Molecular mechanism of Yishen Qingzhuo oral liquid in treating chronic renal failurethe Nrf2/HO-1-mediated ferroptosis pathway.

Abstract

This study investigated the therapeutic effect and underlying mechanism of Yishen Qingzhuo oral liquid (YSQZ) in a rat model of chronic renal failure (CRF). The CRF model was established by 5/6 nephrectomy. Rats were randomly divided into the sham, CRF, and CRF + low/high-dose YSQZ groups (CRF+YSQZ-L/H). Based on the therapeutic effect, the optimal drug dosage was selected. Subsequently, a ferroptosis inducer (erastin) and Nrf2 inhibitor (ML385) were administered, and rats were further divided into the CRF, CRF+YSQZ, CRF+YSQZ+erastin, and CRF+YSQZ+ML385 groups. The CRF group exhibited impaired renal function, along with elevated urinary protein and ferrous ion levels, relative to those in the sham group. Oxidative stress markers were also dysregulated. Histopathological damage was severe in the CRF group, including increased iron deposition, reduced mitochondrial counts, decreased or even complete loss of mitochondrial cristae, and extensive rupture of the mitochondrial outer membrane, indicators of ferroptosis. The expression of Nrf2/HO-1 pathway-related proteins was decreased, whereas fibrosis-related proteins were upregulated. Whereas the CRF group exhibited marked renal impairment, the CRF+YSQZ-L and CRF+YSQZ-H groups displayed significant improvement in renal function. These treatment groups also exhibited reductions in renal pathological damage, iron deposition, and ferroptosis. The expression of proteins related to the Nrf2/HO-1 ferroptosis pathway was increased, whereas fibrosis-associated proteins were downregulated, with more pronounced effects observed in the high-dose group. However, these protective effects of YSQZ were reversed by co-treatment with erastin or ML385. YSQZ exerts therapeutic effects in rats with CRF, likely by inhibiting ferroptosis through activation of the Nrf2/HO-1 signaling pathway.