Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Invited Reviewed

Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD.

Cell Vol. 171 ( 2 ) page： 273-285 2017.10

The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy. Invited Reviewed

Toyokuni S.

Pathol Int. Vol. 66 ( 5 ) page： 245-259 2016.5

Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. Reviewed

Ohara Y, Chew SH, Shibata T, Okazaki Y, Yamashita K, Toyokuni S.

Cancer Science 2017.11

Diameter and rigidity of multi-walled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. Reviewed

Nagai H, Okazaki Y, Chew SH, Misawa N, Yamashita Y, Akatsuka S, Ishihara T, Yamashita K, Yoshikawa Y, Yasui H, Jiang L, Ohara H, Takahashi T, Ichihara G, Kostarelos K, Miyata Y, Shinohara H and Toyokuni S.

Proc. Natl. Acad. Sci. USA Vol. 108 page： E1330-1338 2011

Iron overload signature in chrysotile-induced malignant mesothelioma. Reviewed

Jiang L, Akatsuka S, Nagai H, Chew SH, Ohara H, Okazaki Y, Yamashita Y, Yoshikawa Y, Yasui H, Ikuta K, Sasaki K, Kohgo Y, Hirano S, Shinohara Y, Kohyama N, Takahashi T and Toyokuni S.

J Pathol Vol. 228 page： 366-377 2012.8

Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer. Reviewed

Akatsuka S, Yamashita Y, Ohara H, Liu YT, Izumiya M, Abe K, Ochiai M, Jiang L, Nagai H, Okazaki Y, Murakami H, Sekido Y, Arai E, Kanai Y, Hino O, Takahashi T, Nakagama H and Toyokuni S.

PLoS ONE Vol. 7 ( 8 ) page： e43403 2012.8

Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma. Reviewed

Jiang L, Yamashita Y, Chew SH, AKatsuka S, Ukai S, Wang S, Nagai H, Okazaki Y, Takahashi T and Toyokuni S.

J Pathol Vol. 233 page： 502-414 2014

Iron as Soul of Life on Earth Revisited: From Chemical Reaction, Ferroptosis to Therapeutics

Harigae Hideo, Hino Keisuke, Toyokuni Shinya

FREE RADICAL BIOLOGY AND MEDICINE Vol. 133 page： 1-2 2019.3

Lunar life drives jawbone formation Reviewed International journal Open Access

Sato K., Kouyama N., Akatsuka S., Motooka Y., Wang Q., Hibi H., Toyokuni S.

Journal of Dental Sciences Vol. 20 ( 4 ) page： 2399 - 2406 2025.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Dental Sciences

Background/purpose: The Japan Aerospace Exploration Agency bred mice in the “Kibo” module on the International Space Station to clarify the effects of gravity changes on the body. We determined the effects of lunar gravity (partial gravity, 1/6G) on the jawbone and elucidated its relationship with the oral cavity. Materials and methods: Mandibular bones of C57BL/6J male mice from the Kibo group (1/6G) and the Earth group (1G) were obtained. Ribonucleic acid was extracted from the samples; microarray and gene set enrichment analysis (GSEA) were performed; bone structure and histology were evaluated via micro-computed tomography, immunohistochemistry, and specific staining. Results: Microarray analysis revealed a significant increase in dentin matrix protein 1 (DMP1) expression in the 1/6G group. GSEA revealed enhanced Hedgehog signaling in this group. The weight and density of the cancellous bone were significantly greater in the 1/6G group than in the 1G group, as confirmed by histological analysis. Furthermore, the expression of insulin-like growth factor 1 (IGF-1), which is associated with mastication-induced bone formation, was increased in the 1/6G group. Although secreted phosphoprotein 1 (SPP1), which is associated with bone resorption under low mechanical stress, increased in the 1/6G group, receptor activator of nuclear factor kappa-B ligand (RANKL)-RANK signaling did not increase. No significant differences in the number or activity of osteoclasts were observed between the 1G and 1/6G groups. Conclusion: Bone formation, but not bone resorption, is promoted by lunar gravity and is associated with mastication. Proper oral management is necessary for extended lunar habitation.

