Background: Growing evidence suggests that arrestin domain-containing protein 3 (ARRDC3) plays a pivotal role in enhancing preeclampsia (PE) progression, and activating transcription factor 2 (ATF2) serves as a key regulator of trophoblast cell functions. Therefore, this study aims to investigate the role of the ATF2/ARRDC3 axis in mediating trophoblast cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT), providing mechanistic insights into PE pathogenesis.

Methods: The expression of ARRDC3, ATF2, EMT-related markers, both at mRNA and protein levels, was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses. Trophoblast cell viability, apoptosis rate, invasion, and migration were evaluated using the Cell counting kit-8 (CCK-8) assay, flow cytometry, Transwell assay, and wound healing assay. Additionally, a correlation between ATF2 and the ARRDC3 promoter region was determined using the dual-luciferase reporter and ChIP assays.

Results: ARRDC3 overexpression inhibited trophoblast cell viability, invasion, migration, and EMT, while promoting apoptosis (p < 0.05). ATF2 promoted ARRDC3 expression by binding to its promoter region (p < 0.05). Upregulated ATF2 suppressed trophoblast cell viability, invasion, migration, and EMT; however, these effects were reversed by ARRDC3 knockdown (p < 0.05).

Conclusion: ATF2 binds to the ARRDC3 promoter region, upregulating its expression, thereby inhibiting trophoblast cell functions which in turn accelerate PE progression.