Sci Transl Med. 2026 Jul 15;18(858):eadv1815. doi: 10.1126/scitranslmed.adv1815. Epub 2026 Jul 15.
ABSTRACT
Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality in patients with insulin resistance, and new therapies are urgently needed. We previously developed an orally administered formulation of 2,4-dinitrophenol, here termed controlled-release mitochondrial protonophore (CRMP), and showed that it safely reversed hypertriglyceridemia, hepatic steatosis, and insulin resistance in dysmetabolic rodents and nonhuman primates. Here, we investigated the therapeutic utility of CRMP for treating atherogenesis in a murine model of cardiometabolic syndrome [high-fat cholesterol diet (HFCD)-fed low-density lipoprotein receptor-deficient (Ldlr-/-) mice]. In both early and late disease stages, CRMP treatment diminished total plaque burden and lesion size compared with HFCD. Morphometric analysis of the aortic root revealed that CRMP also decreased neutral lipid and lesional macrophage content and increased plaque stability. Reductions in atheroprogression were associated with lower plasma and hepatic triglyceride levels and improved whole-body insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps. Furthermore, CRMP markedly limited lesional macrophage inflammasome activation and IL-1β release, changes that are consistent with a local immune-dampening effect. Mechanistically, CRMP-mediated reductions in inflammasome activation were driven by mild increases in macrophage mitochondrial inefficiency and lower mitochondrial reactive oxygen species (ROS) production. These effects were context dependent because CRMP failed to curtail lesional IL-1β content and atheroprogression in chow-fed apolipoprotein E-deficient (Apoe-/-) mice. Collectively, these data show that CRMP exerted antiatherogenic effects through uncoupling of oxidative phosphorylation in hepatocytes and macrophages, highlighting the therapeutic potential of mitochondrial uncouplers for treating ASCVD.
PMID:42455898 | DOI:10.1126/scitranslmed.adv1815