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Background <p>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.</p> Methods <p>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&#xa0;assess transcriptional retention. Candidate genes were identified via integrated DNA methylome and transcriptome analysis. <i>Cyp26b1</i> function was tested by perirenal ADSCs-specific knockdown, and involved downstream mechanisms were investigated.</p> Results <p>Perirenal ADSCs exhibited an early dysregulated transcriptional signature in MASLD and retained high transcriptional retention after reversal. Multi-omics identified <i>Cyp26b1</i> as a persistent, epigenetically regulated driver. Knockdown of <i>Cyp26b1</i> in perirenal ADSCs attenuated MASLD progression, potentially by modulating the CCL3–CCR5 axis to alleviate hepatic steatosis and inflammation.</p> Conclusion <p>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 <i>Cyp26b1</i> represent potential theoretical targets for exploring the mechanism and intervention of cellular "memory" in MASLD.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2026年6月29日

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  • Yannan Zhang,
  • Zheng Li,
  • Jinyu Sun,
  • Changhao Xu,
  • Min Gao,
  • Hui Shen,
  • Dongxu Hua,
  • Qiyang Xie,
  • Yi Xiao,
  • Yuanjie Huang,
  • Peng Li,
  • Wei Sun,
  • Xiangqing Kong

摘要

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Graphical Abstract