SECUAH 2026 > Fernández-Vega etal 2026

dianas | Vol 15 No 1 | marzo 2026 | e202603x032

Dehydroisohispanolone, a Selective NLRP3 Inflammasome Inhibitor with Therapeutic Potential in Gout

Eva Fernández-Vega^1,a, Irene Cuadrado¹, Beatriz de las Heras¹, Sonsoles Hortelano², Ana Estévez-Braun³, Laura González-Cofrade¹, María Carmen Terencio^4,5, María Luisa Ferrándiz^4,5

1. Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Madrid, Spain.  2. Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III. Madrid, Spain.  3. Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Tenerife, Spain.  4. Instituto Interunivesitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Valencia, Spain.  5. Facultad de Farmacia y Ciencias de la Alimentación, Burjassot, Spain. 

a. evfern08@ucm.es 

XI Congreso de Señalización Celular, SECUAH 2026.
XX Simposio de Dianas Terapéuticas.
16 a 18 de marzo, 2026. Universidad de Alcalá. Alcalá de Henares, Madrid. España.

Keywords: dehydroisohispanolone; inflammation; NLRP3; natural products; gouty arthritis

Abstract

Natural products constitute a rich source of bioactive molecules with therapeutic potential. Among them, terpenoid compounds have attracted increasing attention due to their diverse pharmacological activities, including anti-inflammatory properties [1]. In particular, Hispanolone-derived diterpenes have been reported to modulate multiple inflammatory signaling pathways. Dehydroisohispanolone (DIH), has previously demonstrated significant anti-inflammatory activity [2]. However, its potential role in the regulation of inflammasome activation has not been fully characterized. In this study, we investigated whether DIH could modulate the activation of the NLRP3 inflammasome in an experimental model of gouty arthritis. Our results showed that DIH effectively suppressed NLRP3 inflammasome activation in lipopolysaccharide (LPS)-primed macrophages stimulated with different canonical NLRP3 activators, including nigericin, ATP, imiquimod, and silica crystals. Treatment with DIH markedly reduced the release of the pro-inflammatory cytokine, interleukin-1β (IL-1β), and significantly decreased pyroptotic cell death. Mechanistic analyses revealed that DIH impaired the oligomerization of the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), a critical step required for the assembly of the inflammasome complex. By disrupting ASC speck formation, DIH prevented the proper formation of the NLRP3 inflammasome platform and consequently inhibited caspase-1 activation and cytokine maturation. Importantly, DIH exhibited selectivity towards the NLRP3 inflammasome pathway, as it did not significantly affect the activation of other inflammasome complexes such as absent in melanoma 2 (AIM2) or NOD-like receptor family CARD domain-containing protein 4 (NLRC4). The anti-inflammatory effects of DIH were evaluated in a murine model of monosodium urate (MSU)-induced gouty arthritis. Administration of DIH significantly reduced joint inflammation triggered by MSU crystal deposition. This effect was accompanied by a decrease in the production of pro-inflammatory cytokines and in myeloperoxidase (MPO) activity in joint tissues. This supports the anti-inflammatory potential of DIH through selective inhibition of NLRP3 inflammasome activation. By preventing ASC oligomerization and subsequent inflammasome assembly, DIH effectively attenuated IL-1β production and inflammasome-mediated inflammatory responses. These findings highlight DIH as a promising candidate for the development of novel therapeutic strategies aimed at treating gout and other inflammatory disorders driven by NLRP3 inflammasome activation.