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Ubc9-Mediated SUMOylation of RPL3, an Unappreciated Mechanism against Hepatocyte Senescence by Repressing the

Hao Xie1,2, Zhichao Gao1, Xin Liu3

  • 1Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 20, 2025
PubMed

Insights

Hepatic Ubc9 SUMOylation prevents liver aging and metabolic dysfunction-associated steatotic liver disease (MASLD). Decreased Ubc9 accelerates aging and fatty liver, while its SUMOylation of RPL3 represses senescence markers like p16.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Aging Research

Background:

  • Ubc9-mediated SUMOylation regulates hepatic functions, but its role in liver aging and MASLD is unclear.
  • An age-dependent decrease in hepatic Ubc9 and protein SUMOylation correlates with increased senescence markers in humans and mice.

Purpose of the Study:

  • To investigate the role of Ubc9 in hepatic aging and MASLD.
  • To elucidate the molecular mechanism by which Ubc9 influences hepatocyte senescence.

Main Methods:

  • Analysis of hepatic Ubc9 expression and SUMOylation in aging humans and mice.
  • Assessment of liver aging and MASLD phenotypes in Ubc9-deficient mice under a methionine- and choline-deficient (MCD) diet.
  • Investigation of the interaction between RPL3, DHX9, and RNA polymerase II in p16 promoter transcription.
  • Evaluation of Ubc9-mediated SUMOylation's effect on RPL3 nuclear translocation and p16 expression.

Main Results:

  • Ubc9 deficiency exacerbates hepatic aging and susceptibility to diet-induced fatty liver and steatohepatitis.
  • Nuclear ribosomal protein L3 (RPL3) interacts with DHX9 to promote p16 transcription and hepatocyte aging.
  • Ubc9-mediated SUMOylation inhibits RPL3 nuclear translocation, repressing p16 expression and attenuating liver aging.

Conclusions:

  • Ubc9-mediated SUMOylation of RPL3 is a critical mechanism against hepatic aging.
  • Targeting Ubc9 SUMOylation may offer a therapeutic strategy for MASLD and liver aging.
Keywords:
DHX9SUMOylationagingmetabolic dysfunction‐associated steatotic liver disease (MASLD)ribosomal protein L3 (RPL3)

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