SNCA/synuclein alpha impairs endometrial receptivity in obesity by disrupting STUB1-TFEB-mediated autophagy

Obesity is recognized as a key contributor to the impaired endometrial receptivity that results in infertility; however, the molecular mechanisms underlying endometrial dysfunction remain incompletely understood. In this study, proteomic and ubiquitination analyses of secretory-phase endometrial tissue revealed a significant upregulation of SNCA/synuclein alpha and dysregulation of macroautophagy/autophagy in women with obesity. SNCA is best known for its role in neurodegenerative protein aggregation disorders. Proteomic and ubiquitination analysis of secretory-phase endometrial tissue revealed a significant upregulation of SNCA and dysregulation of autophagy in women with obesity. This study aimed to elucidate the role and mechanistic basis of SNCA and autophagy in obesity-associated endometrial receptivity defects. We demonstrated that elevated SNCA expression in endometrium and endometrial stromal cells (ESCs) correlated with impaired autophagy and disrupted decidualization in vivo and vitro. Mechanistically, SNCA directly interacted with the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box containing protein 1) in ESCs, thereby disrupting the association between STUB1 and phosphorylated TFEB (transcription factor EB; p-TFEB). This interaction attenuated p‑TFEB degradation, leading to suppressed autophagic flux and ultimately compromised decidualization of ESCs. Conversely, snca knockout alleviated obesity-induced endometrial impairments in mice. Moreover, STUB1 overexpression rescued decidualization and autophagy defects. Notably, metformin intervention restored autophagic activity and endometrial receptivity in obese mice by downregulation of SNCA independent of its autophagy-modulating effects. Together, these findings uncovered a novel pathogenic mechanism in which obesity-driven SNCA overexpression impairs endometrial receptivity by inhibiting STUB1-TFEB-mediated autophagy, positioning the SNCA-STUB1-TFEB axis as a promising therapeutic target for obesity-related endometrial infertility.Abbreviations: BECN1: beclin 1; CCK-8: Cell Counting Kit-8; CQ: chloroquine; DEPs: differentially expressed proteins; DIO: diet-induced obese; ESCs: endometrial stromal cells; FBS: fetal bovine serum; GD7: gestational day 7; GSEA: Gene Set Enrichment Analysis; HFD: high-fat diet; HOXA10: homeobox A10; IGFBP1: insulin like growth factor binding protein 1; IPGTT: intraperitoneal glucose tolerance test; LIF: LIF interleukin 6 family cytokine; PBS: phosphate-buffered saline; PRL: prolactin; Rapa: rapamycin; SNCA/synuclein alpha; SQSTM1/p62: sequestosome 1; STUB1: STIP1 homology and U-box containing protein 1; TC: total cholesterol; TEM: transmission electron microscopy; TFEB: transcription factor EB; UPS: ubiquitin-proteasome system; WOI: window of implantation.