Pathological transcriptional retention of Cyp26b1 in perirenal adipose-derived stem cells contributes to MASLD...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder linked to metabolic syndrome, but its extrahepatic drivers and persistence mechanisms remain unclear.

Transcriptomics was performed on adipose-derived stem cells (ADSCs) from distinct adipose depots in dynamic MASLD mouse models. A dietary reversal model was used to assess transcriptional retention. Candidate genes were identified via integrated DNA methylome and transcriptome analysis. Cyp26b1 function was tested by perirenal ADSCs-specific knockdown, and involved downstream mechanisms were investigated.

Perirenal ADSCs exhibited an early dysregulated transcriptional signature in MASLD and retained high transcriptional retention after reversal. Multi-omics identified Cyp26b1 as a persistent, epigenetically regulated driver. Knockdown of Cyp26b1 in perirenal ADSCs attenuated MASLD progression, potentially by modulating the CCL3-CCR5 axis to alleviate hepatic steatosis and inflammation.

This study reveals an ADSC-mediated perirenal adipose-liver axis and establishes pathological "memory" in ADSCs as a perpetuating factor in MASLD. Transcriptional retention in perirenal ADSCs and its key regulator Cyp26b1 represent potential theoretical targets for exploring the mechanism and intervention of cellular "memory" in MASLD.