DOI： 10.1016/j.jds.2025.03.032

Open Access

Scopus

Iron-catalyzed oxidative stress compromises cancer promotional effect of BRCA2 haploinsufficiency through mitochondria-targeted ferroptosis. Reviewed International journal Open Access

Maeda Y, Motooka Y, Akatsuka S, Tanaka H, Mashimo T, Toyokuni S

Redox biology Vol. 85 page： 103739 2025.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Redox Biology

Pathogenic variants in BRCA2 are hereditary risks for various cancers, including breast, ovary, pancreas and prostate. Genomic instability due to insufficient homologous recombination is thought as responsible for carcinogenesis. Reportedly, endogenous or exogenous aldehydes, including formaldehyde and acetaldehyde, suppress BRCA2 function. However, molecular sequences how BRCA2 insufficiency leads to carcinogenesis remains unelucidated. To assess whether Fenton reaction-based oxidative stress is a promotional risk factor of carcinogenesis in BRCA2 haploinsufficiency, we here applied iron-induced renal carcinogenesis to a newly established rat heterozygous mutation model of Brca2 (mutant, T1942Kfs/+; MUT). Rat MUT model, despite significant increase in spontaneous malignant tumors, showed no promotional effect on renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA) in contrast to our previous study using Brca1 mutant rats. Array-based comparative genome hybridization of renal cell carcinoma in MUT revealed significant increase in the frequency of homozygous Cdkn2A deletion. Whereas acute-phase analysis of the kidney after single or 1-week Fe-NTA administration to MUT showed suppressed lipid peroxidation, consistent with ferroptosis-resistance, ferroptosis and regeneration of tubular cells were coexistent with higher cytoplasmic catalytic Fe(II) levels in the subacute phase of MUT after 3-week Fe-NTA administration. Mechanistically, mitochondrial dysfunction with excess iron, promoted by insufficient BRCA2 presumably for maintaining DNA integrity, eventually initiated ferroptotic process. In conclusion, iron-dependent oxidative stress plays double-edged roles either for cell death or proliferation in carcinogenesis and its biological consequences are distinct between BRCA2 and BRCA1 haploinsufficiency. Our results suggest that iron-catalyzed oxidative stress is not a major driving force of carcinogenesis in BRCA2 pathogenic variants.

DOI： 10.1016/j.redox.2025.103739

LRP2 is a potential molecular target for nonsyndromic pathological myopia Reviewed International journal Open Access

Delaunay, K; Picard, E; Lassiaz, P; Jonet, L; Cannaya, V; Ruiz-Moreno, JM; Kojima, K; Vorum, H; Honore, B; Medrano, JR; Cehofski, LJ; Pussard, E; Kozyraki, R; Torriglia, A; Cases, O; Behar-Cohen, F

JCI INSIGHT Vol. 10 ( 15 ) 2025.8

Terrestrial iron sulfide minerals induce distinct regulation of intracellular redox homeostasis and iron assimilation. Reviewed International journal Open Access

Lyu Q, Kouketsu Y, Tazaki A, Kato M, Motooka Y, Toyokuni S

Ecotoxicology and environmental safety Vol. 298 page： 118327 2025.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Ecotoxicology and Environmental Safety

Repeated exposure to airborne terrestrial natural minerals may cause pneumoconiosis and lung cancer, among which iron sulfide is identified as an aggravating factor. In the biological system, iron-sulfur cluster is an inorganic cofactor that is evolutionarily conserved in all the living organisms. Whereas ferrous iron catalyzes the generation of hydroxyl radicals, sulfur is indispensable as a component of antioxidants, such as glutathione. Imbalanced redox homeostasis contributes to oxidative stress, causing ferroptosis, an iron-dependent regulated necrosis characterized by lipid peroxidation, resulting in various disorders. We undertook this study to understand the cellular regulatory mechanisms against major terrestrial minerals containing iron and sulfur from the viewpoint of cellular redox. We used fundamental iron sulfide minerals collected from natural sources to treat human macrophage and fibroblast cells and investigated the biological responses. Alterations in sulfane sulfur, glutathione and iron have been analyzed using either specific fluorescent probes or inductively coupled plasma mass spectrometry. Iron sulfide microparticles with high Fe/S ratio (pyrrhotite; Fe<inf>1-X</inf>S) induced more reactive sulfane species and glutathione, with less catalytic iron inside cells, whereas the mineral with low Fe/S ratio (pyrite; FeS<inf>2</inf>) exhibited the opposite effects. Notably both showed cytotoxicity, where pyrite caused ferroptosis but pyrrhotite led to non-ferroptotic disruption. Furthermore, assimilated cellular excess iron was secreted via CD63(+) exosome containing iron-loaded ferritin to the extracellular space with higher iron content in pyrrhotite. Our findings suggest that iron and sulfur work complementarily in maintaining intracellular redox homeostasis, which would be crucial to understand the associated pathology.

