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However, assessment of genetic risk factors underlying this prevalence is complicated by a high co-occurrence of other metabolic disorders and variable endogenous and exogenous environmental risk factors. To map the transcriptomic architecture of MASLD hepatic steatosis risk, we conducted an epidemiological-scale investigation using human induced pluripotent stem cell (iPSC)-derived hepatocyte cultures from 193 participants in our longitudinal South Texas Family Study (STFS). iPSC-based models offer greater power to map genetic risk factors by experimentally controlling for confounding organismal and environmental factors. We combined transcriptome-wide gene expression analysis with high-content cellular measurements of neutral lipids to define a core hepatic steatosis MASLD phenotype at baseline (vehicle-treated) and following a lipid challenge. The additive genetic heritability of hepatic steatosis measures was 0.44 (p-value = 0.03) at baseline and 0.42 (p-value = 0.03) at post-lipid challenge. Multivariable linear regression comparing each gene\u2019s expression against hepatic steatosis measures identified 1070 genes at baseline and 1229 genes post-lipid challenge, whose expression showed a transcriptome-wide statistically significant association (standardized |\u03b2| \u2265 0.24; Bonferroni-corrected p-value \u2264 0.001) with baseline and post-lipid challenge hepatic steatosis measures, respectively. Functional annotation and pathway enrichment analyses of these genes implicated a broad range of hepatocellular functions, mapping an overall transcriptomic architecture of MASLD-associated steatosis risk in Mexican Americans. The genes whose expression was positively correlated with hepatic steatosis measures suggest a direct role of variation in fatty acid (FA) and cholesterol uptake, de novo lipogenesis (DNL), and carbohydrate shunts in hepatic steatosis risk, as well as a cellular stress-associated and high-turnover metabolic state marked by elevated FA-oxidation and ketogenesis. In contrast, the genes whose expression was inversely correlated with hepatic steatosis measures suggest a significant role of the cellular cytoskeleton, hepatocyte epithelial integrity, and endosomal and autophagic clearance machinery in steatosis risk.<\/jats:p>","DOI":"10.3390\/cells15171592","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:28:22Z","timestamp":1788280102000},"page":"1592","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Risk in Mexican Americans"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1969-4431","authenticated-orcid":false,"given":"Satish","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, 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Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, College of Sciences, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7640-3469","authenticated-orcid":false,"given":"Ana C.","family":"Leandro","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, College of Sciences, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Marcelo","family":"Leandro","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, College of Sciences, Brownsville, TX 78520, 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