AOC1 regulates labor initiation through spermidine-induced autophagy of placental trophoblast cells via EIF5A hypusination

Parturition depends on precise communication between the mother and fetus. While fetal lung signals are known to help initiate labor, the role of the placenta has remained unclear. Here we show that in steroid receptor coactivator (Src)−1 and −2 double-knockout mice, reduced placental amine oxidase, copper-containing 1 (Aoc1) leads to increased spermidine levels. In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production. Estrogen reciprocally increases Aoc1 expression via estrogen receptor-α (ERα) in concert with SRC-1/2, forming a feedback loop maintaining placental autophagy homeostasis. AOC1 levels are elevated in preterm labor placentas from both mice and humans. Placenta-specific Aoc1 knockout dramatically delays labor by increasing trophoblast autophagy. Importantly, spermidine supplementation rescues inflammation-induced preterm labor in mice. Our findings reveal that placental AOC1–spermidine–EIF5A–autophagy axis is essential for parturition timing and offer a potential therapeutic strategy for preterm birth. A study in mice and humans reveals that a placental enzyme AOC1 and the molecule spermidine help time labor through regulating autophagy. Boosting spermidine prevented preterm birth, suggesting a potential therapy for human premature labor.