Insights into the Virulence and Antimicrobial Resistance of Staphylococcus hyicus Isolates from Spanish Swine Farms.

Staphylococcus hyicus is a significant pathogen in swine, primarily causing exudative epidermitis. Addressing S. hyicus infections requires both the characterization of virulence and antimicrobial resistance (AMR) in farm-recovered isolates. This study aimed to characterize the virulence, AMR, and biofilm formation of S. hyicus isolates from Spanish swine farms. A total of 49 isolates were analyzed, originating from animals with cutaneous, reproductive, and systemic clinical signs. Half of the isolates (49.0%) were positive for at least one virulence factor (VF) gene, with SHETA being the most frequent (28.6%). A high frequency of multidrug resistant (MDR) isolates was observed (83.7%), with significant resistance to commonly used antimicrobials, including lincosamides (83.7%), pleuromutilins (81.6%), penicillins (75.5%), and tetracyclines (73.5%). All isolates exhibited robust in vitro biofilm formation capacity (DC = 15.6 ± 7.0). Significant associations were found between VFs, biofilm formation, and AMR patterns, highlighting the link between the resistance to lincosamides and pleuromutilins (p < 0.001; Φ = 0.57) and macrolides (p < 0.001; Φ = 0.48), and the association of AMR with the ExhC and ExhD VF genes. These findings underscore the need for targeted diagnostics to improve management and therapeutic strategies to mitigate the impact of S. hyicus on swine production.

Neuroinflammation and Brain Health Risks in Veterans Exposed to Burn Pit Toxins.

Military burn pits, used for waste disposal in combat zones, involve the open-air burning of waste materials, including plastics, metals, chemicals, and medical waste. The pits release a complex mixture of occupational toxic substances, including particulate matter (PM), volatile organic compounds (VOCs), heavy metals, dioxins, and polycyclic aromatic hydrocarbons (PAHs). Air pollution significantly impacts brain health through mechanisms involving neuroinflammation. Pollutants penetrate the respiratory system, enter the bloodstream, and cross the blood-brain barrier (BBB), triggering inflammatory responses in the central nervous system (CNS). Chronic environmental exposures result in sustained inflammation, oxidative stress, and neuronal damage, contributing to neurodegenerative diseases and cognitive impairment. Veterans exposed to burn pit toxins are particularly at risk, reporting higher rates of respiratory issues, neurological conditions, cognitive impairments, and mental health disorders. Studies demonstrate that Veterans exposed to these toxins have higher rates of neuroinflammatory markers, accelerated cognitive decline, and increased risks of neurodegenerative diseases. This narrative review synthesizes the research linking airborne pollutants such as PM, VOCs, and heavy metals to neuroinflammatory processes and cognitive effects. There is a need for targeted interventions to mitigate the harmful and escalating effects of environmental air pollution exposures on the CNS, improving public health outcomes for vulnerable populations, especially for Veterans exposed to military burn pit toxins.

Investigating the adherence factors of Escherichia coli at the bovine recto-anal junction.

Shiga toxin-producing Escherichia coli (STEC) are major foodborne pathogens that result in thousands of hospitalizations each year in the United States. Cattle, the natural reservoir, harbor STEC asymptomatically at the recto-anal junction (RAJ). The molecular mechanisms that allow STEC and non-STEC E. coli to adhere to the RAJ are not fully understood, in part because most adherence studies utilize human cell culture models. To identify a set of bovine-specific E. coli adherence factors, we used the primary RAJ squamous epithelial (RSE) cell-adherence assay to coculture RSE cells from healthy Holstein cattle with diverse E. coli strains from bovine and nonbovine sources. We hypothesized that a comparative genomic analysis of the strains would reveal factors associated with RSE adherence. After performing adherence assays with historical strains from the E. coli Reference Center (n = 62) and strains newly isolated from the RAJ (n = 15), we used the bioinformatic tool Roary to create a pangenome of this collection. We classified strains as either low or high adherence and using the Scoary program compiled a list of accessory genes correlated with the "high adherence" strains. While none of the correlations were statistically significant, several gene clusters were associated with the high-adherence phenotype, including two that encode uncharacterized proteins. We also demonstrated that non-STEC E. coli strains from the RAJ are more adherent than other isolates and can outcompete STEC in coculture with RSEs. Further analysis of adherence-associated gene clusters may lead to an improved understanding of the molecular mechanisms of RSE adherence and may help develop probiotics targeting STEC in cattle. IMPORTANCE: E. coli strains that produce Shiga toxin cause foodborne illness in humans but colonize cattle asymptomatically. The molecular mechanisms that E. coli uses to adhere to cattle cells are largely unknown. Various strategies are used to control E. coli in livestock and limit the risk of outbreaks. These include vaccinating animals against common E. coli strains and supplementing their feed with probiotics to reduce the carriage of pathogens. No strategy is completely effective, and probiotics often fail to colonize the animals. We sought to clarify the genes required for E. coli adherence in cattle by quantifying the attachment to bovine cells in a diverse set of bacteria. We also isolated nonpathogenic E. coli from healthy cows and showed that a representative isolate could outcompete pathogenic strains in cocultures. We propose that the focused study of these strains and their adherence factors will better inform the design of probiotics and vaccines for livestock.

