The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice.

ABSTRACT: The role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24^-/- mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans. Nevertheless, inhibition of the inflammasomes would be a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile), other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fibroblasts and a Lmna^G609G/G609G mouse model. In both cases dapansutrile reduced progerin accumulation, NLRP3-inflammasome activation and secretory phenotype of senescence, extended the lifespan of progeroid animals, preserved bodyweight, and reduced kyphosis, inflammation, and senescence. Interes

SUBMITTER: Muela-Zarzuela I 

PROVIDER: S-EPMC11488313 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature