Reduced FBXO22 skews human trophoblast fate equilibrium toward syncytialization via polyubiquitinating the CoREST complex

The precise balance between human trophoblast stem cells (hTSCs) self-renewal and differentiation into syncytiotrophoblasts (STBs) is essential for proper placental development. While the transcriptional and signaling networks regulating this process have been extensively studied, the contribution of protein homeostasis remains poorly understood. Here, we identify FBXO22, the substrate recognition subunit of the SCF E3 ubiquitin ligase complex, as a key regulator of trophoblast fate. We found that FBXO22 was enriched in the nuclei of cytotrophoblasts (CTBs) and levels were reduced markedly in early placental villi from patients with recurrent pregnancy loss (RPL). Experimental loss of FBXO22 compromised hTSC stemness and led to aberrant premature differentiation toward STBs. Mechanistically, FBXO22 selectively ubiquitinates and destabilizes the CoREST complex, thereby coordinating with HDAC1 and LSD1 to regulate histone modifications, including H3K27 acetylation (H3K27ac) and H3K9 dimethylation (H3K9me2). Disruption of this nuclear ubiquitination pathway perturbs the balance between proliferation and differentiation, ultimately impairing placental development. Our findings uncover a previously unrecognized nuclear role of FBXO22 in maintaining cellular homeostasis, linking ubiquitin-mediated protein degradation to trophoblast fate determination and providing new insights into the molecular pathology underlying early pregnancy loss.