Monitoring ferroptosis in vivo: Iron-driven volatile oxidized lipids as breath biomarkers
Yuta Matsuoka, Yoshinori Katsumata, Po–Sung Chu, Rei Morikawa, Nobuhiro Nakamoto, Kohta Iguchi, Ken Takahashi, Tadayuki Kou, Ryo Ito, Kojiro Taura, Shujiro Yazumi, Hiroaki Terajima, Gen Honjo, Genki Ichihara, Yuki Muramoto, Kazuki Sato, Rae Maeda, Hata Kazuhiro, Naoya Toriu, Motoko Yanagita, Masaki Tajima, Sidonia Fagarasan, Ken‐ichi Yamada, Yuki Sugiura
Abstract
Ferroptosis, an iron-dependent cell death mechanism characterized by excessive lipid peroxidation, has been implicated in numerous human diseases and organ pathologies. However, current detection methods necessitate invasive tissue sampling to assess lipid peroxidation, making noninvasive detection of ferroptosis in human subjects extremely challenging. In this study, we employed oxidative volatolomics to comprehensively characterize the volatile oxidized lipids (VOLs) produced during ferroptosis. Polyunsaturated fatty acid-derived VOLs were generated via iron-dependent LPO and released extracellularly as ferroptosis progressed. These VOLs were specifically generated during hepatic ferroptosis in mouse models of acetaminophen-induced liver injury and metabolic dysfunction-associated steatohepatitis (MASH) and were also detectable in the exhaled breath of patients with MASH. Specific VOLs released upon iron-dependent LPO are potential markers of ferroptosis in vivo and may facilitate noninvasive monitoring of cellular health in humans.