ABSTRACT
Lung cancer is one of the most common cancers in the world, and its treatment strategy is mainly surgery combined with radiotherapy and chemotherapy. However, long-term chemotherapy will result in drug resistance, which is also one of the difficulties in the treatment of lung cancer. Ferroptosis is an iron-dependent and lipid peroxidation-driven non-apoptotic cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (Nrf2) is key for cellular antioxidant responses. Numerous studies suggest that Nrf2 assumes an extremely important role in regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. In this review, a brief overview of the research progress of ferroptosis over the past decade will be presented. In particular, the mechanism of ferroptosis and the regulation of ferroptosis by Nrf2 will be discussed, as well as the role of the Nrf2 pathway and ferroptosis in tumor drug resistance, which will provide new research directions for the treatment of drug-resistant lung cancer patients. .
Subject(s)
Humans , Ferroptosis , NF-E2-Related Factor 2/genetics , Lung Neoplasms/genetics , Drug Resistance, Neoplasm , IronABSTRACT
Objective:Iron accumulation is related to the occurrence of postmenopausal osteoporosis. Meanwhile, autophagy abnormality of bone marrow hematopoietic cells is observed in hip osteoporotic fracture. This study is performed to investigate correlation between iron accumulation induced bone loss and hematopoietic autophagy dysfunction to explore the new risk factor of osteoporosis.Methods:Male iron accumulation mice model was established by intraperitoneally injecting ferric ammonium citrate. Serum ferritin and osteogenic indicator P1NP were tested by ELISA. Bone mineral density was measured by micro-CT. Femur and tibia bone marrows were collected for hematopoietic stem and progenitor cells proportion and cell apoptosis analysis. Autolysosome formation was measured by image flow cytometry. We used conditional mouse model Atg7 flox/flox; Vav-Cre(Atg7 -/-) in which Atg7 had been genetically deleted in the hematopoietic system. Bone marrow hematopoietic stem and progenitor cells were collected for RNA sequence. micro-CT scan was conducted for Atg7 -/- femur. Results:Ferritin level of iron accumulation mice was significantly higher than control group( P<0.05). Iron accumulation inhibited P1NP and induced decreased bone mineral density( P<0.05). Iron accumulation bone marrow displayed enhanced hematopoietic stem and progenitor cells proportion( P<0.05), with more cell apoptosis( P<0.05). Hematopoietic autophagy was deteriorated in iron accumulation bone marrow. Transcriptomic profiling showed up-regulation of iron activity in Atg7 -/- mice, with increased iron homeostasis and iron membrane transporter genes, including Lcn2, Tfr2, Slc40a1(Fpn1), Steap3, and Cpox. micro-CT revealed severe bone loss and decreased bone mineral density in Atg7 -/- mice( P<0.05). Conclusion:Iron accumulation induced bone loss is related to inhibition of hematopoietic cells. Hematopoietic autophagy dysfunction is associated with bone loss.