Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

Canine oral cancers are difficult to manage due to complex biology and a lack of non-invasive biomarkers. Proteomic approaches, particularly gel-based liquid chromatography-tandem mass spectrometry (GeLC-MS/MS), have been used on tissue and saliva, but serum remains obscure despite its clinical accessibility and ability to reflect systemic disease. This study evaluated GeLC-MS/MS for serum proteomic profiling in canine oral malignancies, compared to benign and healthy conditions. We analysed 62 serum samples from dogs with oral melanoma (OM, n = 28), oral squamous cell carcinoma (OSCC, n = 10), benign tumours (BN, n = 12) and controls (healthy/periodontitis, n = 12) using GeLC-MS/MS-based proteomics. Significant protein expression differences emerged across groups. In OM and OSCC, phosphodiesterase 4D (PDE4D) was upregulated, while ornithine decarboxylase antizyme 3 (OAZ3), centriolar coiled-coil protein 110 (CCP110), non-specific serine/threonine protein kinase 8 (NEK8), receptor-type tyrosine-protein phosphatase F (PTPRF) and interleukin 23 receptor (IL23R) were downregulated. These proteins are linked to critical pathways, including insulin signalling, insulin resistance, adherens junctions and cell cycle regulation, highlighting their roles in cancer progression and showing potential interactions with common chemotherapy drugs like doxorubicin, cisplatin and cyclophosphamide. This study demonstrates that GeLC-MS/MS-based serum proteomics can successfully identify candidate biomarkers for canine oral malignancies. The discovery of these protein signatures represents promising diagnostic and prognostic targets, with the potential to guide chemotherapeutic selection and improve clinical outcomes in dogs with oral cancer.

Ornithine decarboxylase (ODC) catalyzes the rate-limiting step in polyamine biosynthesis and is one of the shortest-lived mammalian proteins. Its activity and proteasomal degradation are controlled by antizyme (AZ), which disrupts the active ODC homodimer and exposes proteasome-interacting surfaces. Disturbance of the polyamine biosynthesis pathway and their overproduction is associated with multiple diseases, including cancers. We employed activity assays and direct interaction analysis methods to quantify ODC-AZ interaction. Fluorometric activity assay, surface plasmon resonance, microscale thermophoresis and spectral shift assays allowed consistent determination of AZ-ODC binding with previously unavailable sensitivity. Contrary to former studies of this interaction, we show that binding of AZ to ODC occurs with a single-digit nanomolar affinity. Collectively, our orthogonal assays converge on a low-nanomolar interaction (apparent KD 1-4 nM in solution), affinity substantially stronger than previous estimates in the 200-700 nM range. Our results provide new insight into the functioning of the ODC regulatory network, which affects the downstream polyamine synthesis pathway. Such sensitive tools are needed for screening compound libraries and characterizing promising candidates that could affect ODC activity and consequently, polyamine levels.

The gut microbiota impedes infection by enteric pathogens, a process termed colonization resistance. Microbial production of short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, contributes to colonization resistance. Yersinia enterocolitica encounters short-chain fatty acids at several stages during intestinal infection. However, our understanding of how Y. enterocolitica copes with SCFA stress is limited. Here, we found that acetate, propionate, and butyrate restrict Y. enterocolitica growth in vitro. Propionate exerted the most potent toxicity by both pH-dependent and pH-independent mechanisms. pH-dependent propionate growth restriction was worsened in a mutant lacking ornithine decarboxylase, suggesting that this enzyme is involved in counteracting cytoplasmic acidification by propionate under acidic environmental conditions. pH-independent propionate toxicity required phosphate acetyltransferase (phosphotransacetylase) and acetate kinase, pointing to conversion of intracellular propionate to toxic propionyl-CoA by promiscuous phosphotransacetylase and acetate kinase activities as a mechanism of propionate toxicity. We also found that pH-independent propionate toxicity was alleviated by exogenous acetate, taken up via the acetate/succinate transporter SatP. This work advances our understanding of how short-chain fatty acids restrict pathogen growth and highlights strategies used by bona fide pathogens to overcome short-chain fatty acid-mediated colonization resistance.