Chemical genetic analysis of enoxolone inhibition of C. difficile toxin production reveals adenine deaminase and ATP synthase as anti-virulence targets.

Toxins TcdA and TcdB are the main virulence factors of Clostridioides difficile, a leading cause of hospital-acquired diarrhea. Despite their importance, there is a significant knowledge gap of druggable targets for inhibiting toxin production. To address this, we screened non-antibiotic phytochemicals to identify potential chemical genetic probes to discover anti-virulence drug targets. This led to the identification of 18ß-glycyrrhetinic acid (enoxolone), a licorice metabolite, as an inhibitor of TcdA and TcdB biosynthesis. Using affinity-based proteomics, potential targets were identified as ATP synthase subunit alpha (AtpA) and adenine deaminase (Ade, which catalyzes conversion of adenine to hypoxanthine in the purine salvage pathway). To validate these targets, a multi-faceted approach was adopted. Gene silencing of ade and atpA inhibited toxin biosynthesis, while SPR and ITC molecular interaction analyses revealed direct binding of enoxolone to Ade. Metabolomics demonstrated enoxolone induced the accumulation of adenosine, while depleting hypoxanthine and ATP in C. difficile. Transcriptomics further revealed enoxolone dysregulated phosphate uptake genes, which correlated with reduced cellular phosphate levels. These findings suggest that enoxolone's cellular action is multi-targeted. Accordingly, supplementation with both hypoxanthine and triethyl phosphate (TEP), a phosphate source, was required to fully restore toxin production in the presence of enoxolone. In conclusion, through the characterization of enoxolone, we identified promising anti-virulence targets that interfere with nucleotide salvage and ATP synthesis, which may also block toxin biosynthesis.

The Role of the Gut Microbiota in Complications among Hemodialysis Patients.

The composition of the gut microbiota varies among end-stage renal disease (ESRD) patients on the basis of their mode of renal replacement therapy (RRT), with notably more pronounced dysbiosis occurring in those undergoing hemodialysis (HD). Interventions such as dialysis catheters, unstable hemodynamics, strict dietary restrictions, and pharmacotherapy significantly alter the intestinal microenvironment, thus disrupting the gut microbiota composition in HD patients. The gut microbiota may influence HD-related complications, including cardiovascular disease (CVD), infections, anemia, and malnutrition, through mechanisms such as bacterial translocation, immune regulation, and the production of gut microbial metabolites, thereby affecting both the quality of life and the prognosis of patients. This review focuses on alterations in the gut microbiota and its metabolites in HD patients. Additionally, understanding the impact of the gut microbiota on the complications of HD could provide insights into the development of novel treatment strategies to prevent or alleviate complications in HD patients.

Phenotypic and genomic comparison of three human outbreak and one cattle-associated Shiga toxin-producing Escherichia coli O157:H7.

