IGF2 acts downstream of Hippo signaling to regulate organ growth and restore liver regeneration in aging.

Precise regulation of organ size is essential for proper function, yet the underlying logic remains unclear. Here, we identify a Hippo-IGF2 signaling axis as a regulator of organ growth. During mouse liver development, Igf2 is highly expressed in fetal and neonatal hepatocytes to fuel rapid growth but is directly silenced by the Hippo signaling pathway at the postnatal stage, enforcing growth arrest and determining liver size. In contrast, chronic liver injury inactivates Hippo signaling and induces Igf2 expression, which is essential for regeneration. Notably, this regenerative response is defective in aged mice but can be restored by ectopic Igf2 expression. As a hormone, circulating IGF2 can compensate for local deficiencies in response to organ-restricted perturbations, whereas whole-body Hippo activation or Igf2 deletion results in small mice with miniature organs. Hence, the Hippo-IGF2 axis is a general regulator of growth and organ size during development and regeneration.