Antifibrotic Effects of Yi‐Qi‐Jian‐Pi‐Xiao‐Yu Formula in Kidney via HIF1A‐Driven M1 Macrophage Polarization

ABSTRACT Background A traditional Chinese medicine Yi‐Qi‐Jian‐Pi‐Xiao‐Yu (YQJPXY) formula can potentially ameliorate chronic kidney disease (CKD), but its effect on renal fibrosis (RF), a prevalent pathological feature of CKD, remains unclear. Methods To mimic renal injury and fibrosis, a mouse unilateral ureteral obstruction (UUO) model was employed. Using hematoxylin–eosin and Masson's trichrome stains, enzyme‐linked immunosorbent assay, and immunofluorescence, the effects of YQJPXY on renal injury in UUO mice were evaluated. A series of bioinformatics analyses were then conducted to explore the key genes and immune cells involved in the therapeutic mechanism of YQJPXY. Finally, in vivo and in vitro studies provided multifaceted evaluations of YQJPXY against RF from the perspectives of macrophage dynamics and roles of HIF1A. Results YQJPXY treatment significantly reduced levels of TGF‐β1 and IL‐6, attenuated tubular damage, decreased extracellular matrix protein (FN and Col‐I) expressions, and modulated fibrosis and epithelial‐mesenchymal transition markers in UUO mice in a dose‐dependent manner. Bioinformatics analysis identified HIF1A as the key target of YQJPXY against RF. In vivo, HIF1A deficiency lessened RF and recruitment of CD45 + CD11b + and CD45 + F4/80 + macrophages in fibrotic kidneys. During treatment, YQJPXY inhibited HIF1A expression and reduced M1 macrophage polarization. In vitro experiments confirmed that YQJPXY suppresses hypoxia‐induced M1 macrophage polarization and HK‐2 cell transdifferentiation via downregulating HIF1A. Conclusion YQJPXY alleviates RF by attenuating HIF1A‐mediated M1 macrophage polarization, providing a potential therapeutic approach for CKD.