Revised Two-Stage Model of Preeclampsia Based on Autophagic Dysfunction: A Comprehensive Review.

A revised two-stage model of preeclampsia is proposed, centering on an autophagy-dependent requirement for extravillous trophoblast entry into the proximal one-third of the myometrium. The One-Third Myometrium Enigma, introduced here, denotes the unresolved physiological rule that early placentation requires trophoblasts to traverse decidua and reach the proximal one-third of myometrium under hypoxia and nutrient scarcity. The hypothesis posits a timed rise in basal autophagy to sustain trophoblast energy homeostasis and invasion, accompanied by TFEB-driven lysosomal programs that enable villous cytotrophoblast syncytialization. Autophagic dysfunction could contribute to shallow invasion, chronic placental hypoxia, fetal growth restriction, and release of placental injury signals preceding maternal syndrome. Potential failure modes include reduced autophagic flux due to inhibition of autophagosome to lysosome fusion or mistimed persistence of hypoxia signaling, such as prolonged HIF-1α activity. Collectively, this evidence suggests that impaired autophagy is a testable contributor to preeclampsia pathogenesis. Predictions include early risk stratification with circulating autophagy markers and extracellular vesicle microRNAs, and therapeutic benefit from autophagy modulation that targets AMPK or mTOR or activates TFEB with safety constraints. This framework reframes preeclampsia as a disorder of placental quality control and specifies where and when autophagy may be required.