Small-molecule LIFR inhibitors attenuate renal tubulointerstitial fibrosis.

Renal tubulointerstitial fibrosis (TIF), the final common pathway of chronic kidney disease (CKD), is driven by pathological crosstalk between fibroblasts and tubular epithelial cells (TECs). Leukemia inhibitory factor (LIF) contributes to this cellular interaction by binding to LIF receptor (LIFR) and activating downstream ERK and STAT3 pathways. While novel LIFR small-molecule inhibitors EC330 and EC359 have shown therapeutic efficacy in cancer, their potential in treating kidney diseases remains unexplored. Here, we showed that LIF and LIFR were expressed at low levels in healthy adult kidneys but markedly upregulated in fibrotic kidneys, particularly in fibroblasts and TECs. Mechanistically, transforming growth factor-β1 (TGF-β1) drove LIF and LIFR expression in both cell types via a SMAD3-dependent pathway. Both EC330 and EC359 dose-dependently suppressed fibroblast activation and TEC pro-fibrotic responses induced by LIF or TGF-β1, with EC330 exhibiting a superior safety profile. In vivo, EC330 attenuated ERK and STAT3 phosphorylation in fibroblasts and TECs, significantly mitigating both developing TIF in the unilateral ischemia-reperfusion injury model and established TIF in the aristolochic acid model. Collectively, our findings demonstrate that LIFR inhibition is a viable anti-fibrotic strategy and identify EC330 as a promising drug candidate for treating CKD.