Structural Control of Stromal-Immune Coupling by COL24A1 Underlies Pregnancy Maintenance

Successful pregnancy requires dynamic extracellular matrix (ECM) remodeling at the maternal-fetal interface, yet whether individual collagen subtypes actively regulate this process remains unknown. Here, collagen type XXIV alpha 1 chain (COL24A1), a uterine-enriched fibrillar collagen, is identified as a regulator of pregnancy-associated ECM-immune homeostasis. Col24a1-deficient mice exhibit increased embryo resorption, fetal growth impairment, and pregnancy-dependent uterine collagen accumulation and inflammation. Mechanistically, Col24a1 loss promotes expansion of a maladaptive Timp1-high stromal state, accompanied by reduced matrix metalloproteinase 2 activity, impaired ECM degradation, and altered stromal-immune communication and inflammatory immune-cell states. COL24A1 silencing in human endometrial stromal cells similarly impairs decidualization and increases TIMP1 and fibrillar collagen gene expression. Hydroxychloroquine partially rescues embryo resorption and attenuates uterine inflammation, indicating that these pregnancy-associated abnormalities are pharmacologically modifiable. Moreover, a patient with 12 consecutive unexplained early pregnancy losses carrying rare heterozygous COL24A1 variants shows a concordant decidual phenotype with reduced COL24A1 and increased TIMP1, inflammation, and collagen deposition. These findings identify COL24A1 as a collagen subtype-specific regulator of maternal-fetal ECM-immune homeostasis and nominate it as a candidate susceptibility gene for unexplained recurrent pregnancy loss.