In silico screening reveals natural compounds from Ashwagandha, Haritaki, and Tilpushpi as potential inhibitors of tumor-promoting ornithine decarboxylase.

Colorectal cancer (CRC) is a prevalent and increasingly common malignancy that poses significant threats to patient survival and quality of life. This study investigates the role of ubiquitously expressed prefoldin-like chaperone (UXT) in regulating polyamine metabolism, particularly putrescine, and its impact on CRC progression. Through comprehensive bioinformatics analysis, UXT was identified as a key factor positively correlated with putrescine abundance in CRC cell lines. Clinical samples confirmed upregulation of UXT and its positive correlation with putrescine levels. Functional assays revealed that UXT knockdown reduced cell viability, migration, and invasion, while overexpression enhanced these phenotypes. Additionally, UXT knockdown decreased putrescine levels and increased the expression of ornithine decarboxylase antizymes (OAZ1, OAZ2, OAZ3), which negatively regulate polyamine synthesis. Conversely, UXT overexpression exhibited the opposite effects. In vivo experiments using a subcutaneous xenograft tumor model in nude mice showed that UXT overexpression enhanced tumor growth and putrescine levels, and UXT overexpression is associated with an increase in M2 macrophage markers, along with reduced M1-associated markers, while UXT knockdown inhibited these effects. These findings suggest that UXT contributes to CRC progression by regulating polyamine metabolism and macrophage polarization, demonstrating its potential as a therapeutic target to disrupt metabolic pathways essential for cancer cell survival and proliferation.

Using the well-studied two-stage model of skin carcinogenesis, the first transgenic mouse with targeted expression of a polyamine metabolic enzyme was generated 30 years ago. Ornithine decarboxylase (ODC), a key regulating enzyme of polyamine biosynthesis, was constitutively expressed in the outer root sheath cells of hair follicles near the bulge stem cell niche using a keratin 6 promoter in K6/ODC mice. Early studies using K6/ODC mice demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. Treatment with inhibitors of ODC activity blocked the formation of skin tumors and caused the rapid regression of existing tumors. We review how use of the K6/ODC mouse has shown that elevated polyamines in epithelial cells stimulate proliferation and invasiveness, recruit stem cells, alter chromatin remodeling and cell signaling leading to metabolic reprogramming, increase vascularization, activate underlying fibroblasts, and have powerful effects on immune cell function, all contributing to the development and progression of tumors.

Ornithine decarboxylase (ODC) functions as the rate-limiting enzyme in the polyamine (PA) biosynthetic pathway. It catalyzes the decarboxylation of L-ornithine to produce putrescine, thereby initiating the biosynthesis of polyamines. Polyamines are a class of widely distributed polycationic aliphatic compounds in living organisms, including putrescine, spermidine, and spermine. They serve not only as critical regulators of cell growth, proliferation, and differentiation, but also as important signaling molecules involved in plant responses to environmental stress and key precursors in the biosynthesis of diverse secondary metabolites. Focusing on recent advances in plant ODC research, this review summarizes the characteristics and evolutionary relationships of the ODC gene family, the biochemical properties and catalytic mechanism of the enzyme, and its multiple physiological roles in growth, development, secondary metabolism, and stress adaptation. Furthermore, we discuss the complex regulatory mechanisms governing ODC activity at both transcriptional and post-translational levels, with a critical gap in understanding the post-translational regulation of ODC in plants, particularly the mechanisms governing its degradation. Unlike in animals, where antizymes mediate ODC degradation, functional analogs of antizymes have not yet been identified in plants, leaving the degradation pathway largely unexplored. Finally, we review the applications of plant genetic modification targeting ODC in enhancing the production of valuable secondary metabolites in medicinal plants and improving stress tolerance in crops, along with perspectives on future research directions. This review illustrates the diversity of ODC functions and the complexity of its regulatory mechanisms in plant growth, development, stress responses, and secondary metabolism. It also provides a theoretical foundation and insights for exploring ODC as a target for plant genetic modification, which is promising for improving the economic traits and stress resistance of horticultural plants.

