Mechanisms of N6­methyladenosine modification in tumor development and potential therapeutic strategies (Review).

N6­methyladenosine (m6A) modification, as the most common and abundant type of RNA modification in mammalian cells, participates in the processes of mRNA transcription, translation, splicing and degradation, serving to regulate RNA stability. In recent years, a large number of studies have indicated that m6A modification is able to affect tumor progression, participate in tumor metabolism, regulate tumor cell ferroptosis and change the tumor immune microenvironment, thereby affecting tumor immunotherapy. In the current review, the main features of m6A­associated proteins are presented with a focus on the mechanisms underpinning their roles in tumor progression, metabolism, ferroptosis and immunotherapy, also emphasizing the potential of targeting m6A­associated proteins as a promising strategy for the treatment of cancer.

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

Epithelial-mesenchymal transition (EMT) is closely associated with tumor invasion and metastasis. However, key regulators of EMT in pancreatic ductal adenocarcinoma (PDAC) need to be further studied. Bioinformatics analyses of pancreatic cancer public datasets showed that glycogen phosphorylase L (PYGL) expression is elevated in quasimesenchymal PDAC (QM-PDAC) and positively associated with EMT. In vitro cellular experiments further confirm PYGL as a crucial EMT regulator in PDAC cells. Functionally, PYGL overexpression promotes cell migration and invasion in vitro and facilitates liver metastasis in vivo, while PYGL knockdown has opposite effects. Mechanically, hypoxia induces PYGL expression in a hypoxia inducible factor 1α (HIF1α)-dependent manner and promotes glycogen accumulation. Elevated PYGL mobilizes accumulated glycogen to fuel glycolysis via its activity as a glycogen phosphorylase, thus inducing the EMT process, which could be suppressed by the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). Clinically, PYGL expression is upregulated in PDAC and correlates with its malignant features and poor prognosis. Collectively, the data from our study reveal that the hypoxia/PYGL/glycolysis-induced EMT promotes PDAC metastasis, which establishes the rational for targeting hypoxia/PYGL/glycolysis/EMT signaling pathway against PDAC.

Ferroptosis and tumor immunotherapy: A promising combination therapy for tumors.

Low response rate and treatment resistance are frequent problems in the immunotherapy of tumors, resulting in the unsatisfactory therapeutic effects. Ferroptosis is a form of cell death characterized by the accumulation of lipid peroxides. In recent years, it has been found that ferroptosis may be related to the treatment of cancer. Various immune cells (including macrophages and CD8+ T cells) can induce ferroptosis of tumor cells, and synergistically enhance the anti-tumor immune effects. However, the mechanisms are different for each cell types. DAMP released in vitro by cancer cells undergoing ferroptosis lead to the maturation of dendritic cells, cross-induction of CD8+ T cells, IFN-γ production and M1 macrophage production. Thus, it activates the adaptability of the tumor microenvironment and forms positive feedback of the immune response. It suggests that induction of ferroptosis may contribute to reducing resistance of cancer immunotherapy and has great potential in cancer therapy. Further research into the link between ferroptosis and tumor immunotherapy may offer hope for those cancers that are difficult to treat. In this review, we focus on the role of ferroptosis in tumor immunotherapy, explore the role of ferroptosis in various immune cells, and discuss potential applications of ferroptosis in tumor immunotherapy.

ACSL4 is essential for radiation-induced intestinal injury by initiating ferroptosis.

Lipid peroxidation-induced ferroptosis is a newly recognized type of programmed cell death. With the method of RNA sequencing, we found that irradiation (IR) markedly increased the expression of ferroptosis promotive genes, whereas reduced the expression of ferroptosis suppressive genes in murine intestine tissues, when compared with those of liver and lung tissues. By using ferroptosis inducer RSL-3 and inhibitor liproxstatin-1, we found that ferroptosis is essential for IR-induced intestinal injury. Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) is an important component for ferroptosis execution, and we found that ACSL4 expression was significantly upregulated in irradiated intestine tissues, but not in liver or lung tissues. Antibacterial and antifungal regents reduced the expression of ASCL4 and protected against tissue injury in irradiated intestine tissues. Further studies showed that troglitazone, a ACSL4 inhibitor, succeeded to suppresses intestine lipid peroxidation and tissue damage after IR.

Activated Platelets Autocrine 5-Hydroxytryptophan Aggravates Sepsis-Induced Acute Lung Injury by Promoting Neutrophils Extracellular Traps Formation.

Excessive neutrophil extracellular trap (NET) formation is an important contributor to sepsis-induced acute lung injury (ALI). Recent reports indicate that platelets can induce neutrophil extracellular trap formation. However, the specific mechanism remains unclear. Tph1 gene, which encodes the rate-limiting enzyme for peripheral 5-hydroxytryptophan (5-HT) synthesis, was knocked out in mice to simulate peripheral 5-HT deficiency. Cecal ligation and puncture (CLP) surgery was performed to induce sepsis. We found that peripheral 5-HT deficiency reduced NET formation in lung tissues, alleviated sepsis-induced lung inflammatory injury, and reduced the mortality rate of CLP mice. In addition, peripheral 5-HT deficiency was shown to reduce the accumulation of platelets and NETs in the lung of septic mice. We found that platelets from wild-type (WT), but not Tph1 knockout (Tph1 -/- ), mice promote lipopolysaccharide (LPS)-induced NET formation. Exogenous 5-HT intervention increased LPS-induced NET formation when Tph1 -/- platelets were co-cultured with WT neutrophils. Therefore, our study uncovers a mechanism by which peripheral 5-HT aggravated sepsis-induced ALI by promoting NET formation in the lung of septic mice.