Febuxostat, a gout drug, shows promise as topical treatment for psoriasis in mice

Psoriasis affects roughly 2 to 3 percent of the global population, and although biologic therapies have transformed its management, their high cost, relapse rates, and potential adverse effects leave many patients searching for alternatives. Now, a team of researchers has reported that febuxostat, a drug best known for lowering urate in people with gout, may hold unexpected promise as a topical treatment for psoriasis. In a study published in Pharmacia, the investigators showed that an ointment containing febuxostat markedly reduced psoriasis-like skin inflammation in mice, while improving the skin’s antioxidant defenses and altering the expression of two genes central to oxidative stress and inflammatory signaling.

Febuxostat is a highly selective nonpurine inhibitor of xanthine oxidase, the enzyme that generates reactive oxygen species during purine metabolism. Approved for chronic hyperuricemia associated with gout, the drug has demonstrated antioxidant, anti-inflammatory, anti-apoptotic, and tissue-protective effects in numerous experimental disease models. Because oxidative stress is increasingly recognized as a key contributor to psoriasis pathogenesis, with excessive reactive oxygen species driving lipid peroxidation, DNA damage, mitochondrial dysfunction, and activation of inflammatory pathways, the researchers reasoned that inhibiting xanthine oxidase in the skin might interrupt this destructive cycle. Until now, however, the potential of topical febuxostat for psoriasis had never been investigated.

To test the idea, the team prepared ointments containing 0.5, 1, and 2 percent febuxostat by weight, dissolved in dimethyl sulfoxide and incorporated into a white soft paraffin base using the fusion method. Each formulation was characterized for homogeneity, drug content uniformity, spreadability, viscosity, pH, and physical stability over 60 days of storage. Drug content ranged from 98.42 to 99.16 percent of theoretical values across the three concentrations, pH values sat between 6.21 and 6.27, and all formulations remained physically stable throughout the storage period, confirming consistent pharmaceutical quality before animal testing began.

The investigators then induced psoriasis-like dermatitis in adult male BALB/c mice by applying 62.5 milligrams of commercially available 5 percent imiquimod cream to shaved dorsal skin for seven consecutive days. Forty-eight mice were randomly assigned to six groups of eight animals each: a normal control receiving petroleum jelly, an imiquimod control treated with ointment base alone, a positive control treated with clobetasol propionate 0.05 percent cream, and three groups treated with the 0.5, 1, or 2 percent febuxostat ointments. Treatments were applied topically approximately 30 minutes after imiquimod administration each day, and disease severity was scored daily by a blinded investigator using a modified PASI-like system assessing erythema, scaling, and skin thickening.

The results were striking. Imiquimod produced progressive erythema and scaling, with cumulative clinical scores climbing steadily over the treatment week, whereas febuxostat attenuated these manifestations in a concentration-dependent manner. By day seven, the 2 percent formulation had reduced scaling scores to 0.5 and erythema scores to zero, outcomes comparable to or better than those achieved with clobetasol. Histopathological examination of hematoxylin and eosin-stained skin sections reinforced the clinical picture. Imiquimod-treated mice showed marked epidermal hyperplasia, hyperkeratosis, parakeratosis, elongation of the dermoepidermal junction, and dense inflammatory cell infiltration, with epidermal thickness increasing from 38.6 to 112.4 micrometers. The 2 percent febuxostat ointment reduced epidermal thickness to 63.7 micrometers and earned median hyperplasia and infiltration scores of just 1 on the semiquantitative scale, approaching the near-normal architecture seen in clobetasol-treated animals.

Biochemical analyses revealed that the clinical improvements were accompanied by coordinated restoration of the skin’s redox balance. Imiquimod application raised tissue levels of malondialdehyde, a marker of lipid peroxidation, from 1.52 to 5.91 nanomoles per milligram of protein, and nitric oxide from 14.8 to 42.7 micromoles per liter, while superoxide dismutase activity collapsed from 84.7 to 31.4 units per milligram and reduced glutathione fell from 8.92 to 3.18 micromoles per milligram. Treatment with 2 percent febuxostat reversed these changes dramatically, lowering malondialdehyde to 1.89 nanomoles per milligram and nitric oxide to 17.6 micromoles per liter, while restoring superoxide dismutase to 79.1 units per milligram and glutathione to 8.21 micromoles per milligram, values statistically indistinguishable from the normal control group for the antioxidant parameters.

