Steroidogenic compensation and lipid deficiency with enhanced NAD+ salvage in small-for-gestational-age placenta

Fetal growth restriction (FGR) affects approximately 8% of pregnancies in Western countries and is characterised by complex placental adaptations at both metabolic and transcriptional levels. In this study, we integrated RNA sequencing and metabolomic analyses to investigate alterations in steroidogenesis, NAD+ metabolism and ω-3/ω-6 polyunsaturated fatty acid (PUFA) pathways in placental biopsies and trophoblast organoids. Placentas from small-for-gestational-age (SGA10 and SGA3) infants, compared with appropriate-for-gestational-age (AGA) controls, showed increased cholesterol uptake and enhanced steroid biosynthesis. In SGA3 placentas, these changes were accompanied by activation of the NAD+ salvage pathway, supporting elevated steroidogenesis, redox balance and energy metabolism. Despite this compensatory response, concentrations of key steroid metabolites, including androstenedione sulfate and oestrogens, were reduced. Metabolomic profiling further revealed a marked depletion of lysophospholipids enriched in ω-3 and ω-6 PUFAs, along with decreased levels of free arachidonic acid (ARA), docosahexaenoic acid (DHA) and selected prostaglandins and thromboxanes. These alterations suggest mobilisation of lipid stores to counteract reduced PUFA-derived eicosanoid production, a process that may compromise placental vascular regulation and fetal neurodevelopment. Collectively, our results highlight the metabolic plasticity of the FGR placenta and identify coordinated alterations in lipid and NAD+ metabolism as key adaptive responses to placental insufficiency.