This study examined whether GDF15 protects against or promotes liver injury in MASH, using thermoneutral mouse models with genetic deletion of GDF15/GFRAL and recombinant GDF15 treatment, comparing outcomes to matched caloric restriction.
Genetic deletion of GDF15 or GFRAL selectively worsened hepatic inflammation and fibrosis (without changing steatosis or insulin resistance); recombinant GDF15 reduced liver inflammation and fibrosis more than matched caloric restriction despite identical reductions in food intake, body weight, and steatosis — acting via the HPA axis (↑ corticosterone, ↑ hepatic glucocorticoid receptor signaling) rather than β-adrenergic pathways.
Findings are based entirely on mouse models (thermoneutral); direct human translational evidence is lacking. The study does not quantify the magnitude of HPA axis activation or glucocorticoid receptor signaling changes with specific numbers. Long-term safety and efficacy of GDF15-mediated glucocorticoid elevation in humans remain unknown.
GDF15 suppresses MASH-related liver inflammation and fibrosis through a weight-loss-independent neuroendocrine (HPA axis/glucocorticoid) mechanism, not simply by reducing body weight. Clinicians developing or evaluating GDF15-based therapies for MASH should consider hepatic anti-inflammatory effects as a distinct, weight-independent benefit — and monitor for glucocorticoid-related side effects.
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