SERPINE2 At the Granulosa Cell‐Matrix Interface: Emerging Mechanisms in Follicular Development and Ovarian Function

Serpin family E member 2 ( SERPINE2 ), also known as protease nexin‐1, is a secreted serpin enriched in ovarian granulosa and cumulus‐cell compartments. Its location is biologically important because follicle growth, selection, atresia and ovulation all require spatially controlled extracellular proteolysis. Recent experiments have begun to define how SERPINE2 is regulated and what it may do in the ovary. In human granulosa‐lutein cells, bone morphogenetic protein 2 (BMP2) induces SERPINE2 through ALK3‐dependent SMAD2/3‐SMAD4 and p38 MAPK signaling and is accompanied by reduced production of urokinase‐ and tissue‐type plasminogen activators. In buffalo granulosa cells, FOXL2 activates SERPINE2 transcription, whereas promoter‐associated H3K9me3 is linked to its repression in atretic follicles; SERPINE2 perturbation affects proliferation, apoptosis and steroid output. In FecB ‐genotyped sheep granulosa cells, SERPINE2 alters TERT expression, relative telomere length, proliferation, ovulation‐related genes and estradiol secretion. Together, these studies support a model in which intracellular differentiation and chromatin programmes converge on a secreted inhibitor that adjusts the extracellular proteolytic environment and thereby modifies granulosa‐cell state. However, the causal chain from individual protease targets to matrix remodeling, receptor signaling and whole‐animal fertility remains incomplete. WNT/beta‐catenin and ERK1/2 are plausible downstream candidates, but their dependence on SERPINE2 has not been demonstrated in ovarian cells. This review integrates the direct ovarian evidence with follicular matrix biology, separates established mechanisms from tissue‐extrapolated hypotheses, and defines experiments needed to determine whether SERPINE2 is principally a marker of follicular state, a local proteolytic buffer or a tractable regulator of ovarian function.