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

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

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

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

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

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Decoding the molecular enigma behind asbestos and fibrous nanomaterial-induced carcinogenesis. Reviewed International journal

Toyokuni S, Kong Y

Journal of occupational health Vol. 67 ( 1 ) 2025.1

Heterozygous mutation in BRCA2 induces accelerated age-dependent decline in sperm quality with male subfertility in rats. Reviewed International journal Open Access

Motooka Y, Tanaka H, Maeda Y, Katabuchi M, Mashimo T, Toyokuni S

Scientific reports Vol. 15 ( 1 ) page： 447 2025.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

Tumor suppressor BRCA2 executes homologous recombination to repair DNA double-strand breaks in collaboration with RAD51, involving exon 11 and 27. Exon 11 constitutes a region where pathogenic variants (PVs) accumulate, and mutations in this region are known to contribute to carcinogenesis. However, the impact of the heterozygous PVs of BRCA2 exon 11 on the life quality beyond cancer risk, including male fertility, remains unclear. Here, we established a rat model with a frameshift on the seventh BRC repeat in Brca2 exon 11 (Brca2+/p.T1942fs), which is homologous to human BRCA2+/p.T1974fs, using CRISPR/Cas9 system. Our analyses revealed that the heterozygous rats with the PV in the BRCA2 exon 11 showed increased DNA double-strand breaks and apoptosis in spermatogonia and spermatocytes, accelerated testicular germ cell loss, and deterioration in sperm quality according with aging, ultimately resulting in early male reproductive dysfunction. Of note, these alterations in testes and sperm, including DNA fragmentation in spermatozoa, were observed from completion of sexual maturation. The present findings suggest that it is crucial to consider not only cancer risk but also potential declines in reproductive capacity in men carrying BRCA2 exon 11 PVs. Further investigation is warranted to determine whether similar traits appear in humans.

DOI： 10.1038/s41598-024-84184-8

Open Access

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New era of plasma dentistry. Reviewed International journal

Sato K, Tanaka H, Okazaki Y, Hori M, Hibi H, Toyokuni S

Free radical research Vol. 58 ( 12 ) page： 868 - 874 2024.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Free Radical Research

Plasma, which was coined by Irving Langmuir in 1928, is the fourth physical state after the solid/liquid/gas phases. Low-temperature plasma (LTP) is a contradictory condition that involves high energy with free radicals at near-body temperatures and was developed through engineering in the 1990’s. Research on LTP in engineering and medical fields has rapidly developed since the 2000’s. LTP can be applied through direct or indirect exposure, and there are advantages to both methods. In the medical field, LTP has been found to exert several effects, such as wound healing, hemostasis and anticancer effects, mainly based on different levels of oxidative stress. In the dental field, studies have been performed on LTP applications for general dental procedures, such as restorative, periodontal and prosthodontic procedures, and for oral cancer treatment. Many studies have demonstrated the effectiveness of LTP. Compared with other organs, the anatomical characteristic of the oral cavity is easy direct observation, which is highly advantageous for clinical applications. Due to its good accessibility and efficiency, plasma dentistry is expected to be applied to various dental applications in clinics in the near future.

DOI： 10.1080/10715762.2024.2446323

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Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract. Reviewed International coauthorship International journal

Wei Z, Hao C, Radeen KR, Hao Z, Kettimuthu K, Maner-Smith K, Toyokuni S, Fan X

Proceedings of the National Academy of Sciences of the United States of America Vol. 121 ( 48 ) page： e2407842121 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences of the United States of America

The human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis-independent but ferroptosis-mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens-specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.

DOI： 10.1073/pnas.2407842121

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Effects of autophagy on the selective death of human breast cancer cells exposed to plasma-activated Ringer's lactate solution. Reviewed International coauthorship International journal

Yamakawa T, Tanaka A, Miron C, Nakamura K, Kajiyama H, Toyokuni S, Mizuno M, Hori M, Tanaka H

Free radical research Vol. 58 ( 11 ) page： 758 - 769 2024.11

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

Plasma-activated Ringer’s lactate (PAL) solution prepared by irradiating an intravenous solution with a non-equilibrium atmospheric pressure plasma is a potential new cancer therapy having no side effects. However, the induction of autophagy to avoid cell death has been confirmed to occur following exposure to PAL solution. It is thought that the antitumor effect of PAL solution could be weakened by this process, which is meant to maintain homeostasis in cells and assists tumorigenesis. Thus, it would be helpful to devise PAL-based cancer therapies that inhibit autophagy. Unfortunately, it is not yet clear which substances in PAL solution promote autophagy. The present work examined the mechanism by which PAL solution induces autophagy when treating MCF-7 human breast cancer cells. Autophagy was found to be temporarily induced upon exposure to PAL solution, suggesting that this effect contributes to cell proliferation. Although autophagy is associated with reactive oxygen and nitrogen species and/or acidic environments, in this study, significant autophagy was observed using a PAL solution diluted 1/256x without these stressors. Acetate, glyoxylate and 2,3-dimethyltartrate in the PAL solution were determined to promote autophagy. Interestingly, 2,3-dimethyltartrate was found to either induce cell death or autophagy depending on the concentration.

