Biochimica et biophysica acta. Molecular basis of disease · 2026
ZFP36L1-mediated PRDM1 mRNA degradation inhibits inflammatory activation of Kupffer cells and ameliorates DCD liver ischemic-reperfusion injury.
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Du Peng, Deng Meng, Ge Xin, Wang Wendong, Zhang Mingfang, Wang Panliang
Аннотация
BACKGROUND: Ischemia-reperfusion injury (IRI) represents a significant and unavoidable clinical challenge in donation after cardiac death (DCD) liver transplantation. Excessive sterile inflammation plays a critical role in the pathogenesis of liver IRI. This study, guided by bioinformatics insights, investigates the function of ZFP36 ring finger protein like 1 (ZFP36L1) in the activation of Kupffer cells (KCs) in IRI in DCD liver transplantation.
METHODS: A rat DCD liver transplantation model and a lipopolysaccharide (LPS)-induced KCs inflammation model were established. Models were pretreated with ZFP36L1 and/or PR/SET domain 1 (PRDM1) gene overexpression vectors for functional and mechanistic examination.
RESULTS: ZFP36L1 was downregulated in KCs in both the rats with the DCD liver transplantation model and human DCD liver transplantation specimens. Overexpression of ZFP36L1 in rat KCs ameliorated liver injury, reduced the secretion of inflammatory cytokines, alleviated oxidative stress, inhibited cell apoptosis, and suppressed the inflammatory activation of KCs. Parallel anti-inflammatory effects of ZFP36L1 were observed in LPS-treated mouse KCs in vitro. As an RNA-binding protein, ZFP36L1 promoted the degradation of PRDM1 mRNA by specifically binding to AU-rich elements within its 3'-untranslated region (3'-UTR). Overexpression of PRDM1 effectively counteracted the regulatory effects of ZFP36L1, thereby reversing the suppression of inflammatory activation in KCs and exacerbating liver IRI.
CONCLUSION: This study demonstrates that ZFP36L1 mitigates the inflammatory activation of KCs and alleviates DCD liver IRI by inducing PRDM1 mRNA degradation.
METHODS: A rat DCD liver transplantation model and a lipopolysaccharide (LPS)-induced KCs inflammation model were established. Models were pretreated with ZFP36L1 and/or PR/SET domain 1 (PRDM1) gene overexpression vectors for functional and mechanistic examination.
RESULTS: ZFP36L1 was downregulated in KCs in both the rats with the DCD liver transplantation model and human DCD liver transplantation specimens. Overexpression of ZFP36L1 in rat KCs ameliorated liver injury, reduced the secretion of inflammatory cytokines, alleviated oxidative stress, inhibited cell apoptosis, and suppressed the inflammatory activation of KCs. Parallel anti-inflammatory effects of ZFP36L1 were observed in LPS-treated mouse KCs in vitro. As an RNA-binding protein, ZFP36L1 promoted the degradation of PRDM1 mRNA by specifically binding to AU-rich elements within its 3'-untranslated region (3'-UTR). Overexpression of PRDM1 effectively counteracted the regulatory effects of ZFP36L1, thereby reversing the suppression of inflammatory activation in KCs and exacerbating liver IRI.
CONCLUSION: This study demonstrates that ZFP36L1 mitigates the inflammatory activation of KCs and alleviates DCD liver IRI by inducing PRDM1 mRNA degradation.