RNF126 mediates fetal growth restriction via ubiquitination-dependent degradation of the MYH9/MYH10 complex

Fetal growth restriction (FGR) remains a major contributor to neonatal morbidity and mortality worldwide, with limited effective diagnostic and therapeutic options. To better understand its molecular mechanism, we performed integrated multi-omics analyses of placental tissues from FGR pregnancies and normal controls, identifying Ring Finger Protein 126 (RNF126), an E3 ubiquitin ligase, as a key regulator of FGR and a potential biomarker distinguishing FGR from small-for-gestational-age (SGA) fetuses. Placenta-specific RNF126 conditional knockout (cKO) mice demonstrated a causal role of elevated placental RNF126 in FGR development <i>in vivo</i>. Functional studies revealed that RNF126 induced endoplasmic reticulum (ER) stress and apoptosis in trophoblasts. Mechanistically, RNF126 promoted a ubiquitin-proteasome-mediated degradation of the MYH9/MYH10 complex, thereby exacerbating ER stress and impairing trophoblast function, with lysine 833 (K833) of MYH9 identified as a critical ubiquitination site. Collectively, these findings elucidate an RNF126-mediated pathogenic mechanism in FGR and highlight RNF126 as a promising biomarker and therapeutic target.