The deficiency of circSLC8A1 fosters tubular partial EMT-induced renal fibrosis through upregulating Annexin A2 signaling

BACKGROUND: Chronic kidney disease (CKD) progression to renal fibrosis is primarily driven by maladaptive partial epithelial-mesenchymal transition (pEMT) in tubular epithelial cells (TECs), a process lacking effective therapies. Circular RNAs (circRNAs) are stable, tissue-specific regulators, but their involvement in renal pEMT and fibrosis remains unclear. OBJECTIVES: This study investigated the role of the kidney-enriched circRNA, circSLC8A1, in regulating TEC plasticity and fibrosis. METHODS: We conducted an integrative analysis of circSLC8A1 expression across human CKD cohorts and preclinical murine models of kidney fibrosis. To establish functional causality, we employed overexpressing circSLC8A1 in vivo or depleting in cultured TECs. Molecular mechanisms were further elucidated through RNA-protein interaction assays and downstream signaling analyses. RESULTS: circSLC8A1 deficiency functioned as a causal driver of fibrosis, rather than a bystander event. Overexpression of circSlc8a1 markedly attenuated interstitial fibrosis in vivo, whereas its loss exacerbated pEMT in TECs. Mechanistically, circSLC8A1 directly binds to Annexin A2 (ANXA2)-a critical regulator of EMT-and promotes its degradation via the ubiquitin-proteasome pathway. Downregulation of circSLC8A1 increases ANXA2 protein stability, thereby accelerating TEC pEMT. CONCLUSION: circSLC8A1 is a critical regulator of TEC pEMT and renal fibrosis. Its downregulation drives fibrosis by stabilizing ANXA2 protein. The circSLC8A1-ANXA2 interaction represents a novel mechanism disrupting pEMT programs, preserving epithelial homeostasis, and offering a promising therapeutic strategy against renal fibrosis.