LRPPRC deficiency impairs trophoblast function through disrupted phosphatidylinositol metabolism in recurrent...

Is leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) involved in the development of recurrent pregnancy loss (RPL) and, if so, what is the potential mechanism?

LRPPRC deficiency impairs trophoblast viability and promotes apoptosis and oxidative stress through disruption of phosphatidylinositol (PI) metabolism, and low preconception serum PI (18:1/18:1) levels are associated with subsequent miscarriage in women with RPL.

RPL is commonly associated with impaired trophoblast function. LRPPRC works as a multifunctional protein that regulates a myriad of biological processes, including energy metabolism.

The investigation included re-analysis of a public transcriptomic dataset, functional experiments in trophoblast cell models, lipidomic profiling of first-trimester human villous tissues obtained from 11 clinically healthy pregnant women and 11 patients with RPL, and analysis of preconception serum lipids in a cohort of 63 women with a history of RPL, who were prospectively followed for subsequent pregnancy outcomes resulting in 32 normal deliveries and 31 cases of early pregnancy loss.

Bioinformatics screening of the public transcriptomic dataset GSE76862 was first conducted to identify candidate genes dysregulated in RPL villous tissues. Following the identification of LRPPRC, its functional role was investigated through siRNA-mediated knockdown in the human trophoblast cells, specifically assessing the resultant effects on cell viability, apoptosis, and oxidative stress levels. To elucidate the downstream molecular pathways, transcriptomic analysis of the LRPPRC-depleted cells was performed. Subsequent Gene Ontology analyses revealed a significant enrichment of candidate differentially expressed genes that are involved in the phospholipid biosynthetic process. In parallel, comprehensive lipidomic profiling of human villous tissue samples from both RPL patients and matched controls was carried out using mass spectrometry to validate bioinformatic predictions at the metabolite level. To explore translational potential, the preconception serum levels of lipids, including PI species, were measured in a cohort of women with a history of RPL and statistically correlated with their subsequent pregnancy outcomes. Finally, direct functional rescue experiments were executed by exogenously supplementing PI (18:1/18:1) to the culture medium of LRPPRC-deficient trophoblast cells to determine if this intervention could reverse the observed phenotypic impairments.

LRPPRC was downregulated in RPL villous tissues. Functional validation in trophoblast cells demonstrated that knockdown of LRPPRC suppressed viability and increased apoptosis/oxidative stress. Transcriptomics and lipidomics converged on the phospholipid biosynthetic pathway as a key downstream process. Total lipids and specific phospholipids were decreased in RPL villous tissues. Low preconception serum PI (18:1/18:1) levels predicted subsequent miscarriage in the RPL cohort. Exogenous PI (18:1/18:1) supplementation reversed the cellular defects caused by LRPPRC deficiency.

This study analyzed the publicly available transcriptomic dataset GSE76862 from the Gene Expression Omnibus (GEO) repository.

The analysis of preconception serum lipids was performed in a cohort of 63 women with a history of RPL. This sample size remains relatively limited, primarily due to the current availability of patients with documented follow-up pregnancy outcomes.

Our results reveal a pivotal role for PI in the pathogenesis of RPL and highlight its potential as a mechanistic biomarker and therapeutic target.

This study was supported by National Natural Science Foundation of China (82171657 and 81971384) and Shanghai First Maternity and Infant Hospital Basic Research Special Fund (2025A08).

The authors have declared no conflict of interest.

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