Cellular signalling · 2026
The RNA-binding protein EIF3B promotes necroptosis and subsequent metabolic acidosis in acute pancreatitis through stabilization of RIPK3 mRNA.
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Jia JiangKun, Xu Jian, Yu Miao, Tian YuWei
Аннотация
BACKGROUND AND AIMS: Severe Acute Pancreatitis (SAP) is a life-threatening condition driven by pancreatic necroptosis, yet its upstream regulators are poorly understood. This study aimed to investigate the roles of eukaryotic initiation factor 3 subunit B (EIF3B) and its downstream target receptor-interacting protein kinase 3 (RIPK3) in SAP pathogenesis and to elucidate the underlying regulatory mechanism.
METHODS: Expression of EIF3B and RIPK3 was analyzed in human SAP tissues and L-arginine-induced mouse models. In vitro, necroptosis was induced in AR42J pancreatic acinar cells using taurolithocholic acid sodium salt (TLC-S). Functional roles were assessed using small interfering RNA (siRNA), lentiviral overexpression, and Adeno-Associated Virus (AAV)-mediated in vivo knockdown. The interaction between EIF3B and RIPK3 messenger RNA (mRNA) was examined via RNA immunoprecipitation, pull-down, and luciferase reporter assays.
RESULTS: EIF3B and RIPK3 were significantly upregulated in SAP patient tissues and mouse models, correlating with disease severity. In vivo knockdown of either Eif3b or Ripk3 ameliorated pancreatic injury, reduced necroptosis, and corrected metabolic acidosis. In vitro, bidirectional modulation of EIF3B or RIPK3 expression regulated necroptotic injury. Mechanistically, EIF3B associated with the RIPK3 3' untranslated region (3'UTR) and enhanced RIPK3 mRNA stability, thereby increasing RIPK3 protein abundance. The pro-necroptotic effects of EIF3B overexpression were substantially attenuated by simultaneous RIPK3 knockdown.
CONCLUSION: This study identifies EIF3B as a post-transcriptional regulator that promotes RIPK3 abundance and RIPK3-mediated necroptosis in SAP. These findings identify the EIF3B-RIPK3 axis as a potential contributor to pancreatic injury and associated metabolic acidosis in SAP.
METHODS: Expression of EIF3B and RIPK3 was analyzed in human SAP tissues and L-arginine-induced mouse models. In vitro, necroptosis was induced in AR42J pancreatic acinar cells using taurolithocholic acid sodium salt (TLC-S). Functional roles were assessed using small interfering RNA (siRNA), lentiviral overexpression, and Adeno-Associated Virus (AAV)-mediated in vivo knockdown. The interaction between EIF3B and RIPK3 messenger RNA (mRNA) was examined via RNA immunoprecipitation, pull-down, and luciferase reporter assays.
RESULTS: EIF3B and RIPK3 were significantly upregulated in SAP patient tissues and mouse models, correlating with disease severity. In vivo knockdown of either Eif3b or Ripk3 ameliorated pancreatic injury, reduced necroptosis, and corrected metabolic acidosis. In vitro, bidirectional modulation of EIF3B or RIPK3 expression regulated necroptotic injury. Mechanistically, EIF3B associated with the RIPK3 3' untranslated region (3'UTR) and enhanced RIPK3 mRNA stability, thereby increasing RIPK3 protein abundance. The pro-necroptotic effects of EIF3B overexpression were substantially attenuated by simultaneous RIPK3 knockdown.
CONCLUSION: This study identifies EIF3B as a post-transcriptional regulator that promotes RIPK3 abundance and RIPK3-mediated necroptosis in SAP. These findings identify the EIF3B-RIPK3 axis as a potential contributor to pancreatic injury and associated metabolic acidosis in SAP.