During prenatal development, the fetus resides in a relatively low-glucose environment compared to the mother, yet must maintain high anabolic activity to support rapid growth. Here, we discover that in fetal hepatocytes, mTORC1—a central anabolic regulator that is typically inhibited under low glucose conditions—remains active despite effective AMPK activation. Mechanistically, we find that TRPV4, an upstream regulator of mTORC1, is acetylated at K608 in the fetal liver. This acetylation prevents TRPV4 from being inhibited by FBP-unoccupied aldolase, thereby blunting the inhibition of mTORC1 that usually occurs under low glucose conditions. Expression of a non-acetylatable TRPV4-K608R mutant in fetal hepatocytes restores glucose sensitivity, inhibits mTORC1, and impairs hepatic anabolism. Liver-specific expression of this mutant during embryonic development leads to intrauterine growth restriction or death. Our study reveals that the human fetus has evolved unique nutrient-sensing systems to adapt to the long-standing challenges of survival under hunger. The work entitled "TRPV4 acetylation in prenatal liver prevents low glucose-induced inhibition of mTORC1 and safeguards fetal development" was published on Vita. (published on March 13, 2026)
DOI：10.15302/vita.2026.03.0017