Escherichia coli O157:H7-adulterated food products are associated with disease outbreaks in humans. Although cattle feces are a source for E. coli O157:H7 contamination, it is unclear if human-associated outbreak isolates differentially colonize and shed in the feces of cattle from that of non-outbreak isolates. It is also unclear if phenotypes, such as biofilm formation, cell attachment, or toxin production, differentiate environmental E. coli O157:H7 isolates from those associated with human illness. The objective of this study was to compare the genotypes and phenotypes of a diverse set of E. coli O157:H7 isolates, with the intent of identifying differences that could inform cattle colonization and fecal shedding, along with virulence potential in humans. Isolates differed in attachment phenotypes on human Caco-2 cells and bovine-derived recto-anal junction squamous epithelial cells, with curli having a strong impact on attachment to the human-derived cell line. The prototypical E. coli O157 isolate EDL933 had the greatest expression of the adhesin gene iha, yet it had decreased expression of the virulence genes stx2, eae, and ehxA compared the lineage I/II isolates RM6067W and/or FRIK1989. Strong or weak biofilm production was not associated with significant differences in cattle colonization or shedding, suggesting biofilms may not play a major role in cattle colonization. No significant differences in cattle colonization and fecal shedding were detected, despite genomic and in vitro phenotypic differences. The outbreak isolate associated with the greatest incidence of hemolytic uremic syndrome, RM6067W, induced the greatest Vero cell cytotoxicity and had the greatest stx2 gene expression. IMPORTANCE: Foodborne illness has major impacts on global health and imposes financial hardships on food industries. Escherichia coli serotype O157:H7 is associated with foodborne illness. Cattle feces are a source of E. coli O157:H7, and routine surveillance has led to an abundance of E. coli O157:H7 genomic data. The relationship between E. coli O157:H7 genome and phenotype is not clearly discerned for cattle colonization/shedding and improved understanding could lead to additional strategies to limit E. coli O157:H7 in the food chain. The goal of the research was to evaluate genomic and phenotypic attributes of E. coli O157:H7 associated with cattle colonization and shedding, environmental persistence, and human illness. Our results indicate variations in biofilm formation and in vitro cellular adherence was not associated with differences in cattle colonization or shedding. Overall, processes involved in cattle colonization and various phenotypes in relation to genotype are complex and remain not well understood.

A developmental gradient reveals biosynthetic pathways to eukaryotic toxins in monocot geophytes.

Numerous eukaryotic toxins that accumulate in geophytic plants are valuable in the clinic, yet their biosynthetic pathways have remained elusive. A notable example is the >150 Amaryllidaceae alkaloids (AmAs), including galantamine, an FDA-approved treatment for Alzheimer's disease. We show that while AmAs accumulate to high levels in many daffodil tissues, biosynthesis is localized to nascent, growing tissue at the leaf base. A similar trend is found in the production of steroidal alkaloids (e.g., cyclopamine) in corn lily. This model of active biosynthesis enabled the elucidation of a complete set of biosynthetic genes that can be used to produce AmAs. Taken together, our work sheds light on the developmental and enzymatic logic of diverse alkaloid biosynthesis in daffodils. More broadly, it suggests a paradigm for biosynthesis regulation in monocot geophytes, where plants are protected from herbivory through active charging of newly formed cells with eukaryotic toxins that persist as above-ground tissue develops.

Toxicological and Pharmacological Activities, and Potential Medical Applications, of Marine Algal Toxins.

Marine algal toxins have garnered significant attention in the research community for their unique biochemical properties and potential medical applications. These bioactive compounds, produced by microalgae, pose significant risks due to their high toxicity, yet offer promising therapeutic benefits. Despite extensive research identifying over 300 marine algal toxins, including azaspiracids, brevetoxins, cyclic imines, and yessotoxins, gaps remain in the understanding of their pharmacological potential. In this paper, we critically review the classification, bioactive components, toxicology, pharmacological activities, and mechanisms of these toxins, with a particular focus on their clinical applications. Our motivation stems from the increasing interest in marine algal toxins as candidates for drug development, driven by their high specificity and affinity for various biological receptors. We aim to bridge the gap between toxicological research and therapeutic application, offering insights into the advantages and limitations of these compounds in comparison to other bioactive substances. This review not only enhances the understanding of marine algal toxins' complexity and diversity, but also highlights their extensive application potential in medicine and bioscience, providing a foundation for future research and development in this field.

Development and Prospects of Furin Inhibitors for Therapeutic Applications.

Furin, a serine protease enzyme located in the Golgi apparatus of animal cells, plays a crucial role in cleaving precursor proteins into their mature, active forms. It is ubiquitously expressed across various tissues, including the brain, lungs, gastrointestinal tract, liver, pancreas, and reproductive organs. Since its discovery in 1990, furin has been recognized as a significant therapeutic target, leading to the active development of furin inhibitors for potential use in antiviral, antibacterial, anticancer, and other therapeutic applications. This review provides a comprehensive overview of the progress in the development and characterization of furin inhibitors, encompassing peptides, linear and macrocyclic peptidomimetics, and non-peptide compounds, highlighting their potential in the treatment of both infectious and non-infectious diseases.

Metabolic Pathways Affected in Patients Undergoing Hemodialysis and Their Relationship with Inflammation.

