Pregnancy-related disorders, including preterm birth, preeclampsia, recurrent spontaneous abortion, and fetal growth restriction, represent major contributors to global maternal and infant morbidity and mortality. Their pathophysiology involves complex mechanisms such as immune dysregulation, inflammatory responses, oxidative stress, and metabolic disturbances. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein, regulates diverse biological processes-including antiviral immunity, cellular metabolism, oxidative stress, and DNA damage response-through ISGylation, which covalently conjugates ISG15 to target proteins. In recent years, the potential role of ISG15 in pregnancy-related diseases has attracted growing interest. This review systematically outlines the molecular characteristics and functions of ISG15, with a focus on its research advances in preeclampsia, recurrent spontaneous abortion, preterm birth, and fetal growth restriction. Furthermore, it discusses the potential of ISG15 as a novel biomarker or therapeutic target for pregnancy-related disorders, providing new insights for early prevention and clinical management. Collectively, this review positions ISG15 as a critical regulator in pregnancy-related pathologies and underscores its translational potential.

Background: Early pregnancy loss, defined as the spontaneous loss of a pregnancy before 20 weeks of gestation or when the fetus weighs less than 500 g, remains a common obstetric complication, affecting up to 15% of clinically recognized pregnancies. Chromosomal abnormalities, particularly aneuploidies such as trisomies and monosomy X, account for 50-60% of first-trimester losses, with incidence increasing alongside maternal age. Additional risk factors include maternal medical conditions, uterine anomalies, infections, and modifiable lifestyle factors. Pregnancies conceived through assisted reproductive technologies also carry a slightly higher risk of miscarriage, often influenced by maternal age and embryo quality. Methods: Two pathologists, blinded to each other's assessments, analyzed abortive material from patients who experienced spontaneous first-trimester abortion between January 2012 and January 2025 at Agostino Gemelli Hospital, Rome, Italy. Inclusion criteria were defined independently of patient demographics. No restrictions were applied regarding maternal age. With respect to gestational age, only first-trimester miscarriages (≤12 weeks of gestation) were considered. In cases of discordance, the case was reviewed and re-evaluated to reach a final diagnosis. Results: The findings of this study are presented as a proposed histopathological classification and diagnostic framework for first-trimester miscarriages. Specifically, a total of 1168 cases were categorized into eight distinct groups of miscarriage etiology based exclusively on the histomorphological features of chorionic villi and maternal decidua. Conclusions: Histopathological examination of products of conception is essential for confirming intrauterine pregnancy, identifying underlying maternal or fetal causes, and guiding future reproductive management, particularly in recurrent pregnancy loss. This study evaluates histopathological features of first-trimester losses, classifies findings by etiology, and proposes a practical diagnostic guide to support clinical decision-making and improve outcomes in subsequent pregnancies.

Regulatory T cells (Tregs) play a central role in maintaining immune tolerance and supporting maternal-fetal homeostasis throughout human pregnancy. Clinical and experimental evidence demonstrates that dysregulation of peripheral and decidual Tregs manifested as quantitative deficits, impaired suppressive function or lineage instability increased the risk of various pathological pregnancies, such as recurrent implantation failure (RIF), recurrent spontaneous abortion (RSA), pre-eclampsia (PE) and preterm birth (PTB). Recently, novel therapeutic strategies targeting Tregs have emerged in oncology, transplantation, and autoimmune diseases. However, their application in pathological pregnancy remains in its infancy. This review outlines the spatiotemporal dynamics of peripheral and decidual Tregs throughout gestation, elucidating their roles in maintaining maternal-fetal homeostasis and their dysregulation in pathological pregnancies. We also critically evaluated the therapeutic strategies targeting Tregs and Tregs-associated signaling pathways, including hormonal support, traditional intravenous immunoglobulin, as well as emerging interventions such as immunometabolic reprogramming and engineered cellular therapies like chimeric antigen receptor Tregs. This review may provide insights for understanding the roles of Tregs in physiological and pathological pregnancy, as well as provide new idea in the immunotherapy of pathological pregnancy.

Female reproductive disorders present significant challenges worldwide. Transfer RNA-derived small RNAs (tsRNAs), a structurally diverse class of non-coding RNAs mainly comprising tRNA halves (tiRNAs) and tRNA-derived fragments (tRFs), have emerged as key regulators in human health and disease. This review outlines the biogenesis and functions of tsRNAs and summarizes their mechanistic involvement and clinical implications across a range of reproductive pathologies. In pregnancy-related complications, such as embryo implantation failure and recurrent spontaneous abortion, aberrant tsRNA profiles perturb trophoblast behavior, endometrial decidualization, and maternal-fetal crosstalk, thereby compromising placental development and pregnancy outcome. In benign gynecological conditions including premature ovarian failure and endometriosis, dysregulated tsRNAs disrupt granulosa cell survival, promote stromal proliferation, and reshape inflammatory signaling, ultimately altering follicular development and uterine homeostasis. As our understanding of tsRNA-mediated pathways deepens, these molecules offer promising potential as diagnostic biomarkers and therapeutic targets for precision medicine in female reproductive disorders.