INHBE encodes Activin E, a hepatokine secreted by the liver that serves as a critical regulator of metabolic homeostasis, particularly through liver-adipose tissue cross-talk 1. Activin E suppresses adipose tissue lipolysis by signaling through the ALK7/ACVR1C receptor on adipocytes, activating SMAD2/3 and suppressing PPARG target genes 2. This mechanism prevents excessive fatty acid efflux from adipose tissue to the liver, thereby reducing hepatic triglyceride accumulation and protecting against hepatic steatosis 3. Hepatic Activin E expression is induced by elevated circulating fatty acids and ER stress, establishing a feedback loop that preserves energy storage during fasting 3. Clinically, rare loss-of-function variants in INHBE associate with reduced abdominal adiposity, lower waist-to-hip ratio, and approximately 28% reduced odds of type 2 diabetes, identifying Activin E as a potential therapeutic target for metabolic disease 45. However, INHBE disruption paradoxically increases lipolysis and reduces adiposity while promoting hepatic steatosis and insulin resistance, highlighting the complex metabolic role of this hepatokine 1. Additionally, focal INHBE-GLI1 gene fusions have been identified in a molecular subtype of hepatocellular adenoma associated with obesity and bleeding 6.