{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T15:40:11Z","timestamp":1789400411816,"version":"build-2803163510"},"reference-count":67,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82374531"],"award-info":[{"award-number":["82374531"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shenzhen Basic Research Special Project (Natural Science Foundation) Basic Research General Project","award":["JCYJ20240813152313019"],"award-info":[{"award-number":["JCYJ20240813152313019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thyroid hormones profoundly modulate hepatic fatty acid and cholesterol synthesis and turnover. Although nonalcoholic fatty liver disease (NAFLD) shows epidemiological links to hypothyroidism, the genetic substrates of this relationship remain unresolved. Integrating large-scale genome-wide association studies with single-cell transcriptomics, spatial transcriptomics, and single-cell chromatin accessibility via state-of-the-art computational approaches, we interrogated the association between NAFLD and hypothyroidism across organ systems, cellular expression landscapes, and molecular\u2013genetic strata. We uncovered pronounced spatial specificity in genetic risk within the liver, prioritized hepatocytes as the principal shared cell type affected, and, leveraging spatial transcriptomics, advanced a dynamic spatiotemporal two-hit model. We further nominated MAGI3, RRNAD1, and PRCC as high-confidence candidate genes and pinpointed a key risk locus, rs926103. These findings deliver a dynamic, testable framework for the full pathophysiological continuum linking NAFLD and hypothyroidism and yield new targets and leads for precision intervention.<\/jats:p>","DOI":"10.3390\/ijms27041850","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T10:14:32Z","timestamp":1771236872000},"page":"1850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NAFLD and Hypothyroidism: Deciphering Pivotal Genetic Variants, Cellular Expression Landscapes, and Spatial Architectures"],"prefix":"10.3390","volume":"27","author":[{"given":"Ruiqi","family":"Zhao","sequence":"first","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Han","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minling","family":"Lv","sequence":"additional","affiliation":[{"name":"Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6371-3927","authenticated-orcid":false,"given":"Sen","family":"Lin","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8326-4170","authenticated-orcid":false,"given":"Ximing","family":"Wang","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialing","family":"Sun","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4758-0060","authenticated-orcid":false,"given":"Xiaozhou","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"},{"name":"Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/ana.26510","article-title":"Systemic Metabolic Alteration Dependent on the Thyroid-Liver Axis in Early PD","volume":"93","author":"Miyamoto","year":"2023","journal-title":"Ann. 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