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<p>With the increasing global burden of fatty liver disease (FLD), liver transplantation (LT) recipients face heightened risks of steatosis recurrence in graft livers, necessitating urgent reappraisal of immunosuppressant-associated metabolic effects. The effects of mycophenolic acid (MPA), a commonly used immunosuppressant in LT, on hepatic lipid metabolism following LT remain unclear. This study employed a multifaceted approach encompassing cellular, animal, and molecular biology techniques to systematically evaluate the role of MPA in hepatic lipid metabolism. Our results demonstrated that MPA promoted lipid synthesis in healthy hepatic models by upregulating the expression of genes associated with lipogenesis, including <i>SREBP-1c</i>,<i> FASN</i>, and <i>PPARγ</i>, while paradoxically inhibiting lipid accumulation in steatotic hepatic models. Mechanistically, we identified inosine monophosphate dehydrogenase 2 (<i>IMPDH2</i>) as the molecular switch governing this dichotomy. Notably, significantly increased interaction between IMPDH2 and PPARγ was observed following MPA treatment. Our findings highlight the intricate role of MPA in hepatic lipid homeostasis and underscore the importance of further elucidating the effects of MPA across a spectrum of liver conditions to inform tailored treatment strategies following LT.</p>

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Mycophenolic acid exerts dichotomous regulation of hepatic lipogenesis in a metabolic context-dependent manner

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月18日

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  • Zhengye Xu,
  • Hongwei Li,
  • Yanjie Ni,
  • Yifu Feng,
  • Xiaoyuan Jia,
  • Chong Jin,
  • Hongsheng Lu,
  • Kan Chen

摘要

With the increasing global burden of fatty liver disease (FLD), liver transplantation (LT) recipients face heightened risks of steatosis recurrence in graft livers, necessitating urgent reappraisal of immunosuppressant-associated metabolic effects. The effects of mycophenolic acid (MPA), a commonly used immunosuppressant in LT, on hepatic lipid metabolism following LT remain unclear. This study employed a multifaceted approach encompassing cellular, animal, and molecular biology techniques to systematically evaluate the role of MPA in hepatic lipid metabolism. Our results demonstrated that MPA promoted lipid synthesis in healthy hepatic models by upregulating the expression of genes associated with lipogenesis, including SREBP-1c, FASN, and PPARγ, while paradoxically inhibiting lipid accumulation in steatotic hepatic models. Mechanistically, we identified inosine monophosphate dehydrogenase 2 (IMPDH2) as the molecular switch governing this dichotomy. Notably, significantly increased interaction between IMPDH2 and PPARγ was observed following MPA treatment. Our findings highlight the intricate role of MPA in hepatic lipid homeostasis and underscore the importance of further elucidating the effects of MPA across a spectrum of liver conditions to inform tailored treatment strategies following LT.