The anti-inflammatory effects were equally pronounced. Imiquimod drove tissue concentrations of tumor necrosis factor-alpha, interleukin-17A, and interleukin-23 to 88.6, 79.2, and 82.4 picograms per milligram of protein, respectively, compared with 24.8, 18.5, and 20.3 picograms per milligram in normal controls. These cytokines sit at the heart of the interleukin-23/interleukin-17 immune axis that drives psoriasis initiation and maintenance, as activated dendritic cells produce interleukin-23, promoting the differentiation of T helper 17 cells that release interleukin-17A and tumor necrosis factor-alpha, fueling epidermal hyperplasia and sustained inflammation. The 2 percent febuxostat formulation suppressed all three cytokines to 29.7, 25.4, and 27.1 picograms per milligram, approaching normal levels and outperforming the 0.5 and 1 percent formulations, which showed progressively weaker effects.

At the molecular level, the researchers used quantitative real-time PCR to measure expression of NFE2L2, the gene encoding NRF2, the master regulator of cellular antioxidant responses, and NLRP3, a central component of inflammasome-associated inflammatory signaling. Imiquimod downregulated NFE2L2 mRNA to 0.38-fold of normal levels while upregulating NLRP3 mRNA to 4.82-fold, indicating impairment of antioxidant defenses and amplification of inflammasome-related signaling. Febuxostat modulated both genes in a concentration-dependent fashion, with the 2 percent formulation restoring NFE2L2 expression to 0.95-fold and reducing NLRP3 expression to 1.28-fold, values approaching those of the normal control group and comparable to or exceeding the molecular effects of clobetasol.

The authors are careful to note that these transcriptional changes do not by themselves establish direct activation of the NRF2 pathway or inhibition of the NLRP3 inflammasome. The study evaluated the genes only at the mRNA level, without measuring NRF2 protein expression, nuclear translocation, or transcriptional activity, and without assessing NLRP3 protein, inflammasome assembly, caspase-1 activity, or maturation of interleukin-1beta and interleukin-18. Additional limitations include the absence of in vitro drug-release and ex vivo skin permeation studies, the potential contribution of dimethyl sulfoxide, which was present in all febuxostat formulations as a co-solvent and penetration enhancer, and the lack of long-term topical safety or systemic exposure data. Nevertheless, the parallel improvement in clinical severity, histopathology, oxidative stress biomarkers, cytokine levels, and gene expression supports a coordinated antioxidant and anti-inflammatory effect of the treatment.

Because febuxostat may offer a nonsteroidal pharmacological approach through inhibition of xanthine oxidase, in contrast to the glucocorticoid receptor-dependent mechanisms of clobetasol, the findings open a genuinely novel avenue for psoriasis research. The apparent therapeutic similarity between the 2 percent febuxostat ointment and clobetasol propionate across several measured outcomes should be interpreted in terms of the experimental results rather than as evidence of equivalent mechanisms or clinical efficacy, and direct comparison of long-term safety profiles remains beyond the scope of the current work. Still, the study provides a compelling rationale for future pharmaceutical, mechanistic, and translational investigations of topical febuxostat as a potential nonsteroidal candidate for psoriasis, and the prospect that a widely used gout medication might be repurposed as a skin treatment is likely to capture attention well beyond the laboratory.

Subject of Research: Pharmacology

Article Title: Topical febuxostat attenuates imiquimod-induced psoriasiform dermatitis and modulates NFE2L2 ( NRF2 )/ NLRP3 mRNA expression

Article References: Alamir, H. T., Albahadly, W. K., Al-Zubaidy, H. F. S., Sahib, A. S., Altrufi, M. H., & Hamza, N. (2026). Topical febuxostat attenuates imiquimod-induced psoriasiform dermatitis and modulates NFE2L2 (NRF2)/NLRP3 mRNA expression. Pharmacia, 73, Article e207442. https://doi.org/10.3897/pharmacia.73.e207442

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e207442

Keywords: febuxostat, psoriasis, NRF2, NLRP3, oxidative stress, imiquimod, topical treatment, mouse model, Topical, attenuates, imiquimod-induced, psoriasiform