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

Pengfei Qiao1, Yixuan Zhu1, Junming Zhang1

  • 1Department of Renal Replacement Therapy, Northwest University First Hospital, China; School of Medicine, Northwest University, Xi'an, Shaanxi 710069, China.

Mechanisms of Ageing and Development
|May 12, 2026
PubMed

Insights

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) drives kidney fibrosis by promoting cell senescence and metabolic dysfunction. The inhibitor Harmine reverses these effects, offering a potential therapeutic strategy for renal interstitial fibrosis.

Area of Science:

  • Nephrology
  • Cellular Biology
  • Biochemistry

Background:

  • Cellular senescence in proximal renal tubule epithelial cells (TECs) and its senescence-associated secretory phenotype (SASP) contribute to renal fibrosis.
  • The precise molecular mechanisms linking TEC senescence to renal interstitial fibrosis (RIF) are not fully understood.
  • Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is known to accelerate cellular senescence.

Purpose of the Study:

  • To investigate the role of DYRK1A in promoting RIF through TEC senescence.
  • To determine if the DYRK1A inhibitor Harmine can mitigate RIF by targeting DYRK1A and alleviating TEC senescence.
  • To elucidate the molecular pathways, including metabolic dysfunction and inflammation, involved in DYRK1A-induced RIF.

Main Methods:

  • Established a hypoxic HK-2 (human proximal TEC line) senescence model and a mouse unilateral ureteral obstruction (UUO) model.
  • Utilized DYRK1A overexpression plasmids, DYRK1A siRNA, and Harmine for interventions.
  • Assessed fatty acid β-oxidation (FAO), lipid droplet accumulation, DNA damage (γH2AX), SASP, NF-κB activation, fibrotic markers, and ATP production.

Main Results:

  • Hypoxia impaired FAO, induced lipid accumulation, senescence, and SASP in HK-2 cells.
  • In UUO mice, DYRK1A overexpression disrupted mitochondrial FAO via FOXO1 phosphorylation, leading to DNA damage, SASP, NF-κB activation, and fibrosis.
  • Harmine treatment reversed these detrimental effects, reducing collagen deposition and restoring ATP production.
  • DYRK1A and FOXO1 expression strongly correlated with fibrosis severity, lipid accumulation, and senescent cell burden in chronic kidney disease (CKD) patients.

Conclusions:

  • DYRK1A promotes RIF by inducing TEC senescence through FOXO1/NF-κB-mediated metabolic dysfunction.
  • Harmine exhibits anti-senescence and anti-fibrotic effects by inhibiting DYRK1A.
  • This study uncovers a novel regulatory network in renal fibrosis centered on cellular senescence and metabolic regulation.
Keywords:
Cell senescenceChronic kidney diseasesHarmineLipid metabolism disordersRenal proximal tubular cellsTubulointerstitial fibrosis

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