DOI： 10.1080/10715762.2024.2433965

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Low-temperature plasma as a strategy to achieve SDGs. Reviewed International journal

Tanaka H, Ishikawa K, Toyokuni S

Free radical research Vol. 58 ( 10 ) page： 594 - 595 2024.10

Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease. Reviewed International coauthorship International journal Open Access

Peleman C, Hellemans S, Veeckmans G, Arras W, Zheng H, Koeken I, Van San E, Hassannia B, Walravens M, Kayirangwa E, Beyene NT, Van Herck MA, De Vos WH, Pintelon I, van Nassauw L, Oosterlinck B, Smet A, Vits L, Dirinck E, Verrijken A, De Man J, Van Eyck A, Kwanten WJ, Vonghia L, Driessen A, Augustyns K, Toyokuni S, De Winter B, Van Steenkiste C, Francque S, Vanden Berghe T

Cell death and differentiation Vol. 31 ( 9 ) page： 1113 - 1126 2024.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Cell Death and Differentiation

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD. (Figure presented.)

DOI： 10.1038/s41418-024-01348-9

Ferroptosis in health and disease. Reviewed International coauthorship International journal Open Access

Berndt C, Alborzinia H, Amen VS, Ayton S, Barayeu U, Bartelt A, Bayir H, Bebber CM, Birsoy K, Böttcher JP, Brabletz S, Brabletz T, Brown AR, Brüne B, Bulli G, Bruneau A, Chen Q, DeNicola GM, Dick TP, Distéfano A, Dixon SJ, Engler JB, Esser-von Bieren J, Fedorova M, Friedmann Angeli JP, Friese MA, Fuhrmann DC, García-Sáez AJ, Garbowicz K, Götz M, Gu W, Hammerich L, Hassannia B, Jiang X, Jeridi A, Kang YP, Kagan VE, Konrad DB, Kotschi S, Lei P, Le Tertre M, Lev S, Liang D, Linkermann A, Lohr C, Lorenz S, Luedde T, Methner A, Michalke B, Milton AV, Min J, Mishima E, Müller S, Motohashi H, Muckenthaler MU, Murakami S, Olzmann JA, Pagnussat G, Pan Z, Papagiannakopoulos T, Pedrera Puentes L, Pratt DA, Proneth B, Ramsauer L, Rodriguez R, Saito Y, Schmidt F, Schmitt C, Schulze A, Schwab A, Schwantes A, Soula M, Spitzlberger B, Stockwell BR, Thewes L, Thorn-Seshold O, Toyokuni S, Tonnus W, Trumpp A, Vandenabeele P, Vanden Berghe T, Venkataramani V, Vogel FCE, von Karstedt S, Wang F, Westermann F, Wientjens C, Wilhelm C, Wölk M, Wu K, Yang X, Yu F, Zou Y, Conrad M

Redox biology Vol. 75 page： 103211 2024.9

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

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

DOI： 10.1016/j.redox.2024.103211

Ferroptosis induced by plasma-activated Ringer's lactate solution prevents oral cancer progression. Reviewed International journal Open Access

Sato K, Yang M, Nakamura K, Tanaka H, Hori M, Nishio M, Suzuki A, Hibi H, Toyokuni S

Oral diseases Vol. 30 ( 6 ) page： 3912 - 3924 2024.9

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Oral Diseases

Objective: This study aimed to investigate the effect of plasma-activated Ringer's lactate solution (PAL) on oral squamous cell carcinoma (OSCC) cells and carcinogenic processes with a particular focus on iron and collagenous matrix formation. Materials and Methods: We used three OSCC cell lines, one keratinocyte cell line, and two fibroblast lines, and cell viability assays, immunoblotting, flow cytometry, and transmission electron microscopy were performed to evaluate the effect and type of cell death. The effect of PAL treatment on lysyl oxidase (LOX) expression was investigated in vitro and in vivo. Tamoxifen-inducible Mob1a/b double-knockout mice were used for the in vivo experiment. Results: PAL killed OSCC cells more effectively than the control nontumorous cells and suppressed cell migration and invasion. Ferroptosis occurred and the protein level of LOX was downregulated in cancer cells in vitro and in vivo. Additionally, PAL improved the survival rate of mice and suppressed collagenous matrix formation. Conclusions: We demonstrated that PAL specifically kills OSCC cells and that ferroptosis occurs in vitro and in vivo. Furthermore, PAL can prevent carcinogenesis and improve the survival rate of oral cancer, especially tongue cancer, by changing collagenous matrix formation via LOX suppression.

DOI： 10.1111/odi.14827

A guideline on the molecular ecosystem regulating ferroptosis. Reviewed International coauthorship International journal

Dai E, Chen X, Linkermann A, Jiang X, Kang R, Kagan VE, Bayir H, Yang WS, Garcia-Saez AJ, Ioannou MS, Janowitz T, Ran Q, Gu W, Gan B, Krysko DV, Zhu X, Wang J, Krautwald S, Toyokuni S, Xie Y, Greten FR, Yi Q, Schick J, Liu J, Gabrilovich DI, Liu J, Zeh HJ, Zhang DD, Yang M, Iovanna J, Kopf M, Adolph TE, Chi JT, Li C, Ichijo H, Karin M, Sankaran VG, Zou W, Galluzzi L, Bush AI, Li B, Melino G, Baehrecke EH, Lotze MT, Klionsky DJ, Stockwell BR, Kroemer G, Tang D

Nature cell biology Vol. 26 ( 9 ) page： 1447 - 1457 2024.9

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

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

DOI： 10.1038/s41556-024-01360-8

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Papers - TOYOKUNI Shinya