Nephroprotective Effects of Formononetin in Diabetic Kidney Disease: Mechanistic Insights and Therapeutic Potential

Formononetin exhibits potent anti-oxidative and anti-inflammatory properties, but its precise therapeutic targets and mechanisms in diabetic kidney disease (DKD) remain insufficiently defined. This study evaluated the nephroprotective potential of formononetin using both <i>in vitro</i> (HK-2 cells) and <i>in vivo</i> (db/db mice) DKD models. By integrating network pharmacology and RNA sequencing, the antifibrotic actions of formononetin were further elucidated. Mechanistic investigations revealed that the compound reduced renal fibrosis by suppressing TGF-[Formula: see text]1, FN, and [Formula: see text]-SMA expression, and also alleviated renal dysfunction markers, including UACR, Scr, BUN, 24hUTP, KIM-1, and NGAL. These effects were mediated through the modulation of two key pathways such that the inhibition of the PI3K/AKT/mTOR cascade reduced inflammatory and fibrotic signaling, while the activation of the p38/MAPK axis enhanced autophagic flux, and thus promoted tubular epithelial cell homeostasis. Collectively, these findings support formononetin as a promising candidate for DKD therapy due to its combined anti-inflammatory and pro-autophagic mechanisms.