circDLGAP4 ameliorates trophoblastic oxidative stress in HTR8/SVneo trophoblast-derived cells during preeclampsia by enhancing PDK4-driven glycolysis via sponging miR-29c-3p

Preeclampsia (PE), a leading cause of maternal morbidity worldwide, is a multifactorial pregnancy disorder. PE pathogenesis involves trophoblast cell dysfunction induced by pathological stimuli, notably oxidative stress. Circular RNA DLGAP4 (circDLGAP4) has been implicated in the pathogenesis and progression of pregnancy-related disorders; however, its specific roles in PE remain poorly understood. This study aimed to elucidate the functional mechanisms of circDLGAP4 in oxidative stress-induced injury of HTR8/SVneo cells, an immortalized trophoblast-derived cell line, in the context of PE. We observed significant downregulation of circDLGAP4 in trophoblast cells from PE patients. Functional assays demonstrated that circDLGAP4 overexpression enhanced HTR8/SVneo proliferation while suppressing apoptosis. Through microRNA microarray analysis and subsequent validation via RNA pull-down and dual-luciferase reporter assays, we identified miR-29c-3p as a direct target of circDLGAP4, with their functional effects on HTR8/SVneo cells being mutually antagonistic. Further investigations revealed impaired glucose metabolism in PE placental tissues. Under low-glucose conditions, HTR8/SVneo cells exhibited heightened susceptibility to oxidative stress. Mechanistically, circDLGAP4 promoted whereas miR-29c-3p suppressed glucose metabolism in HTR8/SVneo cells. MiR-29c-3p was found to directly target pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme in glucose metabolism, thereby exacerbating oxidative stress-induced HTR8/SVneo cell injury. Rescue experiments confirmed that miR-29c-3p restoration counteracted the protective effects of circDLGAP4 overexpression on glucose metabolism and HTR8/SVneo cell viability under oxidative stress. Collectively, our findings demonstrate that circDLGAP4 mitigates oxidative stress-induced HTR8/SVneo cell injury through the miR-29c-3p/PDK4/glucose metabolism axis, suggesting its potential involvement in PE and relevance as a biomarker or therapeutic target in PE.