DOI： 10.1016/j.ecoenv.2025.118327

Selective Killing of Human Breast Cancer Cells by Plasma-Treated L-Arginine Solution Reviewed International journal Open Access

Du, LY; Miron, C; Kondo, T; Kumagai, J; Mizuno, M; Toyokuni, S; Kajiyama, H; Hori, M; Tanaka, H

PLASMA PROCESSES AND POLYMERS Vol. 22 ( 4 ) 2025.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Plasma Processes and Polymers

l-arginine is a nonessential amino acid that plays an important role in normal immune function and can be used as an adjuvant treatment for cancers. The antitumor effect of nonequilibrium atmospheric pressure plasma treated l-arginine solutions (PTA) was investigated in this research. The cancer-specific killing effect of PTA on human breast epithelial cells (MCF-10A) and human breast cancer cells (MCF-7) was proved. Liquid chromatography-tandem mass spectrometry was used to analyze the organic compounds formed in PTA, and their effects were individually evaluated by MTS assay, revealing that some compounds inhibited cell proliferation but lacked selectivity. PTA's selective cytotoxicity may result from a mixture of various compounds formed in plasma combined in a certain concentration.

DOI： 10.1002/ppap.202400192

Open Access

Web of Science

Scopus

Selenoprotein-mediated redox regulation shapes the cell fate of HSCs and mature lineages. Reviewed International journal Open Access

Aoyama Y, Yamazaki H, Nishimura K, Nomura M, Shigehiro T, Suzuki T, Zang W, Tatara Y, Ito H, Hayashi Y, Koike Y, Fukumoto M, Tanaka A, Zhang Y, Saika W, Hasegawa C, Kasai S, Kong Y, Minakuchi Y, Itoh K, Yamamoto M, Toyokuni S, Toyoda A, Ikawa T, Takaori-Kondo A, Inoue D

Blood Vol. 145 ( 11 ) page： 1149 - 1163 2025.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Blood

The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of messenger RNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we used selenocysteine transfer RNA (tRNASec) gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs’ self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. Although Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.

DOI： 10.1182/blood.2024025402

Web of Science

Scopus

PubMed

Wavelength-dependency of the impact of light on proliferation and DNA damage of corneal cells in vitro Reviewed International journal Open Access

Francon, A; Behar-Cohen, F; Torriglia, A

JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY Vol. 264 2025.3

Silicone oil, an intraocular surgical adjuvant, induces retinal ferroptosis. Reviewed International journal Open Access

Shimizu H, Tanaka H, Tazaki A, Yamada K, Suzumura A, Ota J, Ushio-Watanabe N, Zheng H, Kataoka K, Hara H, Nishikawa Y, Yasukawa T, Suzuma K, Terasaki H, Nishiguchi KM, Kato M, Toyokuni S, Kaneko H

Free radical biology & medicine Vol. 228 page： 33 - 43 2025.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Free Radical Biology and Medicine

