ArticleJCI insight2025
PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes.
Article in JCI insight, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Metabolic dysfunction-associated steatotic liver disease: pathogenic mechanisms and exercise-induced molecular adaptations.Lipids in health and disease · 2026Review
- Gut-Liver Translocation of Bacteroides Uniformis Alleviates Advanced Metabolic Dysfunction-Associated Steatotic Liver Disease by Suppressing Hepatocyte Ferroptosis via Propionic Acid Secretion.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Hepatocyte hedgehog signaling controls ferroptosis to alleviate aging-related organ dysfunction.JCI insight · 2026Article
- Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review).Molecular medicine reports · 2026Review
- Fibrosis and Perinatal Features Correlated with Telomere Shortening in Pediatric Metabolic Dysfunction-Associated Steatotic Liver Disease.Life (Basel, Switzerland) · 2026Article
- Hepatocyte Models for Metabolic Dysfunction-Associated Steatotic Liver Disease: A Comparative Analysis of Non-HepG2 Cell Models.International journal of molecular sciences · 2026Review
- Incretin and Glucagon Signalling in MASLD and MASH: Integrating Metabolic Pathways With Disease Progression.Diabetes, obesity & metabolism · 2026Review
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Authors and funding
38 authors.
Funding
Abstract
Genetic variants in lipid metabolism influence the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and end-stage liver disease (ESLD). The mechanisms by which these variants drive disease are poorly understood. Because of the PNPLA3-I148M variant's strong correlation with all stages of the MASLD spectrum and the lack of tractable therapeutic targets, we sought to understand its impact on cellular function and liver metabolism. Primary human hepatocytes (HAHs) and induced pluripotent stem cell-derived (iPSC-derived) hepatocytes (iHeps) from healthy individuals possessing the PNPLA3-I148M mutation were characterized for changes in lipid metabolism, cellular stress, and survival. Using lipidomics, metabolomics, stable isotope tracing, and flux propensity analysis, we created a comprehensive metabolic profile of the changes associated with the PNPLA3-I148M variant. Functional analysis showed that the presence of the PNPLA3-I148M variant increased endoplasmic reticulum stress, mitochondrial dysfunction, and peroxisomal β-oxidation, ultimately leading to cell death via ferroptosis. Nutritional interventions, ferroptosis-specific inhibitors, and genetic approaches modulating GPX4 activity in PNPLA3-I148M HAHs and iHeps decreased programmed cell death. Our findings indicate that therapies targeting ferroptosis in patients carrying the PNPLA3-I148M variant could affect the development of MASLD and ESLD and highlight the utility of iPSC-based models for the study of genetic contributions to hepatic disorders.
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