Efficacy of 5-fluorouracil and metronomic chemotherapy mediated ornithine decarboxylase antizyme for inhibiting of colorectal cancer.

Meningeal inflammation, as a clinical feature of multiple sclerosis (MS), is associated with worse clinical disease outcomes. In both relapsing and secondary progressive MS and the experimental autoimmune encephalomyelitis (EAE) MS model, the meninges have been found to contain ectopic lymphoid follicles enriched with B cells. The metabolic requirement of meningeal B cell function in MS or EAE is not well elucidated. Using 7-Tesla MRI brain scans of MS patients and leptomeningeal enhancement as a marker, we found a correlation between meningeal inflammation and metabolites of the arginine/polyamine pathway, a finding recapitulated in EAE. Ornithine Decarboxylase (ODC1), the rate limiting enzyme for polyamine biosynthesis, as well as polyamine metabolism was diminished in the dura meningeal B cells from mice with MOG35-55 induced EAE mice as compared to naïve controls. Pharmacological inhibition of ODC1 restricted meningeal T cells but promoted meningeal B cell proliferation. B cell-specific deletion of ODC1 resulted in expansion of B cells with age-associated B cell-like phenotype (CD11c+CD21/35-CD23-IgD-), an increase in MOG-specific IgG in the brain, reduction of hippocampal synaptic density, and exacerbated disease in the MOG1-125 EAE model. Together, these findings demonstrate a divergent role of polyamines in regulating B and T cell responses in the meninges during autoimmunity.

Drought is a major environmental factor restricting plant growth and productivity. Putrescine, a small polyamine, is known to enhance drought tolerance, but the role of key genes in the ornithine-derived pathway and their upstream regulators remains unclear. PoODC, encoding Paeonia ostii ornithine decarboxylase, was strongly upregulated under drought stress in P. ostii. Silencing PoODC reduced, while overexpression in tobacco increased putrescine accumulation and drought tolerance. Its transcription was repressed by PoDPBF4, a basic leucine zipper (bZIP) transcription factor binding to the abscisic acid response element (ABRE) element in the PoODC promoter, which negatively regulated putrescine accumulation and drought tolerance. PoDPBF4 physically interacted with PoPP2A, a drought-inducible protein phosphatase, which dephosphorylated PoDPBF4 at Ser92. This modification promoted PoDPBF4 degradation via the 26S proteasome pathway, reducing its protein stability and weakening its repression of PoODC. Also, silencing PoPP2A impaired drought tolerance, confirming its positive role in drought adaptation. These findings reveal a novel drought-responsive regulatory module in which PoPP2A dephosphorylates PoDPBF4, relieving repression of PoODC and enhancing putrescine biosynthesis. This study provides insights into the post-translational regulation of polyamine metabolism and identifies a potential genetic target for improving drought tolerance in perennial woody plants.

Biocontrol efficacy and mechanism of Bacillus subtilis PL5 against root rot of sweet potato: Insights into antifungal activity and metabolite function.

Prostate cancer is an aggressive disease with limited quantifiable biomarkers. One gene of interest is ODC1, which encodes ornithine decarboxylase, the rate-limiting enzyme converting ornithine to putrescine in polyamine metabolism. Although ODC1 is known to be involved in prostate cancer development, exactly how it drives the disease mechanistically is not fully understood. To explore this, we created a prostate cancer cell model with reduced ODC1 expression and examined its effects on tumour behaviours. Knocking down ODC1 significantly slowed cell growth and movement while increasing cell death. Using RNA sequencing, we identified over one thousand differentially expressed genes, with 565 upregulated and 497 downregulated, primarily linked to angiogenesis and cell adhesion. We also found more than two thousand alternative splicing events connected to cell cycle regulation and protein modification. Notably, genes including CAV1, ITGB1, BNIP3, and YTHDF2 were associated with the AKT signalling pathway, suggesting a functional link between ODC1 activity and cancer progression. These results indicate that ODC1 influences prostate cancer cell behaviour by regulating both gene expression and splicing, particularly affecting pathways involved in angiogenesis, adhesion, and the cell cycle. This points to the AKT pathway and polyamine metabolism as potentially valuable targets for future prostate cancer therapies.