Vitrectomy with silicone oil (SO) endotamponade is an effective treatment for vision-threatening retinal diseases. However, unexplained vision impairment has been reportedly critical side effects. Previously, we reported that the eyes with ocular toxoplasmosis showed retinal ferroptosis with the clinical sign of reduced intravitreal iron (Fe). We also found that total iron levels in sub-silicone oil fluid (SOF) in eyes with SO endotamponade were significantly reduced. We hypothesized that the cause of complications related to SO endotamponade is retinal ferroptosis and that low total iron in SOF is a secondary change that occurs similarly to the changes in ocular toxoplasmosis. In this study, we measured total iron levels in ocular fluid from patients, rabbits with SO endotamponade. Retinal iron taken up from the SOF was evaluated using laser ablation inductively coupled plasma mass spectrometry in human and rabbit eyes. Retinal ferroptosis was confirmed by immunohistochemistry of 4-hydrox-2-nonenal-modified proteins, FeRhoNox-1 staining, western blotting and RT-PCR. We found low total iron levels in the SOF, increased oxidative stress and Fe uptake from the SOF into the retinae of human and rabbit eyes, as well as decreased GPx4 expression, increased FeRhoNox-1 signals and altered Fe-related gene expression in SO-filled rabbit eyes. Of note, the target of ferroptosis was Müller cells. We generated an in vitro silicone oil-filled eye model using MIO-M1 cells (a human Müller cell line). The in vitro SO-filled eye model showed decreased GPx4 expression and increased intracellular catalytic Fe(II), an increase in ferroptosis, prevention of cell death by ferrostatin-1, a ferroptosis inhibitor, and altered Fe-related gene expression. These results indicate that the cause of complications related to SO endotamponade was the induction of retinal (Müller cell) ferroptosis, which can be prevented by ferrostatin-1.

DOI： 10.1016/j.freeradbiomed.2024.12.039

Repeated exposure to low doses of light induces retinal damage in vivo in a wavelength-dependent manner Reviewed International journal Open Access

Françon, A; Jonet, L; Behar-Cohen, F; Torriglia, A

ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY Vol. 290 2025.1

Decoding the molecular enigma behind asbestos and fibrous nanomaterial-induced carcinogenesis International journal Open Access

Toyokuni Shinya, Kong Yingyi

Journal of Occupational Health Vol. 67 ( 1 ) page： n/a 2025.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Society for Occupational Health

Objectives: The natural fibrous mineral, asbestos, has been useful in industry for many centuries. In the 1960s, epidemiology recognized the association between asbestos exposure and mesothelioma, and in 1987 the International Agency for Research on Cancer designated all kinds of asbestos as Group 1 carcinogens. However, various scientific enigmas remained regarding the molecular mechanisms of asbestos-induced mesothelial carcinogenesis. This review article was undertaken to reveal and summarize recent discoveries to resolve those enigmas.Methods: We collected recent important findings from our own laboratory and others to explain why mesothelial cells are the target for asbestos-induced carcinogenesis and what are the key molecular mechanisms.Results: The long incubation period of 30-40 years for mesothelial carcinogenesis after asbestos exposure allows the asbestos fibers to go through the pulmonary parenchyma from the central to peripheral portions and ultimately reach the parietal mesothelium by piercing visceral pleura. Asbestos fibers have affinity for hemoglobin and histones, thus accumulating iron on the surface while traveling through the lung. Mesothelial cells are phagocytic cells, engulfing iron-coated asbestos fibers. Accordingly, homozygous deletion of the p16INK4a tumor suppressor gene, a signature of excess iron-induced carcinogenesis, is acquired through oxidative DNA damage. Recently, exosome-dependent iron transfer from asbestos-fed macrophages to mesothelial cells was reported. Similar molecular mechanisms are observed with multiwalled carbon nanotubes of ~50-nm diameter.Conclusions: Physical dimensions, biopersistence, and affinity to iron/histones are essential for fibrous material to be carcinogenic to mesothelial cells. Therefore, local iron reduction may be a strategy to prevent mesothelial carcinogenesis.

DOI： 10.1093/joccuh/uiae064

BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile-induced mesothelioma via ferroptosis resistance Reviewed International journal

Luo, YG; Toyokuni, S

CANCER SCIENCE Vol. 116 page： 193 - 193 2025.1

Complementary Interplay of Iron and Sulfur: Implications for Cellular Redox Regulation Reviewed International journal

Lyu, QY; Toyokuni, S; Kouketsu, Y

CANCER SCIENCE Vol. 116 page： 1388 - 1388 2025.1

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Papers - TOYOKUNI Shinya