with a log-link function, incorporating age, sex, clinical laboratory parameters, and disease status as covariates. The age-by-sex interaction was examined to assess synergistic effects. Incremental diagnostic value of CS was evaluated using the DeLong test and likelihood ratio test. Results: The serum CS reference interval for healthy individuals was 0.55\u20132.24 mg\/L (males: 0.60\u20132.25 mg\/L; females: 0.54\u20132.20 mg\/L), with a significant sex difference. The age-by-sex interaction effect was significant (two-way ANOVA interaction p = 0.005; GLM interaction \u03b2 = 0.102, p = 0.002). Stratified analysis revealed a significant positive correlation between age and CS in males, but no such association in females. In univariate analysis, CS correlated significantly with total cholesterol (TC), non-HDL-C, hemoglobin A1c (HbA1c), and other biomarkers; CS levels were elevated in Alzheimer\u2019s disease and reduced in Crohn\u2019s disease. In the multivariate GLM, only TC and male sex emerged as independent significant determinants of CS, whereas HbA1c and NAFLD showed borderline effects; no disease group retained independent significance. After adjustment for TC and sex, the residual area under the curves (AUCs) of CS for all diseases were close to 0.50, and DeLong\u2019s test indicated no incremental diagnostic value beyond the baseline model (all p &gt; 0.70). Conclusions: This study is the first to establish a serum CS reference range for the Chinese population. Serum CS levels are independently regulated by TC and sex, with a significant age-by-sex interaction. The associations between CS and disease status were largely mediated by confounding from lipid profiles and age. CS is not suitable as an independent disease biomarker but may serve as a supplementary indicator for assessing lipid metabolism\u2014particularly in male populations, where it may indirectly reflect age-related changes in cholesterol metabolism.<\/jats:p>","DOI":"10.3390\/diagnostics16182953","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:34:01Z","timestamp":1789378441000},"page":"2953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Establishment of Serum Cholesterol Sulfate Reference Intervals and Evaluation of Its Diagnostic and Metabolic Associations in Chinese Adults"],"prefix":"10.3390","volume":"16","author":[{"given":"Yin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Sichuan Clinical Research Center for Laboratory Medicine, and Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Xucong","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Sichuan Clinical Research Center for Laboratory Medicine, and Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Xiaoqian","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pain Management, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Hongmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of High-Altitude Medicine, Center for High Altitude Medicine, High Altitude Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Xinhua","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Sichuan Clinical Research Center for Laboratory Medicine, and Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8635-9310","authenticated-orcid":false,"given":"Zhiguang","family":"Su","sequence":"additional","affiliation":[{"name":"Institute of High-Altitude Medicine, Center for High Altitude Medicine, High Altitude Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1194\/jlr.R300005-JLR200","article-title":"Cholesterol sulfate in human physiology: What\u2019s it all about?","volume":"44","author":"Strott","year":"2003","journal-title":"J. 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