Zyflo (zileuton) / Chiesi - LARVOL DELTA

Stability-Indicating Assay of Novel 5-(Hydroxamic acid)methyl Oxazolidinones with 5-Lipooxygenase Inhibitory Activity. (PubMed, Pharmaceuticals (Basel)) - "Currently, zileuton is the only FDA-approved 5-LO inhibitor, emphasizing the need to develop new agents for the treatment of such diseases... The compounds were found to be stable in human plasma and under thermal degradation conditions with high extraction recoveries (82-90%) but unstable in acidic, basic, and oxidative conditions. The findings show that the compounds are stable in biological conditions; they hold promise for the treatment of inflammatory and allergic diseases."

Journal • Allergy • Oncology

Inhibiting Arachidonate-5-lipoxygenase expression ameliorates osteoarthritis progression by suppressing ferroptosis via the JAK2/STAT3 signaling pathway. (PubMed, Free Radic Biol Med) - "In summary, our study demonstrated knockdown of Alox5 inhibited the JAK2/STAT3 signaling, thereby suppressing ferroptosis and alleviating cartilage damage.Intra-articular injection of the ALOX5 inhibitor Zileuton or AAV-ShAlox5 in the knee joint alleviated cartilage damage in the mouse DMM model.Mechanistically, our study reveals that the JNK-p53-ALOX5 signaling axis alleviates OA by regulating ferroptosis in chondrocytes."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • ALOX5 • IL1B

Lauric acid modulates the cyclooxygenases and nitric oxide pathways and reduces oxidative stress in preventing tracheal hyperresponsiveness in asthmatic Wistar rats. (PubMed, Front Pharmacol) - "A reduction in the contractile reactivity to CCh was observed in the asthmatic group in the presence of indomethacin, zileuton, L-NAME, apocynin, and tempol, inhibitors of COX, 5-LOX, NOS, NADPH oxidase, and a mimetic of superoxide dismutase (SOD), respectively. Treatment with lauric acid at a dose of 25 mg/kg prevented all of these alterations, except for the reduction in GSH levels. In conclusion, LA reduces tracheal hyperresponsiveness in Wistar rats with allergic asthma by negatively modulating both the COX and NO pathways and oxidative stress imbalance."

Journal • Preclinical • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Development of novel salicylic acid derivatives with dual anti-inflammatory and anti-arthritic potentials: synthesis, in vitro bio-evaluation, and in silico toxicity prediction with molecular modeling simulations. (PubMed, RSC Adv) - "These results exhibited superior activity compared to Aspirin, which had IC50 values of 11.21 ± 0.12 and 8.45 ± 0.05 µg mL-1, while demonstrating competitive activity relative to Naproxen (IC50 = 8.13 ± 0.14 and 6.18 ± 0.04 µg mL-1) and Indomethacin (IC50 = 7.16 ± 0.05 and 5.47 ± 0.04 µg mL-1) for COX-1 and COX-2, respectively...This value is comparable to that of naproxen (IC50 = 9.65 ± 0.17 µg mL-1) and zileuton (IC50 = 8.43 ± 0.05 µg mL-1), while demonstrating greater efficacy than aspirin (IC50 = 13.68 ± 0.13 µg mL-1)...Finally, in silico toxicity predictions were conducted, demonstrating a safer profile compared to the utilized drugs. Additionally, docking simulations were performed for the most active derivatives, revealing higher binding affinities, supported by hydrogen bonding, arene-cation interactions, and hydrophobic interactions."

Journal • Preclinical

Zileuton nanocrystals alter intestinal phase I/II metabolic enzymes and epithelial permeability in a sex-dependent manner. (PubMed, Drug Metab Dispos) - "Approximately 5% of asthmatic patients develop hepatocytotoxicity due to zileuton treatment and show several fold elevated levels of ALT in plasma. In the present study, differences in the decrease of ALT levels between the formulations highlight the advantages of the nanocrystal formulation."

Journal • P1/2 data • Asthma • Gastrointestinal Disorder • Immunology • Pulmonary Disease • Respiratory Diseases

Computational and bioactivity investigations of flavonoid fraction from Dodonaea viscosa against oxidative stress and inflammation. (PubMed, Sci Rep) - "It also exhibited strong dual inhibitory effects against COX-2 (IC₅₀ = 38.21 μg/mL) and 5-LOX (IC₅₀ = 40.72 μg/mL), comparable to indomethacin (IC₅₀ = 33.03 μg/mL) and zileuton (IC₅₀ = 33.41 μg/mL). Molecular docking further validated the strong binding affinities of the major flavonoids, with isokaempferide showing particularly stable interactions with COX-2, 5-LOX, and NAD(P)H oxidase. MM-GBSA and hydrogen bond analyses highlighted key residues involved in target inhibition, reinforcing the experimental findings and supporting the potential of D. viscosa flavonoids as promising multifunctional therapeutic leads."

