RT journal article
T1 The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice
A1 Muela-Zarzuela, Inés
A1 Suarez Rivero, Juan Miguel
A1 Boy Ruiz, Daniel
A1 López Pérez, Juan
A1 Sotelo Montoro, Marta
A1 Navarrete Alonso, Maria del Mar
A1 Collado, Isidro G.
A1 González Collado, Isidro
A1 Botubol Ares, José Manuel
A1 Sanz, Alberto
A1 Cordero, Mario D.
A2 Química Orgánica
K1 Dapansutrile
K1 Lonafarnib
K1 NLRP3
K1 progeria
AB The role of the inflammasomes in aging and progeroid syndromes remain understud-ied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24−/− mice to amelio-rate the phenotypes. However, the safety of MCC950 was questioned due to livertoxicity observed in humans. Nevertheless, inhibition of the inflammasomes wouldbe a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile),other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fi-broblasts and a Lmna G609G/G609G mouse model. In both cases dapansutrile reducedprogerin accumulation, NLRP3-inflammasome activation and secretory phenotype ofsenescence, extended the lifespan of progeroid animals, preserved bodyweight, andreduced kyphosis, inflammation, and senescence. Interestingly, dapansutrile furtherimproved the effect of lonafarnib, the only FDA-approved drug for the progeria. Thecombination of both drugs reduced the inflammation and senescence, extended sur-vival and ameliorated various progeroid defects both in vitro and in vivo, comparedwith treatment using lonafarnib alone. These findings and the safety of dapansutriledemonstrated in several clinical trials proposes it as a possible co-adjuvant treatmentwith lonafarnid in HGPS
PB Wiley
SN 1474-9726
YR 2024
FD 2024-09-12
LK http://hdl.handle.net/10498/35694
UL http://hdl.handle.net/10498/35694
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 07-nov-2026