Polyamines such as putrescine, spermine, and spermidine play important roles in plant growth, development, and stress responses. To investigate the roles of arginine decarboxylase (ADC) and ornithine decarboxylase (ODC), the key enzymes involved in putrescine biosynthesis, in response to abiotic stresses such as high temperature, this study conducted the bioinformatic, transcriptional and protein level analyses of the <italic>GlADC</italic> and <italic>GlODC</italic> genes, as well as putrescine content detection in the seaweed <italic>Gracilariopsis lemaneiformis</italic>. One <italic>GlADC</italic> and one <italic>GlODC</italic> gene were identified in the <italic>G. lemaneiformis</italic> genome, which belong to the type Ⅲ pyridoxal-dependent arginine decarboxylase family and the type Ⅲ pyridoxal-dependent ornithine decarboxylase family, respectively. Quantitative real-time PCR analysis showed that both high temperature and high light stresses mainly upregulated the expressions of <italic>GlADC</italic> and <italic>GlODC</italic>, whereas nitrogen starvation downregulated their transcript levels. After prokaryotic expression, recombinant protein expression and purification, and antibody preparation, western blot showed that high temperature promoted the GlADC and GlODC protein levels, high light displayed no significant effect, yet low nitrogen downregulated or had no significant effect on the expression levels of the two proteins. Moreover, putrescine content increased under high temperature and high light stresses. These findings suggest that putrescine and its metabolic enzymes participate in the response of <italic>G. lemaneiformis</italic> to high temperature, high light, and low nitrogen conditions. This study will provide valuable insights into the metabolic pathways of putrescine and its roles in alga stress physiology.

Difluoromethylornithine (DFMO, eflornithine) is a fluorinated analogue of ornithine that serves both as an inhibitor of ornithine decarboxylase and as a therapeutic agent against African trypanosomiasis. Beyond its pharmacological importance, DFMO provides a valuable model for examining how fluorine substitution governs molecular conformation. A comprehensive quantum-chemical study was performed to elucidate the origins of DFMO’s conformational stability. High-level DLPNO-CCSD(T)/CBS calculations revealed that type-I conformers – those maximizing gauche interactions between C–F and C–N bonds – dominate the equilibrium population, confirming the presence of the fluorine gauche effect. natural bond orbital (NBO) analysis showed that this preference arises primarily from hyperconjugative stabilization, particularly the σCH → σ*CN interaction, while steric effects modulate the relative stability among low-energy conformers. The gauche effect is intensified in the zwitterionic form due to electrostatic interactions. In contrast, the bioconformation observed in crystallographic data corresponds to a type-II structure, imposed by strong hydrogen bonding of the amino and carboxyl groups with surrounding residues. Thus, DFMO’s intrinsic conformational preferences are dictated by stereoelectronic effects, but these can be overridden by specific intermolecular interactions in biological environments. This study clarifies the electronic origin of DFMO’s gauche effect and provides insight into how local electronic factors determine the structure of fluorinated amino acid derivatives.

Human embryonic kidney (HEK) 293 cells are widely used for recombinant protein production because of their efficient posttranslational modification capabilities. However, their large-scale culture is often limited by metabolic stress and early apoptosis, leading to insufficient protein yields. In this study, we aim to increase protein expression through the coordinated modulation of metabolic and apoptotic pathways. Using CRISPR/Cas9 technology, we target and knockout the genes of ornithine decarboxylase antizyme 1 (OAZ1), which regulates polyamine metabolism, and caspase 8-associated protein 2 (CASP8AP2), an apoptosis-related protein. We successfully construct an OAZ1/ CASP8AP2 double-knockout HEK293 cell line. Following transfection with the knockout vector and screening of single-cell clones, multiple levels of validation confirm the successful gene knockout. The results show that the double-knockout cells exhibit significantly reduced apoptosis rates. Furthermore, the production of recombinant secreted alkaline phosphatase (SEAP) and vitronectin (VN) increases by 2.1 folds and 2.9 folds, respectively, compared with those in wild-type cells. Metabolic profiling reveals that the cell cycle is arrested in the G1/G0 phase, accompanied by increased specific consumption and production rates of key metabolites. This study demonstrates that concurrent inhibition of apoptosis and optimization of metabolism effectively enhances recombinant protein production in HEK293 cells, suggesting a novel strategy for improving HEK293 cell-based expression.