Journal • Inflammation

Gut microbiota metabolites and key target molecules in allergic rhinitis: a multi-omics study of gut-nose axis regulation via the inflammation-metabolism network. (PubMed, Front Microbiol) - "MPO and PTGDR2 were identified as key potential targets, and Fevipiprant and Zileuton were proposed as candidate drugs. This study provides the first systematic exploration of the "gut-nasal" metabolic axis in AR at a multi-level molecular network level, offering novel perspectives on the disease's underlying mechanisms. The identified targets and candidate drugs provide a valuable foundation for developing new therapeutic strategies, warranting further experimental validation for potential clinical translation."

Journal • Allergic Rhinitis • Immunology • Inflammation • IL1B • IL4R • IL6 • PTGDR2

The Effect of CBD Treatment on MMP-9 Expression in Rodent Seizure Models and Human Epilepsy (AES 2025) - " In this study we used enzyme-linked immunosorbent assays (ELISA) to determine MMP-2 and MMP-9 levels in isolated rat serum from epilepsy models of five different studies: an acute epilepsy model, an acute seizure model treated with CBD, an acute epilepsy model treated with zileuton/celecoxib/CBD, a chronic epilepsy model, and a chronic epilepsy model treated with CBD. Our data suggest a novel approach with implications for epilepsy therapy. The results from this discovery potentially allow for a neuroprotective benefit to help epilepsy patients with a new treatment option."

Preclinical • Cardiovascular • CNS Disorders • Epilepsy • MMP2 • MMP9

Microbiome and metabolomics analyses of the effect of heat-sensitive moxibustion on allergic rhinitis in rats. (PubMed, Front Immunol) - "Untargeted metabolomics results showed that HM treatment regulated the metabolites such as 1-methylhistidine, xi-3-hydroxy-5-phenylpentanoic acid O-beta-d-glucopyranoside, cladosporin, cuminaldehyde, daidzein, Pe(18:0/15:0), N-nervonoyl asparagine, edulitine, N-arachidonoyl glycine, 9alpha-(3-methyl-2E-pentenoyloxy)-4S-hydroxy-10(14)-oplopen-3-one, quisqualic acid, ethyl glucuronide, zileuton O-glucuronide, trichloroethanol glucuronide, Asp Leu Ser Glu, quinolinic acid, and norvaline...To our knowledge, this represents the first investigation to establish comprehensive correlations between gut microbiota and urinary metabolomics profiles in an AR model. Our findings confirm the therapeutic role of heat-sensitive moxibustion in AR recovery and provide mechanistic insights supporting its clinical application, thereby proposing a novel strategic approach for AR treatment."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Allergic Rhinitis • CNS Disorders • Immunology • Infectious Disease • Inflammation • Kaposi Sarcoma • Oncology • Psychiatry • Sarcoma • Solid Tumor • IL4

Aortic Stenosis is Promoted by Ferroptosis via 5-Lipoxygenase (AHA 2025) - "In vitro ferroptosis induction led to a 2.4-fold increase (SEM = ± 0.42) fatty acid peroxidation (p<0.05) and a 3-fold reduction (SEM = ± 0.02) VIC viability (p<0.05), which was significantly reversed by pharmacological inhibition of 5-lipoxygenase with zileuton (1 uM) and ASCL4 with rosiglitazonre (10 mM), independently of lipid mediator and PPAR signaling. An in vivo ferroptosis model by administrating doxorubicin to hyperlipidemic mice increased aortic valve calcification and significantly correlated with concomitant ACSL4 overexpression (R=0.54, p=0.05). In SCAPIS cohort, plasma AA levels independently predicted aortic valve calcification (OR=1.04, q=0.049) and correlated with the ferroptosis biomarker HMOX1 (p<0.05), providing a key clinical coupling to an AA-ferroptosis interplay in CAVD pathogenesis.ConclusionThe 5-lipoxygenase-ACSL4-AA pathway represents a central, pharmacologically targetable mechanism driving ferroptosis and CAVD. These..."

