Targeting DYRK1A with harmine abrogates the FOXO1-NF-κB axis to alleviate cellular senescence and renal fibrosis.

Proximal renal tubule epithelial cell (TEC) senescence and its associated senescence-associated secretory phenotype (SASP) drive renal fibrosis, yet the underlying molecular mechanism remains elusive. Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) accelerates cellular senescence, and its specific inhibitor Harmine is hypothesized to mitigate renal interstitial fibrosis (RIF) by targeting DYRK1A to alleviate TEC senescence. To verify this, we established a hypoxic HK-2 (human proximal TEC line) senescence model and a mouse unilateral ureteral obstruction (UUO) model, with interventions including DYRK1A overexpression plasmids, DYRK1A siRNA, and Harmine. Hypoxia impaired fatty acid β-oxidation (FAO) in HK-2 cells, causing lipid droplet accumulation, senescence, and SASP upregulation. In UUO mice, DYRK1A overexpression promoted FOXO1 phosphorylation, disrupting mitochondrial FAO; this induced DNA damage (elevated γH2AX), SASP release, and activation of NF-κB and fibrotic pathways, while Harmine reversed these effects, reducing collagen deposition and restoring ATP production. Clinically, DYRK1A/FOXO1 expression strongly correlated with tubulointerstitial fibrosis severity (DYRK1A: r = 0.703; FOXO1: r = 0.765; *P < 0.0001), lipid accumulation, and senescent cell burden in chronic kidney disease (CKD) patients. Our findings demonstrate that DYRK1A promotes RIF via FOXO1/NF-κB-mediated metabolic dysfunction and subsequent TEC senescence, and Harmine exerts anti-senescence and anti-fibrotic effects by inhibiting DYRK1A, uncovering a novel regulatory network of renal fibrosis from the cellular senescence perspective.