Natural Resistance to Ovarian Hyperstimulation Syndrome in Estrildid Finches Reveals Macrophage GPR183 as a Potential Therapeutic Target

ABSTRACT Spontaneous ovarian hyperstimulation syndrome (OHSS) is closely associated with follicle stimulating hormone receptor (FSHR) functional mutations. We observed that estrildid finches naturally carry the gain‐of‐function FSHR p.Thr449Ala mutation found in humans, yet do not develop OHSS, thereby providing a novel and system to study aspects of OHSS prevention. Cross‐species single‐cell analysis revealed that macrophages, the most abundant immune cells in ovaries, play a pivotal role in OHSS progression. Macrophage depletion exacerbates the manifestations of OHSS in both birds and rats. Pharmacological activation of the G protein‐coupled receptor 183 (GPR183) in ovarian macrophages, significantly alleviates OHSS symptoms. Mechanistically, GPR183 activation in macrophages maintains ovarian immune homeostasis by downregulating inflammatory factors (Interleukin 1 alpha: IL1A, Interleukin 6: IL6, Interleukin 1 beta: IL1B) and upregulating immune regulators responsive to external stimuli (sphingomyelin phosphodiesterase acid like 3A: Smpdl3a , Macrophage‐expressed gene 1: Mpeg1 , Epithelial stromal interaction 1: Epsti1 , Unc‐93 homolog B1: Unc93b1 , Apolipoprotein B mRNA editing enzyme catalytic subunit 1: Apobec1 ). It markedly altered CD44 molecule ( CD44 )/Syndecan‐4 ( SDC4 ) ‐mediated intercellular communication between macrophages and endothelial/stromal cells, thereby modulating the ovarian microenvironment. This study identifies ovarian macrophages as a key therapeutic target for OHSS and proposes GPR183 as a novel receptor target for precision macrophage‐based interventions.