• circSLC8A1, a kidney-enriched circular RNA, is significantly downregulated in patients with chronic kidney disease (CKD) and correlates with disease severity, renal fibrosis, and poor clinical prognosis. • Loss of circSLC8A1 in tubular epithelial cells (TECs) induces a partial epithelial-mesenchymal transition (pEMT) phenotype, while its overexpression attenuates renal fibrosis in both UUO and UIRI mouse models. • circSLC8A1 directly binds to Annexin A2 (ANXA2) and promotes its ubiquitin–proteasome-dependent degradation, thereby limiting ANXA2 protein stability. • ANXA2 stabilization following circSLC8A1 deficiency accelerates TEC dedifferentiation and fibrogenesis, establishing ANXA2 as a downstream effector of circSLC8A1. • The circSLC8A1-ANXA2 axis represents a novel regulatory mechanism in renal fibrosis and offers promising therapeutic and diagnostic targets for CKD. 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. This study investigated the role of the kidney-enriched circRNA, circSLC8A1, in regulating TEC plasticity and fibrosis. 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. 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. 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.
Wei et al. (Wed,) studied this question.