NSD1-916aa encoded by CircNSD1 contributes to AKI-to-CKD transition through inducing ferroptosis in tubular epithelial cells

Acute kidney injury (AKI) is characterized by a rapid decline in renal function. In severe or recurrent cases, AKI can progress to chronic kidney disease (CKD), marked by renal inflammation and fibrosis. Despite the severity of these outcomes, early-stage diagnostic tools and pharmacological interventions for AKI-to-CKD progression remain limited. In this study, we examined circular RNA (circRNA) expression profiles in mouse renal cortex tissues 14 days post-ischemia/reperfusion (I/R) injury using circRNA sequencing. The renal biopsy samples of patients from AKI patients exhibited reduced CircNSD1 expression, which was inversely associated with inflammation and fibrosis. Overexpression of CircNSD1 attenuated ferroptosis in vivo and in vitro, thereby slowing AKI-to-CKD progression. Mechanistically, CircNSD1 downregulated ACSL4 and SlC39A14 expression through histone H3 lysine 36 (H3K36) methylation, a critical pathway regulating ferroptosis during AKI or hypoxia/reoxygenation (H/R) injury. Furthermore, we identified that CircNSD1 encoded a NSD1-916aa peptide, which may functionally contribute to its observed effect. Collectively, these findings demonstrated that CircNSD1 may serve as a diagnostic and therapeutic target for early detection of AKI-to-CKD transition. Overall design: Renal cortex tissues from male C57BL/6J mice 14 days post-ischemia/reperfusion (I/R) were subjected to high-throughput circRNA sequencing