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Published on: November 10, 2021

Small-molecule LIFR inhibitors attenuate renal tubulointerstitial fibrosis

Jia Xin Zhou1, Tan Tan Long2, Yiqiao Liu1

  • 1State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|July 2, 2026
PubMed

Insights

Leukemia inhibitory factor receptor (LIFR) inhibition effectively treats kidney fibrosis by blocking pro-fibrotic signaling. The drug candidate EC330 shows promise for treating chronic kidney disease (CKD).

Area of Science:

  • Nephrology and Regenerative Medicine
  • Molecular Biology and Pharmacology

Background:

  • Renal tubulointerstitial fibrosis (TIF) drives chronic kidney disease (CKD) progression through fibroblast and tubular epithelial cell (TEC) crosstalk.
  • Leukemia inhibitory factor (LIF) and its receptor (LIFR) mediate this crosstalk via ERK and STAT3 pathways.
  • LIFR inhibitors show cancer efficacy, but their role in kidney disease is unknown.

Purpose of the Study:

  • To investigate the role of LIF/LIFR signaling in renal TIF.
  • To evaluate the therapeutic potential of novel LIFR inhibitors (EC330, EC359) in preclinical kidney fibrosis models.

Main Methods:

  • Assessed LIF and LIFR expression in healthy and fibrotic human kidney tissues.
  • Investigated TGF-β1's role in regulating LIF/LIFR expression via SMAD3.
  • Tested EC330 and EC359 efficacy in suppressing fibroblast activation and TEC pro-fibrotic responses in vitro.
  • Evaluated EC330's in vivo efficacy in unilateral ischemia-reperfusion injury and aristolochic acid-induced TIF models.

Main Results:

  • LIF and LIFR were upregulated in fibrotic kidneys, particularly in fibroblasts and TECs, driven by TGF-β1/SMAD3 signaling.
  • EC330 and EC359 dose-dependently inhibited LIF- or TGF-β1-induced pro-fibrotic responses; EC330 demonstrated better safety.
  • In vivo, EC330 reduced ERK/STAT3 phosphorylation and significantly mitigated both developing and established renal TIF.

Conclusions:

  • LIFR signaling is a key driver of renal tubulointerstitial fibrosis.
  • LIFR inhibition represents a viable anti-fibrotic strategy for CKD.
  • EC330 is identified as a promising therapeutic candidate for treating kidney fibrosis.
Keywords:
EC330EC359LIFR small molecule inhibitorLeukemia inhibitory factorRenal tubulointerstitial fibrosis

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