Biphasic dysregulation of non-muscle myosin IIA drives the AKI-to-CKD transition via an ALDH1A1–retinoic acid–HBEGF/EGFR signaling axis in tubular cells

The decision between successful repair and pathological fibrosis following kidney injury remains a pivotal yet poorly understood process. Here, we identify non-muscle myosin IIA (NM IIA) as a master regulator of renal tubular fate whose biphasic dysregulation dictates the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Using integrated single-cell transcriptomics and multi-model validation, we define this dysregulation as stage-dependent alterations in NM IIA expression and subcellular localization: it is downregulated in AKI, impairing regenerative repair, but pathologically overexpressed and aberrantly localized to the nucleus in CKD, where it drives maladaptive fibrosis. Mechanistically, upon nuclear translocation in tubular epithelial cells, NM IIA directly transactivates Aldh1a1 , thereby enhancing local retinoic acid (RA) biosynthesis. This RA signal subsequently propagates through HBEGF/EGFR signaling to influence repair outcomes. Collectively, our work delineates an NM IIA/ALDH1A1–RA–HBEGF/EGFR axis, revealing how NM IIA, beyond its cytoskeletal function, acts as a transcriptional regulator that integrates mechanical and metabolic cues in the kidney. These findings establish a mechanistic framework for the AKI-to-CKD transition and highlight potential stage-specific therapeutic targets.