Crush syndrome (CS) is a life-threatening illness in traffic accidents and earthquakes. Crush syndrome-induced acute kidney injury (CS-AKI) is considered to be mainly due to myoglobin (Mb) circulation and deposition after skeletal muscle ruptures and releases. Macrophages are the primary immune cells that fight foreign substances and play critical roles in regulating the body’s natural immune response. However, what effect does myoglobin have on macrophages and the mechanisms involved in the CS-AKI remain unclear. This study aims to look into how myoglobin affects macrophages of the CS-AKI model. C57BL/6 mice were used to construct the CS-AKI model by digital crush platform. Biochemical analysis and renal histology confirmed the successful establishment of the CS-AKI mouse model. Ferrous myoglobin was used to treat Raw264.7 macrophages to mimic the CS-AKI cell model in vitro. The macrophage polarization toward M1 type and activation of RIG-I as myoglobin sensor were verified by real-time quantitative PCR (qPCR), Western blotting (WB), and immunofluorescence (IF). Macrophage pyroptosis was observed under light microscopy. The interaction between RIG-I and caspase1 was subsequently explored by co-immunoprecipitation (Co-IP) and IF. Small interfering RNA (siRIG-I) and pyroptosis inhibitor dimethyl fumarate (DMF) were used to verify the role of macrophage polarization and pyroptosis in CS-AKI. In the kidney tissue of CS-AKI mice, macrophage infiltration and M1 type were found. We also detected that in the cell model of CS-AKI in vitro, ferrous myoglobin treatment promoted macrophages polarization to M1. Meanwhile, we observed pyroptosis, and myoglobin activated the RIG-I/Caspase1/GSDMD signaling pathway. In addition, pyroptosis inhibitor DMF not only alleviated kidney injury of CS-AKI mice but also inhibited macrophage polarization to M1 phenotype and pyroptosis via the RIG-I/Caspase1/GSDMD signaling pathway. Our research found that myoglobin promotes macrophage polarization to M1 type and pyroptosis via the RIG-I/Caspase1/GSDMD signaling pathway in CS-AKI.

DTD (D-Tyr-tRNATyr deacylase) is known to be able to deacylate D-aminoacyl-tRNAs into free D-amino acids and tRNAs and therefore contributes to cellular resistance against D-amino acids in Escherichia coli and yeast. We have found that h-DTD (human DTD) is enriched in the nuclear envelope region of mammalian cells. Treatment of HeLa cells with D-Tyr resulted in nuclear accumulation of tRNATyr. D-Tyr treatment and h-DTD silencing caused tRNATyr downregulation. Furthermore, inhibition of protein synthesis by D-Tyr treatment and h-DTD silencing were also observed. D-Tyr, D-Asp and D-Ser treatment inhibited mammalian cell viability in a dose-dependent manner; overexpression of h-DTD decreased the inhibition rate, while h-DTD-silenced cells became more sensitive to the D-amino acid treatment. Our results suggest that h-DTD may play an important role in cellular resistance against D-amino acids by deacylating D-aminoacyl tRNAs at the nuclear pore. We have also found that m-DTD (mouse DTD) is specifically enriched in central nervous system neurons, its nuclear envelope localization indicates that D-aminoacyl-tRNA editing may be vital for the survival of neurons under high concentration of D-amino acids.

Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia and acute kidney injury (AKI). Especially AKI, it is the leading cause of death from CS. There are various cell death forms in AKI, among which ferroptosis is a typical form of cell death. However, the role of ferroptosis has not been fully revealed in CS-AKI. This review aimed to summarize the evidence of ferroptosis in CS-AKI and its related molecular mechanism, discuss the therapeutic significance of ferroptosis in CS-AKI, and open up new ideas for the treatment of CS-AKI. One of the main pathological manifestations of CS-AKI is renal tubular epithelial cell dysfunction and cell death, which has been attributed to massive deposition of myoglobin. Large amounts of myoglobin released from damaged muscle deposited in the renal tubules, impeding the normal renal tubules function and directly damaging the tubules with oxidative stress and elevated iron levels. Lipid peroxidation damage and iron overload are the distinguishing features of ferroptosis. Moreover, high levels of pro-inflammatory cytokines and damage-associated molecule pattern molecules (HMGB1, double-strand DNA, and macrophage extracellular trap) in renal tissue have been shown to promote ferroptosis. However, how ferroptosis occurs in CS-AKI and whether it can be a therapeutic target remains unclear. In our current work, we systematically reviewed the occurrence and underlying mechanism of ferroptosis in CS-AKI.

Histones play crucial roles in both promoting and repressing gene expression, primarily regulated through post-translational modifications (PTMs) at specific amino acid residues. Histone PTMs, including methylation, acetylation, ubiquitination, phosphorylation, lactylation, butyrylation, and propionylation, act as important epigenetic markers. These modifications influence not only chromatin compaction but also gene expression. Their importance extends to the treatment and prevention of various human diseases, particularly cancer, due to their involvement in key cellular processes. Abnormal histone modifications and the enzymes responsible for these alterations often serve as critical drivers in tumor cell proliferation, invasion, apoptosis, and stemness. This review introduces key histone PTMs and the enzymes responsible for these modifications, examining their impact on tumorigenesis and cancer progression. Furthermore, it explores therapeutic strategies targeting histone PTMs and offers recommendations for identifying new potential therapeutic targets.