Hydroxychloroquine confers placental protection in antiphospholipid Syndrome: Mechanistic insights into autophagy regulation and trophoblast dysfunction.

Abstract

Obstetric antiphospholipid syndrome (OAPS) is a disorder mediated by antiphospholipid antibodies (aPL) that is associated with recurrent miscarriage, pre-eclampsia, and fetal growth restriction. Although hydroxychloroquine (HCQ) has shown therapeutic potential in refractory cases, its mechanistic effect on placental pathophysiology remains unclear. HCQ's autophagy-inhibitory properties are well described in oncological and neurodegenerative contexts; however, the role of autophagy dysregulation in OAPS pathogenesis has not been defined. In this study, we first identified aberrant autophagy activation in clinical OAPS placental samples by assessing expression of LC3B-II and P62/SQSTM1. In vitro, aPL-treated HTR-8/SVneo extravillous trophoblasts and trophoblast organoids reproduced this phenotype, with autophagy induction accompanied by impaired proliferation, invasion, migration, and differentiation. HCQ reversed these effects in vitro. Mechanistically, HCQ restored trophoblast function primarily by suppressing autophagy. In a mouse model of OAPS, HCQ treatment reduced fetal resorption and normalized placental autophagy markers. These findings demonstrate that HCQ confers placental protection in OAPS by modulating autophagy and support a pathological role for autophagy dysregulation in aPL-mediated placental dysfunction.