Pharmacologic disruption of HuR-RNA interactions prevents maladaptive tubular repair and AKI-to-CKD progression.

Acute kidney injury (AKI) predisposes survivors to chronic kidney disease (CKD), yet the postinjury mechanisms that drive maladaptive tubular repair are incompletely defined. The RNA-binding protein HuR (ELAVL1) stabilizes inflammatory and profibrotic transcripts but its role in AKI-to-CKD progression is unclear. We used aristolochic acid nephropathy (AAN) to test whether disrupting HuR-RNA interactions with the small molecule KH3 mitigates AKI-to-CKD transition. Single AA exposure produced dose-dependent AKI within 72 h, whereas repeated AA induced a sustained CKD phenotype with tubulointerstitial fibrosis. AA increased HuR expression and cytoplasmic localization in injured tubular epithelial cells and circulating exosomes. KH3 administration reduced blood urea nitrogen (BUN) and creatinine, attenuated albuminuria, preserved tubular histology, and suppressed profibrotic and proinflammatory signaling in both acute and chronic AA models. Mechanistically, KH3 diminished AA-induced activation of NF-κBp65 and AKT, reduced markers of DNA damage, apoptosis, and senescence (such as γ-H2AX, cleaved PARP1/caspase-3, p21, and p16-INK4a), and normalized ferroptosis-associated proteins in AA-treated human proximal tubular cells. These results identify HuR as a central posttranscriptional regulator of maladaptive tubular repair and provide proof-of-concept that pharmacologic targeting of HuR-RNA interactions can prevent progression from AKI to CKD.