{"doi":"10.1101/2025.01.13.632567","title":"Predicting Metabolic Dysfunction Associated Steatotic Liver Disease Risk Using Patient-Derived Induced Pluripotent Stem Cells","abstract":"Background and Aims: Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is reversible at early stages, making early identification of high-risk individuals clinically valuable. Previously, we demonstrated that patient-derived induced pluripotent stem cells (iPSCs) harboring MASLD DNA risk variants exhibit greater oleate-induced intracellular lipid accumulation than those without these variants. This study aimed to develop an iPSC-based MASLD risk predictor using functional lipid accumulation assessments. Methods: We quantified oleate-induced intracellular lipid accumulation in iPSCs derived from three cohorts of diverse ancestry: 1) CIRM cohort (20 biopsy-confirmed MASH cases, 2 biopsy-confirmed MASLD cases, 17 controls), 2) POST cohort (18 MASLD cases, 17 controls), and 3) UCSF cohort (4 biopsy-confirmed MASH cases, 8 controls). Lipid accumulation levels in the CIRM cohort were used to define an iPSC-based MASLD risk score, which was used to predict case/control status in the POST and UCSF cohorts. Results: In all three cohorts, lipid accumulation was higher in MASLD/MASH cases vs. controls (CIRM cases vs. controls 3.32 ± 0.25 vs. 2.70 ± 0.19 -fold change, p=0.06; POST cases vs. controls 3.63 ± 0.33 vs. 2.70 ± 0.31, p=0.05; and UCSF cases vs. controls 4.39±0.46 vs. 2.03±0.20, p=0.0002). The iPSC-based MASLD risk score achieved a sensitivity of 44% and specificity of 75% in the POST cohort and 75% and 100%, respectively, in the UCSF cohort. Differences in cohort disease severity and cardiometabolic profiles may explain performance variability. Conclusion: While validation in larger cohorts is needed, these findings suggest that oleate-induced intracellular lipid accumulation in subject-derived iPSCs is predictive of MASH development. Additional cellular phenotypes and donor information should be explored to improve predictive accuracy to inform MASLD surveillance and prevention strategies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557078,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9669,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":717916,"name":"Parth D. Chhetri","orcid":"0000-0003-0248-2317","position":1,"is_corresponding":false},{"id":493032,"name":"Elizabeth Theusch","orcid":null,"position":2,"is_corresponding":false},{"id":294858,"name":"Grace Lim","orcid":"0000-0001-8013-0080","position":3,"is_corresponding":false},{"id":1445235,"name":"Sheila Teker","orcid":null,"position":4,"is_corresponding":false},{"id":952360,"name":"Yu‐Lin Kuang","orcid":"0000-0003-0560-7939","position":5,"is_corresponding":false},{"id":1456695,"name":"Shahrbanoo Keshavarz Azizi Raftar","orcid":"0000-0002-4492-6716","position":6,"is_corresponding":false},{"id":1444565,"name":"Mohammad Hossein Mehraban","orcid":"0000-0002-5512-0726","position":7,"is_corresponding":false},{"id":758297,"name":"Antonio Silvestre Muñoz","orcid":"0000-0002-2987-409X","position":8,"is_corresponding":false},{"id":1273113,"name":"Varun Saxena","orcid":"0000-0003-1278-3455","position":9,"is_corresponding":false},{"id":693934,"name":"Dounia Le Guillou","orcid":"0000-0002-1614-5381","position":10,"is_corresponding":false},{"id":271167,"name":"Aras N. Mattis","orcid":"0000-0002-5813-164X","position":11,"is_corresponding":false},{"id":478433,"name":"Jacquelyn J. Maher","orcid":"0000-0002-2509-8484","position":12,"is_corresponding":false},{"id":471244,"name":"Marisa W. Medina","orcid":"0000-0002-3631-0129","position":13,"is_corresponding":false},{"id":1396680,"name":"Yuanyuan Qin","orcid":"0000-0002-0673-3200","position":0,"is_corresponding":true}],"reference_count":23,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"39868283","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}