Dendrobine, a neuroprotective and anticancer sesquiterpenic alkaloid, is primarily sourced from endangered Dendrobium orchids, posing sustainability challenges to its production. Endophytic fungi, such as Trichoderma longibrachiatum MD33, offer an alternative; however, unresolved biosynthetic pathways and low yields hinder industrial scalability. Enhancing fungal metabolism through nanotechnology could address these limitations; however, nanoparticle-mediated engineering remains unexplored for dendrobine biosynthesis. This study aimed to (1) optimize dendrobine production in T. longibrachiatum MD33 using gold nanoparticles (CH-AuNPs) functionalized with alkaloid precursors and (2) elucidate the biosynthetic pathway to enable targeted metabolic engineering. CH-AuNPs were chemically synthesized, functionalized with L-phenylalanine, L-tyrosine, and tyramine, and applied to fungal cultures at concentrations of 0.5-20.0 mg/L. Multi-omics analyses (transcriptomics, proteomics, and metabolomics) identified pathway enzymes, and oxidative stress markers and dendrobine yields were quantified. Dose-dependent CH-AuNP exposure (10.0mg/L optimal) elevated dendrobine production by 63.7%, balancing pathway activation and oxidative stress. Multi-omics analysis revealed a hybrid terpenoid-alkaloid pathway, wherein sesquiterpene scaffolds from the mevalonate pathway merge with ornithine-derived piperidine moieties. This process is regulated by sesquiterpene synthases (TPS), cytochrome P450s (CYP71D1), and O-methyltransferases (COMT). Metabolomic analysis provided direct evidence for the rechanneling of nitrogen metabolism, with depletion of glutamate and ornithine pools and accumulation of polyamine pathway intermediates such as putrescine, supporting the transcriptional upregulation of ornithine decarboxylase (ODC). Mechanistically, low-to-moderate oxidative stress induced by CH-AuNPs activated redox-sensitive transcription factors and stress-responsive pathways, which in turn upregulated terpenoid and alkaloid biosynthesis genes. This controlled stress response enhanced precursor flux and enzyme activity, leading to increased dendrobine synthesis without triggering cellular damage in the cells. Concentrations > 10.0mg/L suppressed metabolism owing to oxidative damage. CH-AuNPs act as precision tools to upregulate dendrobine biosynthesis in T. longibrachiatum MD33, resolving the hybrid pathway and establishing this fungus as a sustainable production platform for dendrobine. The dose-dependent response highlights the dual role of nanoparticle-mediated engineering in metabolic enhancement and stress induction. This integration of nanotechnology and multi-omics bridges the critical gaps in fungal biotechnology, enabling scalable and eco-friendly alkaloid synthesis. Future applications include CRISPR-AuNP genome editing and bioreactor optimization, which will advance pharmaceutical and environmental biotechnologies.

Fusobacterium nucleatum is a prominent member of the oral microbiota and has been linked to various human diseases, including periodontitis, preterm birth, and colorectal cancer. Despite its clinical significance, the metabolic requirements that support its growth and viability remain poorly understood. In this study, we identify the oda gene, which encodes ornithine decarboxylase, as essential for F. nucleatum survival due to its role in putrescine biosynthesis. We demonstrate that depletion of putrescine leads to severe growth and morphological defects, accompanied by widespread transcriptional changes. These findings reveal an underappreciated metabolic vulnerability and highlight the critical role of polyamine homeostasis in maintaining cellular integrity in this notorious anaerobe.

