Ligustroflavone protects against acute kidney injury by inhibiting ferroptosis via acting on GSK3β/NRF2 signaling.

Abstract

Ferroptosis exerts a recognized role in the pathogenesis of acute kidney injury (AKI) and is considered a critical target for improving its prognosis. Emerging evidence indicates that ferroptosis serves a pivotal role in pathogenesis of AKI and targeting ferroptosis provides a promising therapeutic strategy in treatment of AKI. In the present study, ligustroflavone (LIG), which is a flavonoid with oral activity extracted from Ligustrum lucidum, was found to inhibit ferroptosis through activation of nuclear factor erythroid 2‑related factor 2 (NRF2) via inhibition of GSK3β in vivo and in vitro. In vivo, cisplatin (CDDP) and ischemia‑reperfusion injury (IRI)‑induced murine models of AKI were constructed to evaluate the possible effects of LIG. In vitro, the protective effects of LIG were assessed in cultured mouse renal proximal tubular epithelial cells (TKPTs). Immunostaining, reverse transcription‑quantitative PCR, western blot and lipid peroxidation assays were performed to detect renal tubular injury and ferroptosis. The results of the present study demonstrated that LIG administration significantly ameliorated CDDP or IRI induced renal damage in mice. Additionally, administration of LIG significantly ameliorated lipid peroxide accumulation and inhibited ferroptosis in the kidneys of AKI mice. In vitro, LIG treatment markedly ameliorated CDDP‑induced lipid peroxidation and ferroptosis in cultured TKPTs via GSK3β inhibition and NRF2 activation. Furthermore, knockout of GSK3β also protected against CDDP‑induced cell death and LIG exerted no additional protective effects in GSK3β‑knockout TKPTs. Together, the present findings offer a new potential strategy for AKI therapies by targeting ferroptosis.

Key Findings

• Ligustroflavone (LIG) inhibits ferroptosis by activating NRF2 via inhibition of GSK3β in vivo and in vitro.
• LIG administration significantly ameliorated cisplatin and ischemia-reperfusion injury induced acute kidney injury in murine models.
• Knockout of GSK3β protected against cisplatin-induced cell death, and LIG showed no additional protective effects in GSK3β-knockout cells.

Clinical Significance

Citation

Song Jiayu, Wang Long, Wang Yaruet al.. Ligustroflavone protects against acute kidney injury by inhibiting ferroptosis via acting on GSK3β/NRF2 signaling. International journal of molecular medicine. 2026-Jul.