4-octyl itaconate reduces NLRP3 inflammasome constitutive activation with cryopyrin-associated periodic syndrome p.R262W, p.D305N and p.T350M variants

Molina-López, Cristina; Hurtado-Navarro, Laura; O'Neill, Luke A.J.; Pelegrin, Pablo

Publication:
4-octyl itaconate reduces NLRP3 inflammasome constitutive activation with cryopyrin-associated periodic syndrome p.R262W, p.D305N and p.T350M variants

dc.contributor.author	Molina-López, Cristina
dc.contributor.author	Hurtado-Navarro, Laura
dc.contributor.author	O'Neill, Luke A.J.
dc.contributor.author	Pelegrin, Pablo
dc.contributor.department	Bioquímica y Biología Molecular B e Inmunología	es
dc.date.accessioned	2025-09-03T07:51:24Z
dc.date.available	2025-09-03T07:51:24Z
dc.date.copyright	© 2025, The Author(s)
dc.date.issued	2025-05-23
dc.description.abstract	Cryopyrin-associated periodic syndrome (CAPS) is a condition characterized by dominant genetic variants in the NLRP3 gene, leading to the formation of constitutively active inflammasomes. These inflammasomes play a crucial role in the inflammatory episodes experienced by CAPS patients, primarily driven by the production of interleukin (IL)-1. Although treatment with IL-1 blockers is effective for CAPS, some patients develop refractory responses and adverse reactions to these therapies. Consequently, there is a need for novel treatments for CAPS patients. Promising candidates are the derivatives of itaconate, which have been shown to impair NLRP3 inflammasome activation and IL-1 release in blood mononuclear cells from CAPS patients. In this study, we provide insight into the inhibitory mechanisms of the itaconate derivative 4-octyl itaconate (4-OI) on NLRP3 with different (p.R262W, p.D305N and p.T350M) gain-of-function mutations associated with CAPS. Notably, 4-OI effectively blocks the basal auto-activation of the inflammasome formed by NLRP3 p.R262W, p.D305N and p.T350M variants, resulting in reduced caspase-1 activation, gasdermin D processing, and IL-18 release. Furthermore, after lipopolysaccharide priming of macrophages, 4-OI also decreases IL-1 gene expression and release. Overall, 4-OI impairs CAPS p.D305N-associated inflammasome function at multiple levels, and therapeutic agents based on itaconate could be a promising therapeutic approach to managing inflammatory episodes in CAPS patients carrying p.R262W, p.D305N or p.T350M variants.	es
dc.format	application/pdf	es
dc.format.extent	30	es
dc.identifier.citation	Cellular and Molecular Life Sciences Vol. 82, 209, (2025)
dc.identifier.doi	https://doi.org/10.1007/s00018-025-05699-5
dc.identifier.eissn	1420-9071
dc.identifier.issn	1420-682X
dc.identifier.uri	http://hdl.handle.net/10201/158084
dc.language	eng	es
dc.publisher	Springer, Birkhäuser Verlag
dc.relation	MCIN/AEI/10.13039/501100011033 (PID2020-116709RB-I00, CNS2022-135105, RED2022-134511-T, PRE2018-086824), Fundación Séneca (21897/PI/22, 21214/FPI/19), Instituto Salud Carlos III (AC22/00009).	es
dc.relation.publisherversion	https://link.springer.com/article/10.1007/s00018-025-05699-5	es
dc.rights	info:eu-repo/semantics/openAccess	es
dc.rights	Attribution 4.0 Internacional	*
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	*
dc.subject	Itaconate	es
dc.subject	Autoinflammatory disease	es
dc.subject	CAPS	es
dc.subject	NLRP3	es
dc.subject	Inflammasome	es
dc.title	4-octyl itaconate reduces NLRP3 inflammasome constitutive activation with cryopyrin-associated periodic syndrome p.R262W, p.D305N and p.T350M variants	es
dc.type	info:eu-repo/semantics/article	es
dspace.entity.type	Publication	es