Worldwide, 3.9 million individuals rely on kidney replacement therapy. They experience heightened susceptibility to cardiovascular diseases and mortality, alongside an increased risk of infections and malignancies, with inflammation being key to explaining this intensified risk. This study utilized semi-targeted metabolomics to explore novel metabolic pathways related to inflammation in this population. We collected pre- and post-session blood samples of patients who had already undergone one year of chronic hemodialysis and used liquid chromatography and high-resolution mass spectrometry to perform a metabolomic analysis. Afterwards, we employed both univariate (Mann-Whitney test) and multivariate (logistic regression with LASSO regularization) to identify metabolites associated with inflammation. In the univariate analysis, indole-3-acetaldehyde, 2-ketobutyric acid, and urocanic acid showed statistically significant decreases in median concentrations in the presence of inflammation. In the multivariate analysis, metabolites positively associated with inflammation included allantoin, taurodeoxycholic acid, norepinephrine, pyroglutamic acid, and L-hydroorotic acid. Conversely, metabolites showing negative associations with inflammation included benzoic acid, indole-3-acetaldehyde, methionine, citrulline, alphaketoglutarate, n-acetyl-ornithine, and 3-4-dihydroxibenzeneacetic acid. Non-inflamed patients exhibit preserved autophagy and reduced mitochondrial dysfunction. Understanding inflammation in this group hinges on the metabolism of arginine and the urea cycle. Additionally, the microbiota, particularly uricase-producing bacteria and those metabolizing tryptophan, play critical roles.

Thermoregulation Effects of Phoneutria nigriventer Isolated Toxins in Rats.

Body temperature is primarily regulated by the hypothalamus, ensuring proper metabolic function. Envenomation by Phoneutria nigriventer can cause symptoms such as hypothermia, hyperthermia, sweating, and shivering, all related to thermoregulation. This study aims to analyze and identify components of the venom that affect thermoregulation and to evaluate possible mechanisms. Rats were used for thermoregulation analysis, venom fractionation by gel filtration and reverse-phase chromatography (C18), and sequencing by Edman degradation. The venom exhibited hypothermic effects in rats, while its fractions demonstrated both hypothermic (pool II) and hyperthermic (pool III) effects. Further separations of the pools with C18 identified specific peaks responsible for these effects. However, as the peaks were further purified, their effects became less significant. Tests on U87 human glioblastoma cells showed no toxicity. Sequencing of the most active peaks revealed masses similar to those of the Tachykinin and Ctenotoxin families, both known to act on the nervous system. The study concludes that molecules derived from venom can act synergistically or antagonistically. Additionally, toxins that affect thermoregulation are poorly studied and require further characterization. These toxins could potentially serve as sources for the development of new thermoregulatory drugs.

Transcriptomic Analysis Reveals Diverse Expression of Scorpion Toxin Genes in Mesobuthus martensii.

Scorpions, an ancient group of venomous invertebrates, have existed for over 430 million years. Their toxins, important for predation and defense, exhibit a variety of biological and pharmacological activities. Research on scorpion toxins has spanned decades. Notably, the toxin genes of Mesobuthus martensii (Scorpiones: Buthidae), a well-known Chinese herbal medicine, have been described at genomic and proteomic levels. However, previous studies primarily focused on the toxin genes expressed in the venom glands, overlooking their expression in multiple tissues. This study analyzed transcriptomes from 14 tissues of M. martensii. Gene annotation revealed 83 toxin and toxin-like genes, including those affecting sodium, potassium, calcium, and chloride ion channels. Approximately 70% of toxin genes were highly expressed in the vesicle; additionally, some exhibited low or no expression in the vesicle while showing high expression in other tissues. Beyond the vesicle, high expression levels of toxin genes were observed in metasoma segments II-V, blood, lateral eyes, chelicerae, legs, pedipalp chelae, femurs, and patellae. This expression pattern suggests that toxin genes are recruited from multiple tissues and may help prevent intraspecific harm during courtship and competition for prey. These findings inspire further research into the evolutionary recruitment process of scorpion toxins.

Host Tropism and Structural Biology of ABC Toxin Complexes.

