A novel PRR15‐TGF‐β axis in decidual microenvironment dysfunction associated with advanced maternal age

Advanced maternal age (AMA) represents an escalating reproductive challenge worldwide. While aneuploidy in aged oocytes has historically dominated research focus, the maternal uterine environment, particularly the decidua, has emerged as an equally critical determinant of pregnancy success.1, 2 Nevertheless, two fundamental questions remain unresolved: first, what specific alterations within the aged decidual microenvironment account for declining reproductive outcomes? Second, can a key regulatory axis be identified that may be therapeutically targeted to restore decidual function in AMA women? A recent study by Xie et al. provides substantial insight into these questions.3 Integrated single-cell RNA sequencing, organoid modelling, and functional assays revealed a profoundly remodelled AMA decidua, marked by pro-fibrotic reprogramming, impaired stromal differentiation, and immune dysregulation. At the heart of this pathology lies PRR15, a novel decidual stromal cell (DSC)-specific regulator. Its age-related downregulation releases hyperactive TGF-β/SMAD signalling, driving fibroblast-to-myofibroblast transition (FMT) and decidualization failure (Figure 1). This work identifies a key molecular driver and shows that uterine fibrotic programming begins in the first trimester, shifting the paradigm from an oocyte-centric to a decidua-centric model of AMA infertility.4 Nevertheless, several mechanistic gaps need filling. How exactly does PRR15 repress TGF-β/SMAD signalling? Through direct SMAD2/3 interaction, ligand sequestration, or stabilisation of antagonists like SKI/BAMBI? The upstream regulators mediating PRR15 induction during decidualization are also unknown, whether it directs progesterone signalling or crosstalk with pathways like BMP/WNT. Ultimately, it remains to be determined if PRR15 acts as a molecular switch governing the context-dependent dual roles of TGF-β in implantation, and what triggers the spatiotemporal shift from physiological to pathological signalling in the AMA decidua. From a translational medicine perspective, puzzles remain. Is the dampened expression of feedback regulators like CHRD and BAMBI in AMA fibroblasts hardwired by epigenetic changes? Could reversing this, possibly in tandem with PRR15 restoration, alleviate the pro-fibrotic state? The part played by immune cells is also not fully resolved. Additionally, the functional role of decidual immune cells remains to be fully clarified: do macrophages and NK cells that acquire a pro-fibrotic signature (e.g. COL3A1+ and TGM2+) actively deposit extracellular matrix in situ? Co-culture assays could validate their direct contribution to fibrosis. The EEC2 epithelial subset exhibits enhanced EMT markers without population expansion, whether this represents a pathological, sustained transitional state and whether stabilising epithelial identity could prevent fibrotic amplification merit investigation. The study also notes a general weakening of cell-cell communication in the AMA decidua. Is this a driving cause or a downstream effect of stromal defects? Testing if localised delivery of missing signals (e.g. PRL and AREG) can patch this network without off-target effects would be instructive. The therapeutic implications of targeting the PRR15-TGF-β axis are considerable. While the TGF-β receptor inhibitor SB431542 can reverse phenotypes caused by PRR15 knockdown, systemic TGF-β inhibition carries significant toxicity risks. The development of DSC-targeted delivery systems (e.g. leveraging PRLR-targeted nanoparticles) to confine therapeutic action to the decidual niche remains an open challenge. Although PRR15 supplementation is proposed, the protein's stability in the uterine milieu is unknown, and alternative strategies such as mRNA-based delivery may prove more efficacious.5 Furthermore, since the study focuses on first-trimester decidua, whether this fibrotic programming persists into later gestation and whether pre-conception PRR15 modulation could prevent downstream complications such as preeclampsia remain open questions. Despite these unresolved questions, the study represents a landmark contribution. It solidifies the decidual microenvironment as a core pathogenic site in AMA, reframing the entire problem. Pinpointing the PRR15-TGF-β axis as a central malfunction, it gives us a molecular handle on uterine ageing and a potential lever for interventions.6 By demonstrating that age-related reproductive decline is a multi-cellular, multi-pathway process originating in the maternal compartment, Xie et al. have laid the foundation for next-generation diagnostics and precision therapeutics targeting decidual health. Filling in the mechanistic details they've outlined will undoubtedly accelerate the journey toward better outcomes for women choosing later pregnancy. Hui Luo drafted the manuscript and prepared the graphical abstract. Ruizhi Feng, Jie Zheng and Ming Zhang reviewed and revised the manuscript. All authors approved the final version of the manuscript. We thank the advice and suggestions from our lab members. This work was financially supported by the Basic and Clinical Medical Research Joint Fund of Zhongnan Hospital, Wuhan University (No. ZNLH202206 to Ming Zhang). The authors declare no conflict of interest. Not applicable.