Therapeutic Gfral silencing via antisense oligonucleotides ameliorates cancer-associated cachexia and extends survival in tumor-bearing mice.

Cancer cachexia is a life-threatening wasting syndrome that can be driven by tumor-derived GDF15 signaling through the brainstem-restricted receptor GFRAL. Despite its clinical importance, central genetic interventions targeting this axis remain limited. Here, we develop a potent antisense oligonucleotide (Gfral-ASO, A427) that specifically silences Gfral expression in the central nervous system. Using orthotopic mouse models of severe colon (MC38) and pancreatic (KPC and MPC1) cancers, we show that a single intracerebroventricular administration of Gfral ASO markedly blunts GFRAL expression and pathogenic c-Fos neuronal activation in the area postrema and nucleus tractus solitarius. This central blockade reverses cachectic phenotypes, restoring body weight, muscle mass, and adipose depots. Notably, Gfral ASO achieves superior restoration of muscle (grip) strength compared with systemic anti-GDF15 neutralizing antibody. Crucially, silencing central GFRAL signaling profoundly extends survival of tumor-bearing mice. Our findings highlight central GFRAL antagonism via ASO as a promising therapeutic strategy for cancer cachexia.