GDF15 suppresses liver inflammation independently of weight loss through neuroendocrine glucocorticoid signaling.

Growth differentiation factor 15 (GDF15) is strongly associated with metabolic dysfunction-associated steatohepatitis (MASH), yet whether it promotes or protects against liver injury remains unclear. Using thermoneutral mouse models that closely resemble human MASH, genetic deletion of GDF15 or its receptor GFRAL selectively worsened hepatic inflammation and fibrosis without altering steatosis or insulin resistance. Conversely, recombinant GDF15 reduced liver inflammation and fibrosis more effectively than matched caloric restriction despite identical reductions in food intake, body weight, and steatosis, demonstrating weight-loss-independent hepatoprotection. These effects required GFRAL but were independent of β-adrenergic signaling. Instead, GDF15 activated the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating corticosterone and hepatic glucocorticoid receptor signaling. Spatial transcriptomics and RNA sequencing demonstrated that GDF15 remodeled the hepatic immune-fibrotic niche by suppressing inflammatory macrophages, plasma B cells, and activated stellate cells while promoting pro-resolving immune programs. Together, these findings identify a GDF15-GFRAL-HPA axis that restrains liver inflammation independently of weight loss.