Human stem cell-derived hepatic cells recapitulate polygenic risk in MASLD development and highlight CD36 as a key mediator
Life Sciences, 2026
Gatzios A., Stinckens M., Verhoeven A., Rombaut M., De Win D., Heymans A., Loosen A., Van Goethem F., De Kock J., Rodrigues R., Boeckmans J., Vanhaecke T.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Metabolic Diseases Hepatology | Pathophysiology | Cell Culture Supernatant |  Olink Target 48 |
Abstract
Several genetic variants have been identified that impact outcomes in patients with metabolic dysfunction-associated steatohepatitis (MASH), but cellular platforms to identify molecular targets for treatment remain scarce. This study aims to employ a polygenic risk score for hepatic fat content (PRS-HFC) in a human-based in vitro model to identify potential druggable targets related to a genetic risk for MASH.
Ninety-two human skin-derived precursor (hSKP) cell lines were genotyped and classified according to their PRS-HFC. Per risk category, five cell lines were selected and differentiated to hepatic progenitor-like cells (hSKP-HPCs) before being exposed to MASH-related triggers or control medium. Lipid accumulation, fatty acid uptake, generation of oxidative stress, secretion of inflammatory mediators, and alterations of the transcriptome were assessed. Potential drug targets were modulated using siRNA.
hSKP-HPCs displayed a positive correlation between lipid accumulation and PRS-HFC, both in the control and ‘MASH’ condition. hSKP-HPCs with high PRS-HFC exhibited increased secretion of interleukin 6 and enhanced fatty acid uptake. Bulk RNA barcoding and sequencing revealed distinct gene expression profiles depending on genetic predisposition and predicted increased CD36-signalling as potential upstream regulator thereof. Silencing of CD36 effectively reduced lipid accumulation in cultures with high PRS-HFC and attenuated expression of genes related to de novo lipogenesis, lipolysis and inflammation.
hSKP-HPCs recapitulate the effect of the PRS-HFC on lipid accumulation and inflammation. CD36 appeared to at least partially mediate these effects, and its silencing further substantiated its role in conferring high genetic risk for MASH, highlighting CD36 as a potential therapeutic target for genetically-driven MASH.