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Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH) and is associated with the occurrence and development of nonalcoholic fatty liver disease (NAFLD). However, the specific mechanism by which OSA induces NAFLD remains unclear. Therefore, effective interventions are lacking. This study aims to investigate the role and mechanism of ferroptosis in OSA‐related NAFLD using clinical data analyses, cell‐based molecular experiments, and animal experiments. Indicators of liver function, lipid accumulation, and ferroptosis are also examined. RNA‐seq, qPCR, western blotting, gene intervention, and E3 ligase prediction using UbiBrowser and co‐IP are used to explore the potential underlying mechanisms. The results show that ferroptosis increases in the liver tissues of patients with OSA. Chronic IH promotes NAFLD progression in mice and is alleviated by a ferroptosis inhibitor Fer‐1. The increased secretion of IL6 by macrophages can promote the expression of MARCH3 in hepatocytes under intermittent conditions, and subsequently promote the ubiquitination and degradation of GPX4 to regulate ferroptosis and lipid accumulation in hepatocytes. Hence, targeted inhibition of MARCH3 may alleviate IH‐induced ferroptosis and lipid accumulation in liver tissues and inhibit the progression of NAFLD. [ABSTRACT FROM AUTHOR]

Background: Hypoxia plays an important role in the chemotherapy resistance of nasopharyngeal carcinoma (NPC). Ferroptosis is a newly discovered form of programmed cell death and ferroptosis inducers showed promising therapeutic effects in some cancers. However, the sensibility of NPC cells to ferroptosis under the hypoxic microenvironment is still unclear, and this study was designed to clarify it. Methods: NPC cells, treated with erastin, were placed in a normoxia or hypoxic environment (5% CO2, 94% N2 and 1% O2) at 37℃for 24 h. After exposed to hypoxia, ferroptosis-associated phenotypes were detected by CCK8, MDA, GSH, lipid ROS and Fe. The gene expression profiles of head and neck squamous cell carcinoma (HNSCC) tissues were downloaded from the TCGA database to screen construction molecule. BAP1 was screened out and its functions on erastin-induced ferroptosis in NPC cells were detected by knockdown of BAP1. Luciferase reporter assay and co-IP experiment were performed to explore the molecular mechanism. Finally, the tumour xenograft model was applied to further verify these results in vivo. Results: CCK8 assay showed that IC50 of NPC cells treated with erastin under hypoxia was significantly lower than that under normoxia. Hypoxia significantly increased the levels of lipid ROS and MDA, and decreased GSH content induced by erastin. A prognostic risk model for HNSCC with six ferroptosis-related genes was constructed and validated based on TCGA database. BAP1 was significantly up-regulated under hypoxia, and luciferase reporter assay showed that HIF-1α was an upstream transcription regulator of BAP1. Knockdown of BAP1 in NPC cells significantly increased the IC50 value of erastin under hypoxia and significantly ameliorated erastin-induced ferroptosis under hypoxia in aspect of lipid ROS, MDA content and GSH. Co-IP results showed that BAP1 mediated deubiquitination of H2A and decreased SLC7A11 expression. Finally, knockdown of BAP1 reduced sensitivity to erastin-induced ferroptosis in a tumour xenograft model. And the level of H2A was significantly decreased in xenograft tumors of BAP1 knockdown cells. Conclusion: Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in NPC by stabilizing H2A. Ferroptosis inducers targeting BAP1 may be an effective way to improve chemotherapy resistance in NPC, especially in the hypoxic microenvironment. [ABSTRACT FROM AUTHOR]

Gasar porous Mg–3 wt% Ag alloy is prepared by metal–gas eutectic directional solidification process. The pore structure is related to the solidification mode of the alloy. The pores grow stably under the solidification conditions of planar, cellular, and columnar dendrites but not under the condition of equiaxed dendrites. The numerical simulation shows that the solidification velocity and temperature gradient decrease rapidly with an increase in the sample height, but their ratio remains unchanged. During the solidification process, the solidification mode of the alloy changes from cellular crystals to columnar dendrites, and finally to equiaxed dendrites. The calculated results of the solidification mode transition are consistent with the microstructure morphologies of the Mg–Ag alloy at different heights. [ABSTRACT FROM AUTHOR]