ABC toxin complexes are a class of protein toxin translocases comprised of a multimeric assembly of protein subunits. Each subunit displays a unique composition, contributing to the formation of a syringe-like nano-machine with natural cargo carrying, targeting, and translocation capabilities. Many of these toxins are insecticidal, drawing increasing interest in agriculture for use as biological pesticides. The A subunit (TcA) is the largest subunit of the complex and contains domains associated with membrane permeation and targeting. The B and C subunits, TcB and TcC, respectively, package into a cocoon-like structure that contains a toxic peptide and are coupled to TcA to form a continuous channel upon final assembly. In this review, we outline the current understanding and gaps in the knowledge pertaining to ABC toxins, highlighting seven published structures of TcAs and how these structures have led to a better understanding of the mechanism of host tropism and toxin translocation. We also highlight similarities and differences between homologues that contribute to variations in host specificity and conformational change. Lastly, we review the biotechnological potential of ABC toxins as both pesticides and cargo-carrying shuttles that enable the transport of peptides into cells.

Marine toxins in environment: Recent updates on depuration techniques.

Marine toxins pose a significant safety risk, leading to human intoxications and causing substantial economic losses in seafood-producing regions. The development of rapid, cost-effective, efficient, and reliable approaches for the containment of these substances is therefore crucial in order to mitigate the adverse impact of marine toxins. This research conducted a comprehensive review on the toxicity and influencing factors of marine toxins production. Additionally, depuration technologies, including adsorption, advanced oxidation processes, biodegradation, heating treatment, temporary maintenance and purification, and drug inhibition, were systematically summarized. The study also provided a comparative analysis of the advantages and disadvantages of various depuration technologies and proposed strategies for future development.

The epsilon toxin from Clostridium perfringens stimulates calcium-activated chloride channels, generating extracellular vesicles in Xenopus oocytes.

The epsilon toxin (Etx) from Clostridium perfringens has been identified as a potential trigger of multiple sclerosis, functioning as a pore-forming toxin that selectively targets cells expressing the plasma membrane (PM) myelin and lymphocyte protein (MAL). Previously, we observed that Etx induces the release of intracellular ATP in sensitive cell lines. Here, we aimed to re-examine the mechanism of action of the toxin and investigate the connection between pore formation and ATP release. We examined the impact of Etx on Xenopus laevis oocytes expressing human MAL. Extracellular ATP was assessed using the luciferin-luciferase reaction. Activation of calcium-activated chloride channels (CaCCs) and a decrease in the PM surface were recorded using the two-electrode voltage-clamp technique. To evaluate intracellular Ca2+ levels and scramblase activity, fluorescent dyes were employed. Extracellular vesicles were imaged using light and electron microscopy, while toxin oligomers were identified through western blots. Etx triggered intracellular Ca2+ mobilization in the Xenopus oocytes expressing hMAL, leading to the activation of CaCCs, ATP release, and a reduction in PM capacitance. The toxin induced the activation of scramblase and, thus, translocated phospholipids from the inner to the outer leaflet of the PM, exposing phosphatidylserine outside in Xenopus oocytes and in an Etx-sensitive cell line. Moreover, Etx caused the formation of extracellular vesicles, not derived from apoptotic bodies, through PM fission. These vesicles carried toxin heptamers and doughnut-like structures in the nanometer size range. In conclusion, ATP release was not directly attributed to the formation of pores in the PM, but to scramblase activity and the formation of extracellular vesicles.

Transcriptomic and functional effects from a chemical mixture based on the exposure profile in Baltic Sea salmon, on metabolic and immune functions in zebrafish embryo.

The Baltic Sea is one of the world's most contaminated seas with long-standing adverse health status of its wildlife such as the Baltic Sea salmon, resulting in reduced fecundity and increased mortality. While adverse health effects have been reported among wild fish from the Baltic Sea, the toxicity mechanisms underlying these adversities, and the chemical effect drivers mediating them are poorly understood. To address this knowledge gap, we utilized the zebrafish (Danio rerio) embryo model to determine molecular and functional effects brought on by exposure to a technical mixture including 9 organohalogen compounds detected in serum from wild-caught Baltic Sea salmon. To align with the salmon exposure scenario, an internal dose regimen was opted to establish same relative proportions of the compounds in the zebrafish (whole body) as observed in the salmon serum. Through transcriptomic profiling, we identified dose-dependent effects on immune system and metabolism as two critical functions overlapping with adverse effects observed in wild fish from the Baltic Sea. We then determined likely effect drivers by comparing gene responses of the mixture with those of individual mixture components. Aligned with our transcriptome results, the number of total macrophages was reduced and the zebrafish's ability to respond to a tissue damage suppressed in a dose-dependent manner. This study brings forth a key advancement in delineating the impact of chemical pollutants on the health of wild fish in the Baltic Sea.

