Formononetin inhibits p53 signaling pathway activation to delay cellular senescence and ameliorates diabetic kidney disease.

Diabetic kidney disease (DKD) continues to pose a substantial public health challenge, in which cellular senescence is recognized as a pivotal driver of disease progression. While formononetin (FN) has been documented to exhibit anti-senescence properties, its potential as a therapeutic agent for DKD and the molecular mechanisms involved remain unexplored. To evaluate the efficacy of FN using an in vitro model of high glucose (HG)-induced injury in MPC-5 podocytes. Transcriptomic profiling was employed to assess the influence of FN on global gene expression and to identify key signaling pathways affected by FN treatment. Furthermore, we sought to investigate the anti-senescence effects of FN and its regulatory role in the p53 signaling pathway in vitro. To elucidate the functional role of MDM2 in the anti-senescence mechanism of FN, MDM2 expression was silenced in MPC-5 cells using gene-specific knockdown. Finally, a mouse model of DKD was generated by combining a high-fat diet with intraperitoneal streptozotocin injections, and the therapeutic as well as anti-senescence effects of FN were evaluated in vivo. In the HG-induced MPC-5 cell model, FN treatment significantly enhanced cell viability and reduced the secretion of senescence-associated secretory phenotype (SASP) factors in the supernatant. Transcriptomic analysis revealed the p53 signaling pathway as a central target of FN under HG conditions. FN treatment markedly suppressed β-galactosidase (β-GAL) activity, upregulated the expression of MDM2 and CCND1, downregulated the expression of p53 and p21, and inhibited p53 transcriptional activity in MPC-5 cells. These protective effects were abrogated upon MDM2 silencing. In DKD mice, FN administration improved renal function, alleviated histopathological damage, reduced renal SASP levels and β-GAL activity, and normalized the expression of key proteins in the p53 pathway. Our findings demonstrate that FN confers significant therapeutic benefits against DKD in both cellular and animal models. The mechanism underlying these benefits involves the delay of cellular senescence through suppression of the p53 signaling pathway.