Hepatic ischemia-reperfusion injury(HIRI)has been considered as an inevitable process of liver transplantation.Hepatocyte ferroptosis is a key factor in HIRI development,yet precise mechanism and potential therapies a...Hepatic ischemia-reperfusion injury(HIRI)has been considered as an inevitable process of liver transplantation.Hepatocyte ferroptosis is a key factor in HIRI development,yet precise mechanism and potential therapies are still unclear.Here,we demonstrated a strong correlation between hepatocyte ferroptosis and the downregulation of poly(rC)-binding protein(PCBP2),which compromised the stability of antiporter system Xce(consisted of SL3A2/SLC7A11).Besides,inhibiting PCBP2 contributed to facilitating cofactor p300 to enhance the transcriptional activity of HIF1a,leading to the expression and secretion of HMGB1.Then,released HMGB1 from ferroptotic hepatocytes worsened M1 macrophage recruitment and immune response during HIRI.Additionally,acteoside(ACT)was shown to assist PCBP2 in stabilizing the mRNA stability of Slc3a2 and Slc7a11,as well as enhance the binding affinity of PCBP2esystem Xce.Beyond that,ACT also supported PCBP2 to limit HMGB1-induced M1 macrophage recruitment through imposing restrictions on p300 and HIF1a.Furthermore,specific knockdown of PCBP2 in hepatocytes directly interposed the therapeutic efficacy of ACT on HIRI mice.In conclusion,ACT alleviated hepatocyte ferroptosis and HIRI via promoting PCBP2 to maintain the stability of system Xce and limit HIF1a/p300-HMGB1 signaling.These findings highlight the therapeutic benefits of ACT in treating HIRI and offer insights into innovative therapeutic strategies.展开更多
Background and aim:a-complex protein-2(aCP2)encoded by the poly(rC)binding protein 2(PCBP2)gene is responsible for the accumulation of type I collagen in fibrotic livers.In this study,we silenced the PCBP2 gene using ...Background and aim:a-complex protein-2(aCP2)encoded by the poly(rC)binding protein 2(PCBP2)gene is responsible for the accumulation of type I collagen in fibrotic livers.In this study,we silenced the PCBP2 gene using a small interfering RNA(siRNA)to reverse alcohol-and cytokine-induced profibrogenic effects on hepatic stellate cells(HSCs).Methods:Primary rat HSCs and the HSC-T6 cell line were used as fibrogenic models to mimic the initiation and perpetuation stages of fibrogenesis,respectively.We previously found that a PCBP2 siRNA,which efficiently silences expression of aCP2,reduces the stability of type I collagen mRNA.We investigated the effects of the PCBP2 siRNA on cell proliferation and migration.Expression of type I collagen in HSCs was analyzed by quantitative real-time PCR and western blotting.In addition,we evaluated the effects of the PCBP2 siRNA on apoptosis and the cell cycle.Results:PCBP2 siRNA reversed multiple alcohol-and cytokine-induced profibrogenic effects on primary rat HSCs and HSC-T6 cells.The PCBP2 siRNA also reversed alcohol-and cytokine-induced accumulation of type I collagen as well as cell proliferation and migration.Moreover,the combination of LY2109761,a transforming growth factor-b1 inhibitor,and the PCBP2 siRNA exerted a synergistic inhibitive effect on the accumulation of type I collagen in HSCs.Conclusions:Silencing of PCBP2 using siRNA could be a potential therapeutic strategy for alcoholic liver fibrosis.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.82274186 to Xiaojiaoyang Li)National Key Research and Development Program on Modernization of Traditional Chinese Medicine(No.2022YFC3502100 to Xiaojiaoyang Li,China)+2 种基金National High-Level Talents Special Support Program(China)to Xiaojiaoyang LiFundamental Research Funds for the Central Universities(Grant No.2023-JYBJBZD-046 to Xiaojiaoyang Li,China)High-level traditional Chinese medicine key subjects construction project of National Administration of Traditional Chinese Medicine-Beijing University of Chinese Medicine,Chinese Medicine Epidemic Disease(Grant No.zyyzdxk-2023264,China).
文摘Hepatic ischemia-reperfusion injury(HIRI)has been considered as an inevitable process of liver transplantation.Hepatocyte ferroptosis is a key factor in HIRI development,yet precise mechanism and potential therapies are still unclear.Here,we demonstrated a strong correlation between hepatocyte ferroptosis and the downregulation of poly(rC)-binding protein(PCBP2),which compromised the stability of antiporter system Xce(consisted of SL3A2/SLC7A11).Besides,inhibiting PCBP2 contributed to facilitating cofactor p300 to enhance the transcriptional activity of HIF1a,leading to the expression and secretion of HMGB1.Then,released HMGB1 from ferroptotic hepatocytes worsened M1 macrophage recruitment and immune response during HIRI.Additionally,acteoside(ACT)was shown to assist PCBP2 in stabilizing the mRNA stability of Slc3a2 and Slc7a11,as well as enhance the binding affinity of PCBP2esystem Xce.Beyond that,ACT also supported PCBP2 to limit HMGB1-induced M1 macrophage recruitment through imposing restrictions on p300 and HIF1a.Furthermore,specific knockdown of PCBP2 in hepatocytes directly interposed the therapeutic efficacy of ACT on HIRI mice.In conclusion,ACT alleviated hepatocyte ferroptosis and HIRI via promoting PCBP2 to maintain the stability of system Xce and limit HIF1a/p300-HMGB1 signaling.These findings highlight the therapeutic benefits of ACT in treating HIRI and offer insights into innovative therapeutic strategies.
基金This work was supported by an award(1R01AA021510)from the National Institutes of Health.
文摘Background and aim:a-complex protein-2(aCP2)encoded by the poly(rC)binding protein 2(PCBP2)gene is responsible for the accumulation of type I collagen in fibrotic livers.In this study,we silenced the PCBP2 gene using a small interfering RNA(siRNA)to reverse alcohol-and cytokine-induced profibrogenic effects on hepatic stellate cells(HSCs).Methods:Primary rat HSCs and the HSC-T6 cell line were used as fibrogenic models to mimic the initiation and perpetuation stages of fibrogenesis,respectively.We previously found that a PCBP2 siRNA,which efficiently silences expression of aCP2,reduces the stability of type I collagen mRNA.We investigated the effects of the PCBP2 siRNA on cell proliferation and migration.Expression of type I collagen in HSCs was analyzed by quantitative real-time PCR and western blotting.In addition,we evaluated the effects of the PCBP2 siRNA on apoptosis and the cell cycle.Results:PCBP2 siRNA reversed multiple alcohol-and cytokine-induced profibrogenic effects on primary rat HSCs and HSC-T6 cells.The PCBP2 siRNA also reversed alcohol-and cytokine-induced accumulation of type I collagen as well as cell proliferation and migration.Moreover,the combination of LY2109761,a transforming growth factor-b1 inhibitor,and the PCBP2 siRNA exerted a synergistic inhibitive effect on the accumulation of type I collagen in HSCs.Conclusions:Silencing of PCBP2 using siRNA could be a potential therapeutic strategy for alcoholic liver fibrosis.