Role of tri18 gene in Epiroridin E production and toxin resistance mechanisms in Paramyrothecium roridum.

Type D trichothecene toxins represent a class of macrocyclic trichothecene toxins with significant cytotoxicities towards human and crops. These toxins can also be used as anti-tumor compounds by the combination of antibody-drug conjugate. Therefore, it is urgent to investigate the biosynthetic routine of type D trichothecene toxins and explore type D trichothecene toxin-resistant genes, in order to ameliorate the hazard of trichothecene toxins and to facilitate the heterologous expression of toxin-biosynthetic cluster. In this study, tri18 gene was firstly knocked out in Paramyrothecium roridum, leading to the complete absence of type D trichothecene toxin epiroridin E, which can be restored by the complement of tri18 gene. Additionally, the knockout of tri18 gene led to a significant reduction in the pathogenicity of P. roridum towards pumpkin. Meanwhile, the enzymatic properties of Tri18 protein towards trichothecene deoxynivalenol (DON) toxin were also characterized. Moreover, tri3 and tri17KR with broad spectrum toxin-resistance function within the tri cluster were initially discovered through heterologous expression in toxin-sensitive Saccharomyces cerevisiae. And this study provides innovative type D trichothecene toxin resistant enzymes, which can provides green platform for the production of type D trichothecene toxins, thus promoting the application of these toxins in biomedical field.

Two decades of data on the neurotoxic Gymnodinium catenatum dynamics and paralytic shellfish toxins contamination of molluscs in the southwestern Mediterranean: What have we learned?

Harmful algal blooms have been documented in the Moroccan Western Mediterranean region since 1993, primarily associated with the presence of paralytic shellfish toxins (PSTs) produced by the dinoflagellate Gymnodinium catenatum. The proliferation of this neurotoxic species has led to recurring bans on the harvesting of molluscs, resulting in significant socio-economic repercussions and threats to human health. In the present study, we examine the dynamics of G. catenatum and mollusc PST contamination patterns over a 20-year period (2002-2021) in two distinct marine ecosystems: M'diq Bay and the Oued Laou Estuary. For the PST contamination, we considered two commercially important shellfish species: the smooth clam, Callista Chione, and the cockle, Acanthocardia tuberculata. The highest G. catenatum abundances were consistently observed from November to February in both sites. Our data revealed inter-annual variations in G. catenatum abundance, peaking at 91,840 cells.L-1 in November 2011. PST contamination levels in A. tuberculata were significantly higher than those observed in C. chione. Furthermore, we identified a significant correlation (Pearson, P-value <0.05) between PST contamination of smooth clams and the abundance of G. catenatum. The contamination of A. tuberculata by PSTs reached very high levels, with up to 13,500 µg STX di-HCl eq. kg-1 of shellfish meat, exceeding the established safety thresholds by 16-fold. Additionally, there has been an increase in the prevalence and incidence of PSTs over the years. Notably, we observed a substantial increase in G. catenatum blooms and PST events in the Western Mediterranean during the last decade (2010-2021). The examined data suggest that rainfall could play a pivotal role in G. catenatum bloom dynamics by enriching marine waters with nutrients. The statistical model selection approaches indicated that nutrient concentrations (i.e., nitrate and phosphorus) were the most significant parameters for G. catenatum blooms in the studied area.

Physiological and transcriptomic response of dinoflagellate Gymnodinium catenatum to nitrate deficiency.

The paralytic shellfish toxin producing dinoflagellate Gymnodinium catenatum is a globally distributed species and often forms massive blooms. However, the physiological and molecular responses of G. catenatum to nitrate starvation have not been thoroughly investigated. Our results showed that multiple forms of N could be utilized by G. catenatum under nitrate-deficient conditions. Nitrate deficiency adversely affected the growth, cellular Chlorophyll a (Chl a) content, and toxin production of G. catenatum. Transcriptomic analysis revealed significant down-regulation of gene expressions involved in the light reaction of photosynthesis, while genes related to fatty acids synthesis and antioxidation were significantly upregulated in the N-depleted cultures. Our results suggested that excess carbon was channeled into lipid synthesis for energy storage, and antioxidant reactions were upregulated to eliminate toxic peroxides caused by nitrate limitation. These findings highlight the adaptative strategy of G. catenatum in low-nitrate environments, which are crucial factors driving its bloom formation.