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This population-based study aims to investigate the association of the novel inflammation-lipid composite biomarker high-sensitivity C-reactive protein-to-HDL cholesterol ratio (CHR) with gallstones and evaluate whether MAFLD mediates this relationship.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>This cross-sectional analysis utilized data from the National Health and Nutrition Examination Survey (NHANES, 2021\u20132023) to assess the correlation between the CHR and gallstone prevalence through weighted logistic regression. To evaluate potential nonlinear relationships and assess heterogeneity across key demographics, restricted cubic splines (RCS) were employed to model the association, complemented by subgroup analyses stratified by age, sex, and other covariates. A mediation analysis was used for elucidating the mediating effects of MAFLD.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Among 4,078 participants, 432 (10.60%) had gallstones. After adjusting for confounders, each unit increase in CHR was associated with a 165% increased risk of gallstones (OR: 2.65, 95% CI: 1.43\u20134.93, <jats:italic>P<\/jats:italic>\u2009=\u20090.006). The RCS curve demonstrated a nonlinear association between the CHR and gallstones (<jats:italic>P<\/jats:italic>\n              <jats:sub>overall<\/jats:sub> &lt; 0.001, <jats:italic>P<\/jats:italic>\n              <jats:sub>nonlinear<\/jats:sub> &lt; 0.001). Mediation analysis indicated that MAFLD explained 27.1% of this association.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>CHR is positively associated with gallstones, with MAFLD partially mediating this relationship. Managing CHR levels and preventing MAFLD may reduce gallstone incidence.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12876-025-03805-2","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T15:18:08Z","timestamp":1744903088000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MAFLD mediates the association between CHR and gallstones in the U.S. adults: evidence from NHANES 2021\u20132023"],"prefix":"10.1186","volume":"25","author":[{"given":"Xin","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi\u2019an","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuxiang","family":"Luan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyu","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huahu","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shishi","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"3805_CR1","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s13017-020-00336-x","volume":"15","author":"M Pisano","year":"2020","unstructured":"Pisano M, Allievi N, Gurusamy K, Borzellino G, Cimbanassi S, Boerna D, et al. 2020 World Society of Emergency Surgery updated guidelines for the diagnosis and treatment of acute calculus cholecystitis. 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