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<p>Ischemia-reperfusion (I/R) injury represents a prevalent etiology of permanent vision loss across multiple ocular pathologies. Apoptotic death and inflammation of retinal ganglion cells (RGCs) induced by I/R injury constitutes a major contributor to visual dysfunction. Nevertheless, the molecular mechanisms that initiate the apoptotic and inflammation cascade in RGCs remain largely uncharacterized. Recent investigations have demonstrated that PRD1-BF1-RIZ1 homeodomain protein 16 (PRDM16) attenuates renal cell death in acute kidney injury. However, its specific function and regulatory mechanisms in I/R-induced RGCs apoptosis and inflammation remain poorly understood. Here, we demonstrate that PRDM16 expression is markedly upregulated in RGCs and mouse retinas following I/R injury. Functionally, PRDM16 overexpression markedly attenuates I/R-induced RGCs apoptosis and inflammation, while its RGC-specific deletion exacerbates retinal structural damage and functional deficits. Mechanistically, PRDM16 binds to the Ribosomal Protein L5 (RPL5) promoter and enhances its transcription. Additionally, co-immunoprecipitation assays revealed a physical association between PRDM16 and RPL5. This PRDM16-mediated enrichment of RPL5 subsequently suppresses p53 signaling, leading to the upregulation of FCGR2B. Increased FCGR2B, in turn, inhibits the overactivation of MAPK (p38 and JNK) signaling and the assembly of the NLRP3/IL-1β inflammasome axis. In conclusion, these findings identify PRDM16 as a critical endogenous protective regulator that alleviates retinal I/R-induced damage through modulation of the RPL5/p53/FCGR2B/MAPK axis. Targeting PRDM16 regulatory networks may therefore represent a promising therapeutic strategy for retinal ischemic diseases.</p> Graphical abstract <p>Ischemia–reperfusion injury induces apoptosis and inflammation in RGCs. PRDM16 is upregulated in response to ischemic stress and exerts a protective effect by transcriptionally activating RPL5. Increased RPL5 suppresses p53 expression, leading to upregulation of FCGR2B and subsequent inhibition of p38 MAPK and JNK signaling. Additionally, co-immunoprecipitation assays reveal a physical association between PRDM16 and RPL5. This regulatory cascade attenuates caspase-3 activation and inflammatory mediator (NLRP3 and IL-1β) expression, ultimately protecting RGCs from ischemia-induced injury.</p>

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PRDM16 protects retinal ganglion cells from ischemia-reperfusion Injury by regulating the RPL5/p53 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • Yuqing Feng,
  • Zhou Li,
  • Jinfang Lu,
  • Xujun Peng,
  • Zijin He,
  • Ao Jia,
  • Yaohui Bao,
  • Qiang Zheng,
  • Xuan Xu,
  • Yuxuan Ma,
  • Chun Zou,
  • Huiling Li,
  • Dongshan Zhang

摘要

Ischemia-reperfusion (I/R) injury represents a prevalent etiology of permanent vision loss across multiple ocular pathologies. Apoptotic death and inflammation of retinal ganglion cells (RGCs) induced by I/R injury constitutes a major contributor to visual dysfunction. Nevertheless, the molecular mechanisms that initiate the apoptotic and inflammation cascade in RGCs remain largely uncharacterized. Recent investigations have demonstrated that PRD1-BF1-RIZ1 homeodomain protein 16 (PRDM16) attenuates renal cell death in acute kidney injury. However, its specific function and regulatory mechanisms in I/R-induced RGCs apoptosis and inflammation remain poorly understood. Here, we demonstrate that PRDM16 expression is markedly upregulated in RGCs and mouse retinas following I/R injury. Functionally, PRDM16 overexpression markedly attenuates I/R-induced RGCs apoptosis and inflammation, while its RGC-specific deletion exacerbates retinal structural damage and functional deficits. Mechanistically, PRDM16 binds to the Ribosomal Protein L5 (RPL5) promoter and enhances its transcription. Additionally, co-immunoprecipitation assays revealed a physical association between PRDM16 and RPL5. This PRDM16-mediated enrichment of RPL5 subsequently suppresses p53 signaling, leading to the upregulation of FCGR2B. Increased FCGR2B, in turn, inhibits the overactivation of MAPK (p38 and JNK) signaling and the assembly of the NLRP3/IL-1β inflammasome axis. In conclusion, these findings identify PRDM16 as a critical endogenous protective regulator that alleviates retinal I/R-induced damage through modulation of the RPL5/p53/FCGR2B/MAPK axis. Targeting PRDM16 regulatory networks may therefore represent a promising therapeutic strategy for retinal ischemic diseases.

Graphical abstract

Ischemia–reperfusion injury induces apoptosis and inflammation in RGCs. PRDM16 is upregulated in response to ischemic stress and exerts a protective effect by transcriptionally activating RPL5. Increased RPL5 suppresses p53 expression, leading to upregulation of FCGR2B and subsequent inhibition of p38 MAPK and JNK signaling. Additionally, co-immunoprecipitation assays reveal a physical association between PRDM16 and RPL5. This regulatory cascade attenuates caspase-3 activation and inflammatory mediator (NLRP3 and IL-1β) expression, ultimately protecting RGCs from ischemia-induced injury.