ALKBH5 contributes to preeclampsia through m6A-dependent upregulation of FPR2

Preeclampsia (PE) is a pregnancy-specific disorder of unknown etiology that poses significant risks to both maternal and fetal health. The underlying mechanisms of the epigenetic modification N 6 -methyladenosine (m 6 A) in its pathogenesis remain incompletely understood. To investigate the role of m 6 A demethylase alkylation repair homolog protein 5 (ALKBH5) in PE, we analyzed clinical placental samples, employed an oxidative stress model in HTR8/SVneo trophoblasts, and generated a PE mouse model. Bioinformatics analysis identified FPR2 as a downstream target of ALKBH5, and this interaction was validated by RIP and dual‑luciferase reporter assays. Subsequent functional studies demonstrated that FPR2 directly modulates the ALKBH5‑dependent regulation of trophoblast activity. We found that ALKBH5 expression was upregulated in placental tissues from PE patients and PE mouse models, correlating with a global decrease in m 6 A levels. In an oxidative stress model using HTR8/SVneo trophoblasts, ALKBH5 knockdown partially restored the impaired invasion and migration induced by H 2 O 2 . Integrated bioinformatics analysis of the RM2Target and GEO databases identified formyl peptide receptor 2 (FPR2) as a downstream target of ALKBH5. Functionally, FPR2 overexpression reversed the protective effects of ALKBH5 inhibition in H 2 O 2 -treated HTR8/SVneo cells, while the FPR2 antagonist WRW4 ameliorated PE-like features in the mouse model. Mechanistically, ALKBH5 binds to the 3’ untranslated region (3’ UTR) of FPR2 mRNA, reduces its m 6 A methylation, and enhances its stability. ALKBH5 contributes to preeclampsia pathogenesis by erasing m 6 A modifications on FPR2 mRNA, thereby enhancing its stability and expression, which in turn disrupts trophoblast function. The ALKBH5–FPR2 axis thus constitutes a promising therapeutic target for PE intervention.