Science advances, Volume 11, Issue 43, 24 4 2025, Pages eadx3794 The designer cytokine IC7Fc attenuates atherosclerosis development by targeting hyperlipidemia in mice. In Het Panhuis W, Thiemann E, van Dijk DMAH, Been B, Jarrett KE, Meurs A, Kooijman S, Hovingh MV, Modder M, van Os BW, Sluiter TJ, Blomberg N, Pronk ACM, Afkir S, Streefland TCM, Lalai RA, Taveras MO, Zhang S, Adams TE, Terry LV, Turpin-Nolan SM, de Vries MR, Giera M, Rose-John S, Zelcer N, de Boer JF, de Aguiar Vallim TQ, Febbraio MA, Rensen PCN, Schönke M
The chimeric cytokine IC7Fc conveys the metabolic signaling properties of the glycoprotein 130 receptor cytokines interleukin-6 and ciliary neurotrophic factor via membrane-bound signaling. IC7Fc was previously shown to slow the progression of type 2 diabetes mellitus, and here, we demonstrate its effect on atherosclerotic development. In APOE*3-Leiden.CETP mice, an atherosclerosis-prone model with a humanized lipoprotein metabolism, IC7Fc markedly lowered plasma triglyceride and total cholesterol levels. This was mechanistically explained by an inhibition of de novo lipogenesis in the liver, increased synthesis of bile acids from cholesterol, and down-regulated apolipoprotein B synthesis, which resulted in decreased cholesterol secretion in very low-density lipoprotein particles. As a consequence, IC7Fc treatment considerably reduced atherosclerotic lesion formation and vascular inflammation compared with current antihyperlipidemic therapy. In conclusion, IC7Fc is a promising pharmacological treatment for cardiometabolic diseases targeting hyperlipidemia and inflammation.
