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IRF1-Regulated CCL25/CCR9 Promotes Chronic Kidney Disease Progression Through PI3K/AKT-Mediated Oxidative Stress and

Shaorong Yan1, Yueping Chen1, Hong Liang Chen1

  • 1Department of Clinical Laboratory, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, China.

Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research
|July 15, 2026
PubMed

Insights

Interferon regulatory factor 1 (IRF1) drives chronic kidney disease (CKD) progression by upregulating chemokine ligand 25 (CCL25) and its receptor CCR9. This pathway exacerbates oxidative stress and inflammation via PI3K/AKT signaling.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Immunology

Background:

  • Chronic kidney disease (CKD) pathogenesis involves complex mechanisms including oxidative stress and inflammation.
  • The phosphatidylinositol 3 kinases/protein kinase B (PI3K/AKT) signaling pathway is implicated in CKD.
  • Chemokine ligand 25 (CCL25) and its receptor CCR9 may regulate the PI3K/AKT pathway in CKD.

Purpose of the Study:

  • To investigate the role of CCL25/CCR9 in CKD progression.
  • To elucidate the involvement of CCL25/CCR9 in modulating oxidative stress and inflammation via the PI3K/AKT pathway.
  • To identify upstream regulatory factors of CCL25/CCR9 in CKD.

Main Methods:

  • Adenine-induced CKD rat model and indoxyl sulfate-induced CKD cell model.
  • Bioinformatics analysis (JASPAR, Cistrome DB) to predict CCL25/CCR9 upstream factors.
  • Intervention with anti-CCL25, PI3K/AKT activator (740Y-P), and IRF1 knockdown (sh-IRF1).
  • Measurement of renal function, pathology, oxidative stress markers, inflammatory cytokines, and protein expression.
  • Chromatin immunoprecipitation PCR (ChIP-PCR) to confirm IRF1 binding to the CCL25 promoter.

Main Results:

  • CCL25 and CCR9 were upregulated in CKD models.
  • CKD rats exhibited enhanced oxidative stress, inflammation, renal fibrosis, and dysfunction.
  • Anti-CCL25 treatment reduced PI3K/AKT markers, oxidative stress, and inflammation; 740Y-P reversed these effects.
  • IRF1 was identified as a transcription factor for CCL25, increased in CKD models, and bound to the CCL25 promoter.
  • IRF1 knockdown decreased CCL25 and CCR9 expression.

Conclusions:

  • IRF1-regulated CCL25/CCR9 signaling promotes CKD progression.
  • The mechanism involves PI3K/AKT-mediated oxidative stress and inflammatory responses.
  • Targeting the IRF1-CCL25/CCR9 axis may offer therapeutic strategies for CKD.
Keywords:
CCL25/CCR9PI3K/AKT signaling pathwaychronic kidney diseaseinflammatory responseinterferon regulatory factor 1oxidative stress

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