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 Xc^- (consisted of SL3A2/SLC7A11). Besides, inhibiting PCBP2 contributed to facilitating cofactor p300 to enhance the transcriptional activity of HIF1α, 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 PCBP2-system Xc^-. Beyond that, ACT also supported PCBP2 to limit HMGB1-induced M1 macrophage recruitment through imposing restrictions on p300 and HIF1α. 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 Xc^- and limit HIF1α/p300-HMGB1 signaling. These findings highlight the therapeutic benefits of ACT in treating HIRI and offer insights into innovative therapeutic strategies.

Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or liver transplantation. It contributes to postoperative organ failure or tissue rejection, eventually affecting patient prognosis and overall survival. The pathological mechanism of HIRI is highly complex and has not yet been fully elucidated. The proposed underlying mechanisms include mitochondrial damage, oxidative stress imbalance, abnormal cell death, immune cell hyperactivation, intracellular inflammatory disorders and other complex events. In addition to serious clinical limitations, available antagonistic drugs and specific treatment regimens are still lacking. Therefore, there is an urgent need to not only clarify the exact etiology of HIRI but also reveal the possible reactions and bottlenecks of existing drugs, helping to reduce morbidity and shorten hospitalizations. We analyzed the possible underlying mechanism of HIRI, discussed various outcomes among different animal models and explored neglected potential therapeutic strategies for HIRI treatment. By thoroughly reviewing and analyzing the literature on HIRI, we gained a comprehensive understanding of the current research status in related fields and identified valuable references for future clinical and scientific investigations.

Background: The mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer (CRC) is limited. Synthetic lethality arises with a combination of two or more separate gene mutations that causes cell death, whereas individual mutations keep cells alive. This study aimed to identify the genes responsible for resistance to trametinib in CRC cells, using a synthetic lethal short hairpin RNA (shRNA) screening approach. Methods: We infected HT29 cells with a pooled lentiviral shRNA library and applied next-generation sequencing to identify shRNAs with reduced abundance after 8-day treatment of 20 nmol/L trametinib. HCT116 and HT29 cells were used in validation studies. Stable ring finger protein 183 (RNF183)-overexpressing cell lines were generated by pcDNA4-myc/his-RNF183 transfection. Stable RNF183-knockdown cell lines were generated by infection of lentivi-ruses that express RNF183 shRNA, and small interference RNA (siRNA) was used to knock down RNF183 transiently. Quantitative real-time PCR was used to determine the mRNA expression. Western blotting, immunohistochemical analysis, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the protein abundance. MTT assay, colony formation assay, and subcutaneous xenograft tumor growth model were used to evaluate cell proliferation. Results: In the primary screening, we found that the abundance of RNF183 shRNA was markedly reduced after treatment with trametinib. Trametinib induced the expression of RNF183, which conferred resistance to drug-induced cell growth repression and apoptotic and non-apoptotic cell deaths. Moreover, interleukin-8 (IL-8) was a downstream gene of RNF183 and was required for the function of RNF183 in facilitating cell growth. Additionally, elevated RNF183 expression partly reduced the inhibitory effect of trametinib on IL-8 expression. Finally, xenograft tumor model showed the synergism of RNF183 knockdown and trametinib in repressing the growth of CRC cells in vivo. Conclusion: The RNF183-IL-8 axis is responsible for the resistance of CRC cells to the MEK1/2 inhibitor trametinib and may serve as a candidate target for combined therapy for CRC.

AIM: To explore the effects of neurotrophin-3 (NT-3)-genetically modified Schwann cells (NT-3-SCs) on differentiation of neural stem cells (NSCs) into the neuron-like cells. METHODS: The NSCs were co-cultured with NT-3-SCs. Report gene LacZ genetically modified Schwann cells (LacZ-SCs) and normal SCs respectively in vitro. 7 d later, the differentiation of NSCs was studied by immunohistochemistry, and the percentage of neuron-like cells was calculated. RESULTS: NSCs differentiated to the GFAP-positive cells (glial-like cells) and NF-positive cells (neuron-like cells) in vitro. Compared to the normal SCs, NT-3-SCs more efficiently promoted NSCs to differentiate into the neuron-like cells. The effect of LacZ-SCs was as the same to the normal SCs. CONCLUSION: NT-3-SCs promote NSCs to differentiate into the neuron-like cells. [