Harmine attenuates renal fibrosis via Twist1 suppression: A novel anti-fibrotic strategy for chronic kidney disease with efficacy/safety profiling.

Abstract

Renal fibrosis, a pathological hallmark of chronic kidney disease (CKD), accounts for over 40 % of end-stage renal disease cases globally, with IgAN nephropathy and diabetic nephropathy representing >60 % of progressive CKD subtypes. Despite its clinical burden, no FDA-approved anti-fibrotic therapies exist to halt disease progression, underscoring a critical unmet need. Emerging evidence highlights Twist1, a basic helix-loop-helix (bHLH) transcription factor, as a pivotal driver of renal fibrosis by orchestrating epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) accumulation in tubular epithelial cells (TECs). In our experiment, Twist1 expression correlates strongly with fibrosis severity and inversely with estimated glomerular filtration rate (eGFR) in IgAN nephropathy and diabetic nephropathy biopsies. Here, we identify Harmine, a β-carboline alkaloid, as a first-in-class Twist1 inhibitor with therapeutic potential for renal fibrosis. In vitro, Harmine dose-dependently suppressed hypoxia-induced EMT in HK-2 cells, reducing vimentin expression and restoring E-cadherin at 5 μmol/L and 10 μmol/L. In murine models, Harmine (2.5, 5, 10 mg/kg/day) attenuated renal fibrosis in unilateral ischemia-reperfusion injury (uIRI) and unilateral ureteral obstruction (UUO) models. Safety profiling revealed an in vitro LD50 > 50 μM in HK-2 cells within 48 h, and no observable adverse effects in mice at therapeutic doses, with serum creatinine remaining stable throughout treatment. This study elucidates a novel mechanism for renal fibrosis inhibition through Twist1 suppression and positions Harmine as a promising candidate for preclinical development. By targeting a central node in fibrogenesis while maintaining systemic safety, Harmine addresses a critical gap in CKD therapy and warrants further investIgANtion in clinical trials.