LEFTY2 is a TGF-β superfamily member that functions as a negative regulator of left-right axis determination and endometrial receptivity. Developmentally, LEFTY2 is expressed in the anterior visceral endoderm during early primate gastrulation and plays a critical role in axis patterning 1. Mutations in LEFTY2 are associated with situs inversus totalis and heterotaxy, disorders characterized by reversed or randomized organ asymmetry 2. Mechanistically, LEFTY2 functions through multiple signaling pathways. In embryonic stem cells, optimal LEFTY2 expression controls the balance between self-renewal and differentiation by regulating Smad2 phosphorylation 3. In endometrial tissues, LEFTY2 inhibits receptivity by downregulating Orai1 expression and store-operated calcium entry (SOCE), suppressing expression of receptivity genes including Cox2, Bmp2, and Wnt4 4. LEFTY2 also antagonizes trypsin-induced calcium signaling through L-type calcium channels 5. Clinically, LEFTY2 dysregulation is implicated in unexplained infertility and endometrial cancer progression. In endometrial carcinoma cells, LEFTY2 suppresses migration and proliferation by inhibiting focal adhesion kinase (FAK) activity and upregulating miR-200a and E-cadherin 6. Additionally, LEFTY2 alleviates hepatic fibrosis by inhibiting the TGF-β1/Smad3 pathway and hepatic stellate cell activation 7. These findings suggest LEFTY2 represents a potential therapeutic target for reproductive and fibrotic diseases.