Ligustroflavone alleviates chronic kidney disease by inhibiting ferroptosis through the GSK3β/NRF2 signaling pathway.

Abstract

Objectives: Chronic kidney disease (CKD) is a global public health concern, characterized by a gradual decline in kidney function, with death of renal tubular epithelial cells (RTECs) as a key pathological mechanism. This study investigated the protective effect of ligustroflavone in CKD and its potential molecular mechanisms.

Methods: In vivo, the unilateral ureteral obstruction (UUO) and folic acid-induced nephropathy (FAN) mouse models were employed to assess the effects of ligustroflavone. In vitro, RTECs were treated with erastin. Western blotting, qRT-PCR, immunofluorescence (IF), and immunohistochemistry (IHC) were performed to detect renal tubular injury both in vivo and in vitro.

Results: In vivo, ligustroflavone treatment significantly improved renal tubular damage and interstitial fibrosis in mice. Furthermore, our results demonstrated that ligustroflavone alleviated ferroptosis of RTECs by inhibiting GSK3β activity and reducing lipid peroxidation in mice. In vitro, ligustroflavone treatment inhibited erastin-induced ferroptosis in RTECs. In addition, ligustroflavone inhibited activation of myofibroblasts induced by ferroptosis of RTECs. Mechanistically, ligustroflavone exerted it's protect effects through the GSK3β/NRF2 pathway by inhibiting GSK3β and activating NRF2, thereby promoting GPX4 expression and suppressing ferroptosis.

Conclusions: In summary, ligustroflavone inhibits ferroptosis in RTECs and confers protection in CKD. These findings suggest that ligustroflavone holds promise as a potential therapeutic agent for CKD.