Late-breaking abstract • Cardiovascular • Hematological Disorders • ACSL4 • HMOX1

Attenuation of Vancomycin-Associated AKI with Zileuton (KIDNEY WEEK 2025) - "The mechanism of renal protection seems to involve reducing oxidative injury to proximal tubule cells. This would allow optimal vancomycin use to treat difficult infections and make a significant impact towards combatting the antimicrobial resistance crisis."

Acute Kidney Injury • Infectious Disease • Nephrology • Renal Disease

From Gut to Lung: Lipoxygenase Dependent Oxylipin Amplification Drives 15-HETE Induced Pulmonary Hypertension in C57BL6/J Mice (AHA 2025) - "Our findings suggest that the gut appears to play a previously underappreciated role in the development of PH, highlighting the potential of targeting LOX pathways and gut–lung interactions in the treatment of PAH."

Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CCL11 • IL15

5-Lipoxygenase triggers depressive-like behaviors via activating NLRP3-induced pyroptosis in CUMS-exposed mice. (PubMed, Neuropharmacology) - "Notably, inhibiting 5-LOX with zileuton effectively alleviated depressive-like behaviors, increased the expression of monoamine neurotransmitters and exerted neuroprotective effects in CUMS-exposed mice...These findings indicate that 5-LOX contributes to the pathogenesis of depression via promoting NLRP3-mediated cell pyroptosis. Thus, 5-LOX inhibition could be applied as a clinic intervention for the treatment of depression."

Journal • Preclinical • CNS Disorders • Depression • Psychiatry • LOX • NLRP3

Flufenamic acid-based sulfonohydrazide and acetamide derivatives NSAI as inhibitors of multi-targets COX-1/COX-2/5-LOX: design, synthesis, in silico ADMET and binding mode studies. (PubMed, BMC Chem) - "Meclofenamic and Zileuton are examples of dual COX/LOX inhibitors that provide improved stomach protection and safer cardiovascular characteristics...The COX-1 inhibition of compounds 14 and 15 was higher than that of Celecoxib (IC50 = 77.4 µM), with an IC50 range of 15-26 µM...Conjugates 14 and 17 markedly raised levels nrf2. Molecular docking studies were used to validate the findings of this investigation."

Journal • Cardiovascular • Inflammation

Zileuton Attenuates Acute Kidney Injury in Glycerol-Induced Rhabdomyolysis by Regulating Myeloid-Derived Suppressor Cells in Mice. (PubMed, Int J Mol Sci) - "Zileuton (Z), a selective inhibitor of 5-lipoxygenase (5-LOX), has demonstrated efficacy in enhancing renal function recovery in animal models of AKI induced by agents such as cisplatin, aminoglycosides, and polymyxins. Collectively, these findings suggest that Zileuton confers reno-protective effects in a murine model of RI-AKI, potentially through modulation of mitochondrial dynamics and suppression of MDSC-mediated inflammatory pathways. Further research is warranted to elucidate the precise mechanisms by which Z regulates MDSCs and to assess its therapeutic potential in clinical contexts."

Journal • Preclinical • Acute Kidney Injury • Nephrology • Renal Disease • CX3CL1 • CX3CR1 • ITGAM • TFAM • TGFB1

Exploration of zileuton protective mechanisms against vancomycin-associated nephrotoxicity. (PubMed, Toxicol Appl Pharmacol) - "These preliminary findings indicate that zileuton may be protective against vancomycin-associated renal injury potentially by rescuing HO-1 levels and reducing oxidative stress in proximal tubular cells. Attenuation of nephrotoxicity would allow the optimal clinical use of vancomycin to treat drug-resistant bacterial infections, which could reduce patient harm and hospitalization costs."

Journal • Acute Kidney Injury • Infectious Disease • Nephrology • Renal Disease • KEAP1

Modulation of Neutrophil Recruitment and Inflammatory Signaling in Acute Respiratory Distress Syndrome by Leukotriene Inhibitors Montelukast and Zileuton. (PubMed, FASEB J) - "These findings indicate that leukotriene pathway inhibition limits neutrophil recruitment and activation in ARDS by modulating receptor expression and ERK1/2 signaling. Montelukast and zileuton may offer a targeted strategy to attenuate hyperinflammation in ARDS."

