Despite widespread use of low-dose aspirin to prevent preeclampsia in high-risk pregnancies, up to one-third of women still develop the condition, raising questions about why prophylaxis fails in some cases.^1,2 In a recent study from The Chinese University of Hong Kong (CUHK) identified a previously underrecognized culprit—overexpression of glycine-N-acyltransferase (GLYAT) in the placenta.¹ This enzyme accelerates the local breakdown of salicylic acid, blunting aspirin’s beneficial effects.¹ These findings offer a biological explanation for aspirin resistance and suggest that targeting placental metabolism may improve outcomes in vulnerable pregnancies.¹

Preeclampsia remains a major global threat to maternal and fetal health, affecting 3%-8% of pregnancies worldwide.^1,3 It is a complex, multifactorial condition linked to defective placentation at the maternal-fetal interface, leading to placental ischemia, oxidative stress, and systemic endothelial dysfunction.¹ Prophylactic low-dose aspirin (LDA) is widely recommended to reduce the risk of preterm preeclampsia in high-risk pregnancies.^1,2 However, a significant proportion of women still develop preeclampsia despite timely aspirin use, suggesting that key mechanisms of treatment failure remain poorly understood.¹

To investigate this clinical gap, CUHK researchers conducted a mechanistic sub-study nested within a larger clinical trial involving high-risk pregnant women enrolled in the regional FORECAST trial—a multicenter study evaluating first-trimester screening and LDA use for preeclampsia prevention in Asia.¹ All participants had initiated aspirin before 16 weeks of gestation and were stratified into responders (no preeclampsia) and nonresponders (early-onset preeclampsia despite aspirin).¹ Preeclampsia was diagnosed by a senior obstetrician according to the International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria, defined as new-onset hypertension (systolic ≥140mmHg or diastolic ≥90mmHg) after 20 weeks of gestation, along with proteinuria and/or evidence of maternal organ dysfunction or fetal growth restriction.¹ Compliance was verified to eliminate adherence bias, allowing the team to focus on physiological and molecular differences underlying treatment failure.¹

A stepwise analysis was performed to evaluate potential contributors to aspirin nonresponsiveness.¹ Genetic analysis using genome-wide association and targeted post-genome-wide association study (GWAS) approaches revealed no significant associations between polymorphisms in aspirin pharmacokinetic or pharmacodynamic genes and clinical outcome.¹ Similarly, systemic metabolic studies showed no difference in plasma esterase activity or placental concentrations of acetylsalicylic acid and its metabolites between groups.¹ After ruling out common contributors such as pharmacogenetic variants and systemic aspirin metabolism, a key differentiator emerged: elevated expression of the enzyme GLYAT in nonresponders.¹

GLYAT catalyzes the glycine conjugation of salicylic acid, reducing its bioactivity.¹ Multivariate analysis confirmed GLYAT as an independent predictor of aspirin nonresponse.¹ Functional assays further showed that GLYAT overexpression suppressed aspirin’s beneficial actions, including its proangiogenic, anti-inflammatory, and antisenescence effects.¹ These were evidenced by diminished Flt1 and HIF1α expression, increased phosphorylated p65, and upregulation of placental senescence markers such as p53.¹ The findings suggest that GLYAT-mediated metabolism within the placenta may undermine aspirin’s therapeutic potential, despite normal systemic levels.¹ This mechanism highlights the importance of placental biology in shaping treatment response, moving beyond the one-size-fits-all use of aspirin.¹

In summary, identifying GLYAT as a key placental enzyme driving aspirin nonresponsiveness sheds light on a novel biological barrier to preeclampsia prevention.¹ The results underscore the need to look beyond maternal circulation and explore local placental factors when investigating treatment failure.¹ Future therapies targeting placental metabolism may offer more effective, personalized approaches to protect high-risk pregnancies.