Tetrodotoxin (TTX) is a neurotoxin that binds to sodium channels and blocks sodium conduction. Importantly, TTX has been increasingly detected in edible aquatic organisms. Because of this and the lack of specific antidotes, TTX poisoning is now a major threat to public health. However, it is of note that ultra-low dose TTX is an excellent analgesic with great medicinal value. These contradictory effects highlight the need for further research to elucidate the impacts and functional mechanisms of TTX. This review summarizes the latest research progress in relation to TTX sources, analogs, mechanisms of action, detection methods, poisoning symptoms, therapeutic options, biosynthesis pathways, and mechanisms of transport and accumulation in pufferfish. This review also provides a theoretical basis for reducing the poisoning risks associated with TTX and for establishing an effective system for its use and management to ensure the safety of fisheries and human health.

The potent toxicity of tetrodotoxin (TTX) has long constrained sustainable growth in pufferfish aquaculture. Takifugu bimaculatus, an economically important species farmed along the coast of Fujian, China, remains poorly understood regarding how it transports and accumulates this potent neurotoxin. To address this gap, we combined transcriptomic and proteomic analyses to characterize the molecular responses of T. bimaculatus to TTX exposure. After oral administration, TTX primarily accumulated in the liver, ovaries, and skin. Multi-omics profiling revealed 163 differentially expressed genes (DEGs) and 88 differentially expressed proteins (DEPs) in liver tissue, together with 239 DEGs and 179 DEPs in ovarian tissue. KEGG pathway analysis suggests that the liver maintains homeostasis by regulating ion concentrations and restructuring lipid raft architectures, alongside coordinated carrier protein activity. This likely supports active TTX uptake and directed transport toward the ovaries and skin, followed by metabolic clearance. By contrast, ovarian tissues appear to establish a stable, long-term reservoir through cytoskeletal remodeling, enhanced interactions with the extracellular matrix, and activated endocytic pathways. Together, these findings offer insights into how T. bimaculatus accumulates and transports TTX, laying groundwork for identifying key transporter genes, clarifying TTX metabolic pathways, and developing practical food safety controls.