Journal • Acute Respiratory Distress Syndrome • Chronic Obstructive Pulmonary Disease • Critical care • Inflammation • Pulmonary Disease • Respiratory Diseases • IL1B • IL6 • TNFA

Intestinal mast cell-derived leukotrienes mediate the anaphylactic response to ingested antigens. (PubMed, Science) - "Compared with connective tissue mast cells found throughout the body, intestinal mast cells largely resided in the epithelium, displayed divergent transcriptomes and effector functions, and had a diminished ability to generate histamine, but they enhanced leukotriene synthesis. Mice genetically deficient in cysteinyl leukotriene synthesis, or those treated with the arachidonate 5-lipoxygenase (aLOX5) antagonist zileuton, were protected from oral antigen-induced responses, whereas those elicited by intravenous injection were unaltered."

Journal • Food Hypersensitivity

Cysteinyl leukotrienes stimulate gut absorption of food allergens to promote anaphylaxis in mice. (PubMed, Science) - "Blocking DPEP1 with cilastatin, deleting Dpep1, or administering LTD4 orally enhanced allergen transport in resistant mice. Conversely, pretreatment of susceptible mice with a synthesis inhibitor, zileuton, abrogated allergen absorption and oral anaphylaxis, indicating that this could be an approach to treating food allergy."

Journal • Preclinical • Allergy • Food Hypersensitivity • Immunology • DPEP1

Protection against vancomycin-associated nephrotoxicity by zileuton: role of mitochondria revealed by electron microscopic study. (PubMed, Ultrastruct Pathol) - "Our findings indicate that mitochondrial injury is a major mechanism of vancomycin-associated nephrotoxicity, and restoration of mitochondrial morphology is associated with nephroprotection by zileuton. These findings would be valuable for nephroprotective strategies to reduce vancomycin-associated nephrotoxicity, allowing optimal vancomycin use to treat bacterial infections."

Journal • Acute Kidney Injury • Infectious Disease • Nephrology • Renal Disease

Embelin Mitigates the Impact of Perinatal Inflammation on Neuron Development by Inhibiting 5-Lipoxygenase-Mediated Ferroptosis. (PubMed, Phytother Res) - "Embelin, along with the 5-LOX inhibitor Zileuton and 5-LOX mRNA silencing, significantly inhibited 5-LOX expression in neurons...The findings highlight Embelin's ability to specifically target and mitigate 5-LOX-induced ferroptosis, facilitating recovery from perinatal inflammation-induced neurodevelopmental deficits. Embelin demonstrates significant neuroprotective potential by inhibiting 5-LOX-mediated ferroptosis and oxidative stress, offering a promising therapeutic strategy for perinatal brain injury and related neurodevelopmental disorders."

Journal • CNS Disorders • Developmental Disorders • Inflammation • Psychiatry • Vascular Neurology • LOX

Multicellular hepatic in vitro models using NANOSTACKSTM: human-relevant models for drug response prediction. (PubMed, In Vitro Model) - "In addition, the preclinical DILI screening potential of the orbital-induced mixing flow monoculture and triculture models was assessed by testing the hepatotoxicity of zileuton, buspirone, and cyclophosphamide. NANOSTACKS™ represents a promising tool for the development of complex in vitro models."

Journal • Preclinical • Hepatology • Liver Failure • CYP3A4

Drug development studies supporting zileuton as a parenteral adjuvant to attenuate antibiotic-associated nephrotoxicity. (PubMed, Antimicrob Agents Chemother) - "Different dosing strategies of zileuton to attenuate vancomycin-, polymyxin B-, and amikacin-associated nephrotoxicity were evaluated in rats over 10 days. This would allow the optimal use of glycopeptides, polymyxins, and aminoglycosides to treat difficult infections. Further studies are warranted to repurpose zileuton as a nephroprotectant."

Journal • Infectious Disease

Inhibition of 5-lipoxygenase ameliorates diabetic kidney disease by attenuating proximal tubular cell ferroptosis: Non-dialysis CKD, Diabetic Kidney Disease (KSN 2025) - "Zileuton was used to inhibit 5-lipoxygenase activity...Inhibition of 5-lipoxygenase not only mitigates ferroptotic tubular cell death but also alleviates hyperglycemia-induced renal dysfunction. This suggests that 5-lipoxygenase could serve as a potential therapeutic target for the treatment of DKD."

Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Metabolic Disorders • Nephrology • Renal Disease • ACSL4 • GPX4

5-lipoxygenase is critically involved in joint inflammation and damage in experimental osteoarthritis. (PubMed, Inflammopharmacology) - "5-Lox is critical for joint inflammation and degradation in a mouse model of osteoarthritis. Inhibiting 5-Lox with Zileuton effectively prevented joint damage and inflammation, even when it was given weeks after the inciting stimulus, suggesting that it is a potential strategy to limit the progression of osteoarthritis."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • LOX