Peyman, MonaBarroso Fernández, EmmaTurcu, Andreea L.Estrany Jr, FrancescSmith, DáireJurado Aguilar, JavierRada, PatriciaMorisseau, ChristopheHammock, Bruce D.Valverde, Ángela M.Palomer Tarridas, Francesc XavierGaldeano Cantador, CarlosVázquez Cruz, SantiagoVázquez Carrera, Manuel2024-12-172024-12-172023-10-110753-3322https://hdl.handle.net/2445/217146Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the key role of these kinases on endoplasmic reticulum (ER) stress, ALT-PG2 attenuated the levels of ER stress and inflammatory markers. Overall, the findings of this study indicate that targeting sEH with degraders is a promising pharmacological strategy to promote AMPK activation and to reduce ER stress and inflammation.1 p.application/pdfengcc by-nc-nd (c) Mona Peyman, et al., 2023http://creativecommons.org/licenses/by-nc-nd/3.0/es/EpòxidsInflamacióNeurologiaEpoxy compoundsInflammationNeurologyinfo:eu-repo/semantics/article7397942024-12-17info:eu-repo/semantics/openAccess