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Hypoxia suppresses the development and hatchability of\n                    <jats:italic>C. irritans<\/jats:italic>\n                    during the tomont stage, which often develops on the seafloor under hypoxic conditions. Despite this knowledge, the underlying adaptation mechanisms of tomonts remain poorly understood. We aimed to determine how hypoxia reprograms tomont metabolism and whether ferroptosis contributes to hypoxia-induced vulnerability. Herein, metabolomic profiling revealed 2,964 differential metabolites under hypoxia. Notably, there were significantly elevated glucose levels, suggesting enhanced glycolytic activity. Enzymatic and qRT-PCR analyses further confirmed hypoxia-induced metabolic reprogramming, including increased hexokinase and pyruvate kinase activities and upregulation of glycolysis-related genes. Hypoxia also induced surface depressions, disrupted cell walls, mitochondrial deformation, reduced mitochondrial membrane potential, disrupted energy homeostasis, and increased NAD\u207a\/NADH ratio fluctuations and lactate accumulation. To probe ferroptotic susceptibility under hypoxia, hypoxic tomonts were exposed to the ferroptosis inducer erastin, resulting in a hatchability of 13% and promoting reactive oxygen species (ROS) accumulation, lipid peroxidation, and mitochondrial damage. Fluorescence staining revealed strong PI and ROS signals in hypoxic tomonts exposed to the ferroptosis inducer erastin. Notably, mitochondrial dysfunction was accompanied by Ca\n                    <jats:sup>2<\/jats:sup>\n                    \u207a and Fe\n                    <jats:sup>2<\/jats:sup>\n                    \u207a accumulation. Ferroptosis-related genes were upregulated at 24\u00a0h post-hypoxia induction. In contrast,\n                    <jats:italic>gpx4<\/jats:italic>\n                    and mitochondrial electron transport chain components were downregulated at 48\u00a0h post-hypoxia induction. These findings demonstrate that hypoxia triggers glycolytic reprogramming and mitochondrial dysfunction in\n                    <jats:italic>C. irritans<\/jats:italic>\n                    , whereas erastin induces ferroptosis under hypoxic stress. This study provides new insights into protozoan hypoxia adaptation and highlights ferroptosis as a potential therapeutic target for controlling parasitic infections in marine aquaculture.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s44154-025-00275-0","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T02:52:56Z","timestamp":1768186376000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hypoxia-induced oxidative stress and mitochondrial damage initiate ferroptosis in Cryptocaryon irritans, a protozoan parasite of marine fish"],"prefix":"10.1007","volume":"6","author":[{"given":"Baotun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueli","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huicheng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jizhen","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hebing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanfu","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anxing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"275_CR1","first-page":"757","volume":"65","author":"H Abe","year":"2000","unstructured":"Abe H (2000) Role of histidine-related compounds as intracellular proton buffering constituents in vertebrate muscle. 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