Mammals produce cyclo -octasulfur to suppress lipid peroxidation and ferroptosis
Elemental sulfur is an evolutionarily ancient metabolite, yet its generation, storage, and function in animals have remained unclear. We show that mammals harbor elemental sulfur in the form of its most stable allotrope, cyclo -octasulfur (S 8 ). We found that S 8 accumulates to millimolar concentrations in mitochondrial membranes and in lipid droplets in both mouse and human cells. We further identified lipid droplet–associated nitric oxide synthase as a source of S 8 biosynthesis and found that S 8 accumulation in lipid droplets limits lipid peroxidation and suppresses ferroptosis. Accordingly, intra-articular injection of solubilized S 8 reduces lipid peroxidation in a mouse model of osteoarthritis. Together, these findings reveal an endogenous pool of S 8 in mammals that may protect cells from oxidative membrane damage by modulating cellular sensitivity to ferroptosis.
Authors
- Tomoaki Ida (ORCID: https://orcid.org/0000-0002-4443-6127)
- Yuka Unno (ORCID: https://orcid.org/0000-0002-9877-0200)
- Mieko Arisawa (ORCID: https://orcid.org/0000-0002-9561-2653)
- Uladzimir Barayeu (ORCID: https://orcid.org/0000-0001-8426-166X)
- Seiryo Ogata (ORCID: https://orcid.org/0000-0001-5422-7823)
- James A. Olzmann (ORCID: https://orcid.org/0000-0001-7751-8316)
- Yasuo Watanabe (ORCID: https://orcid.org/0000-0003-2232-0091)
- Ryo Ushioda (ORCID: https://orcid.org/0000-0003-2775-8746)
- Yukihiro Tsuchiya (ORCID: https://orcid.org/0000-0002-1526-3351)
- Marcus Conrad (ORCID: https://orcid.org/0000-0003-1140-5612)
- Kazuki Fusegawa
- Takayuki Shimizu (ORCID: https://orcid.org/0000-0002-2956-9386)
- Minkyung Jung (ORCID: https://orcid.org/0000-0002-6489-1696)
- Albert van der Vliet (ORCID: https://orcid.org/0000-0003-0923-0016)
- Tsuyoshi Takata (ORCID: https://orcid.org/0000-0002-6691-2569)
- Shintaro Noguchi
- Takashi Suzuki (ORCID: https://orcid.org/0000-0003-0195-815X)
- Tianli Zhang (ORCID: https://orcid.org/0000-0002-0543-4006)
- Frauke Gräter (ORCID: https://orcid.org/0000-0003-2891-3381)
- Lorenzo Catti (ORCID: https://orcid.org/0000-0003-0727-0620)
- Masanobu Morita (ORCID: https://orcid.org/0000-0002-5259-5371)
- Hozumi Motohashi (ORCID: https://orcid.org/0000-0002-7261-1033)
- Huige Li (ORCID: https://orcid.org/0000-0003-3458-7391)
- Dennis J. Stuehr (ORCID: https://orcid.org/0000-0002-0960-6848)
- Camilo A. Aponte-Santamaria (ORCID: https://orcid.org/0000-0002-8427-6965)
- Naoko Tanda (ORCID: https://orcid.org/0000-0002-6460-6074)
- Takaaki Akaike (ORCID: https://orcid.org/0000-0002-0623-1710)
- Eikan Mishima (ORCID: https://orcid.org/0000-0002-3706-2745)
- Bernd Moosmann (ORCID: https://orcid.org/0000-0002-7703-7712)
- Takakazu Nakabayashi (ORCID: https://orcid.org/0000-0003-2942-2189)
- Akira Nishimura (ORCID: https://orcid.org/0000-0002-0168-9829)
- Tobias P. Dick (ORCID: https://orcid.org/0000-0003-1367-973X)
- Seji Asamitsu (ORCID: https://orcid.org/0009-0007-3315-3061)
- Ning Xia (ORCID: https://orcid.org/0000-0002-5553-1752)
- Michito Yoshizawa (ORCID: https://orcid.org/0000-0002-0543-3943)
- Ryo Yamaguchi (ORCID: https://orcid.org/0000-0002-9356-7051)
- Mike Lange (ORCID: https://orcid.org/0000-0002-4728-9927)
- Fumiko Yano (ORCID: https://orcid.org/0000-0002-0602-1094)
- Paulius Greicius
- Takanori Ishida
- Saber Boushehri
- Yuexuan Pan
- Tetsuro Matsunaga
Institutions
- University of Vermont (US)
- SHOWA Medical University (JP)
- Cleveland Clinic (US)
- Kyushu University (JP)
- Horiba (Japan) (JP)
- Kyoto Sangyo University (JP)
- Iwate University (JP)
- German Cancer Research Center (DE)
- Johannes Gutenberg University Mainz (DE)
- Tohoku University (JP)
- Akita University (JP)
- Heidelberg University (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Max Planck Institute for Polymer Research (DE)
- Life Science Institute (JP)
- Target (Germany) (DE)
- DKFZ-ZMBH Alliance (DE)
- SHOWA Medical University Hospital (JP)
- Max Planck School Matter to Life
- Technical University of Munich (DE)
- Heidelberg Institute for Theoretical Studies (DE)
- Showa Pharmaceutical University (JP)
- University of California, Berkeley (US)
- Nara Women's University (JP)
Publication Details
- Journal
- Science
- Published
- 2026-09-24
- DOI
- https://doi.org/10.1126/science.aec5473
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00