Abstract Bipolar androgen therapy (BAT) is the use of testosterone as treatment for castration-resistant prostate cancer (CRPC). We and others have shown that BAT activates the androgen receptor (AR), which can suppress tumor growth in this context. This body of work suggests that AR can function as a tumor suppressor in CRPC. Contextual requirements for AR to behave as a tumor suppressor will be discussed, including high pre-treatment AR activity and limited tumor heterogeneity. A key mechanism by which BAT suppresses CRPC tumor growth is through inhibition of transcription of the proto-oncogene MYC, although MYC-independent mechanisms of BAT-mediated growth suppression also contribute. This downregulation of MYC relieves transcriptional interference with the AR, further amplifying AR activation by BAT. Our recent work suggests AR activation by BAT leads to metabolic reprogramming of CRPC with marked increase in polyamine synthesis and secretion. This occurs through AR binding at enhancer sites upstream of the ODC1 promoter to increase the abundance of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. AR stimulation of polyamine synthesis in prostate cancer is conserved from normal prostate, and in fact occurs even in cells of distinct embryological origin such as T lymphocytes. The increase in polyamine synthesis following BAT seems to facilitate therapeutic resistance, as genetic and pharmacologic blockade of ODC regulation by AR enhances therapeutic efficacy in models of CRPC. These data provided the rationale for an ongoing clinical trial testing the safety and efficacy of BAT in combination with an inhibitor of polyamine synthesis for patients with CRPC. Altogether, we hope these studies of the requirements and consequences of AR functioning as a tumor suppressor in CRPC will lead to new approaches to treatment of this disease. Citation Format: Laura A. Sena. Androgen receptor as a tumor suppressor in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr IA004.

Polyamines, small organic polycations, are essential for life, and cells maintain polyamines via synthesis and uptake. Recently, we identified Hol1 as the high-affinity polyamine transporter in Saccharomyces cerevisiae. Hol1 is a conserved fungal-specific transporter with Candida albicans having two HOL1 homologs (orf19.4889 and orf19.2991) and no identifiable HOL1 homolog in mammals. Deleting both HOL1 homologs blocked efficient polyamine uptake in C. albicans, establishing Hol1 as the high-affinity polyamine transporter in C. albicans. Combined deletion of HOL1 and SPE1, encoding ornithine decarboxylase (ODC), the first enzyme in the polyamine synthesis pathway, resulted in a severe growth defect, confirming the importance of polyamines for C. albicans growth. In addition, cells lacking HOL1 and SPE1 failed to form hyphae when exposed to serum, suggesting a role for polyamines in C. albicans virulence. In accord with this hypothesis, in the mouse model of disseminated candidiasis, the homozygous spe1Δ mutant, like the WT strain, readily colonized the kidney and all mice died within 2 weeks following intravenous inoculation. In contrast, the homozygous spe1Δ hol1Δ mutant was avirulent with all mice surviving the infection. Consistent with these genetic results, simultaneously treating WT cells with l-α-difluoromethylornithine, an irreversible inhibitor of ODC, to inhibit polyamine biosynthesis and with the polyamine transport inhibitor Trimer44NMe to inhibit uptake substantially impaired C. albicans growth and hyphal differentiation. We conclude that polyamines are critical for C. albicans virulence and could be of potential therapeutic interest via combined targeting of polyamine synthesis and the fungal-specific polyamine transporter Hol1.IMPORTANCEFungal infections are a growing concern, and a predominant human opportunistic pathogen is the fungus Candida albicans. Current antifungals commonly target cell wall and cell membrane biosynthesis or integrity; however, resistant strains are emerging. Polyamines are essential small organic cations that cells synthesize and import. We identify polyamines as a possible new target for antifungal therapies. The Hol1 polyamine transporter is unique to fungi and is distinct from mammalian transporters, so it is an intriguing antifungal target. As proof of concept, we show that combined knock-out of Hol1 and a polyamine biosynthesis gene impairs C. albicans growth and hyphal differentiation in culture and virulence in mouse infection assays. Moreover, we identify a polyamine analog that robustly inhibits Hol1 function, providing insights into potential new therapeutics.