Three-Dimensional Regulation of Ferroptosis at the Intersection of Iron, Sulfur, and Oxygen Executing Scrap and Build Toward Evolution

BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile‐induced mesothelioma via ferroptosis resistance

“…Ferroptosis is a recently established concept of cell death defined by catalytic Fe(II)‐dependent regulated necrosis accompanied by lipid peroxidation. 35 , 40 , 45 Whereas chrysotile‐induced Mut MMs were more oxidatively stressed as seen by 8‐OHdG 46 than the other groups, they simultaneously revealed more ferroptosis resistance by a variety of factors we examined, including decreased BAP1 47 and increased xCT (Slc7A11) 48 and GPX4. 49 We recently developed a monoclonal antibody, HNEJ‐1, 50 , 51 to detect ferroptosis, 34 which also demonstrated ferroptosis resistance in MMs especially of chrysotile/Mut, along with PTGS2.…”

“…As we reported, derangement of iron metabolism is the key pathogenic mechanism for asbestos‐induced carcinogenesis both on mesothelial cells 6,8 and macrophages 36–38 . Iron addiction with ferroptosis resistance may represent the pathogenesis 39,40 . All the asbestos fibers had high affinity for hemoglobin and histones, 32,41 and mesothelial cells are also phagocytic cells 5,42 that constitute the essential portion of carcinogenesis via physical breakage of the genome by iron‐coated scissor‐like asbestos fibers 7 .…”

“…[36][37][38] Iron addiction with ferroptosis resistance may represent the pathogenesis. 39,40 All the asbestos fibers had high affinity for hemoglobin and histones, 32,41 and mesothelial cells are also phagocytic cells 5,42 that constitute the essential portion of carcinogenesis via physical breakage of the genome by iron-coated scissor-like asbestos fibers. 7 Recently, we found that macrophages fall into ferroptosis during the scavenging process of iron-coated asbestos fibers, 36 which still emit exosomes filled with Fe(III)-loaded ferritin to the target mesothelial cells, causing oxidative stress.…”

“…Overview schema of how BRCA1 haploinsufficiency influences the development of MMs.Finally, we evaluated the difference in ferroptosis resistance8 depending on fibers during MM carcinogenesis. Ferroptosis is a recently established concept of cell death defined by catalytic Fe(II)-dependent regulated necrosis accompanied by lipid peroxidation 35,40,45. Whereas chrysotile-induced Mut MMs were more oxidatively stressed as seen by 8-OHdG46 than the other groups, they simultaneously revealed more ferroptosis resistance by a variety of factors we examined, including decreased BAP147 and increased…”