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<p>Ferroptosis is a critical driver of renal tubular cell death in acute kidney injury (AKI). The present study aimed to investigate the protective effects of chrysophanol (CHR) against AKI-associated ferroptosis and delineate the mechanistic pathway involving Sirtuin 3 (SIRT3)-mediated deacetylation of NRF2. AKI was induced by lipopolysaccharide (LPS) in wild-type (WT) and SIRT3 knockout (SIRT3<sup>−/−</sup>) mice. To evaluate its prophylactic potential, WT mice were pretreated with CHR (20 and 40&#xa0;mg/kg, i.g.) for three consecutive days prior to a single LPS injection (15&#xa0;mg/kg, i.p.), while dexamethasone (2.5&#xa0;mg/kg, i.p.) served as a positive control. Renal function, histopathology, and mitochondrial ultrastructure were evaluated. To assess the inflammatory response, levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured. Additionally, ferroptosis markers, including glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and Fe<sup>2+</sup>, were determined using biochemical assay kits. NRF2 acetylation and nuclear translocation were further analyzed via Western blot. Pretreatment with CHR substantially attenuated renal dysfunction in AKI mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels. It also mitigated histopathological injury in kidney tissues. This protective effect was characterized by a significant reduction in TNF-α, IL-6, and IL-1β levels and the suppression of ferroptosis via restoring GSH while reducing MDA and Fe<sup>2+</sup> deposition. Mechanistically, CHR enhanced SIRT3 expression, culminating in NRF2 deacetylation and its consequent translocation into the nucleus, ultimately promoting the activation of GPX4. Molecular docking experiments suggested a potential interaction between CHR and the active site pocket of SIRT3. Notably, the protective effects of CHR against both AKI and ferroptosis were largely abrogated in SIRT3<sup>−/−</sup> mice. CHR protects against LPS-induced AKI by inhibiting ferroptosis. This prophylactic process is linked to SIRT3-mediated deacetylation of NRF2, highlighting the potential of CHR as a preventive strategy for sepsis-induced renal injury.</p> Graphical Abstract <p></p>

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Chrysophanol ameliorates ferroptosis in acute kidney injury by promoting SIRT3-mediated NRF2 deacetylation

  • 期刊论文

  • 发表日期：

    2026年5月5日

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  • Mengdi Cui,
  • Hao Tian,
  • Jinyue Zhu,
  • Jing Zhu,
  • Qiyuan Wang,
  • Yinshui Zou

摘要

Ferroptosis is a critical driver of renal tubular cell death in acute kidney injury (AKI). The present study aimed to investigate the protective effects of chrysophanol (CHR) against AKI-associated ferroptosis and delineate the mechanistic pathway involving Sirtuin 3 (SIRT3)-mediated deacetylation of NRF2. AKI was induced by lipopolysaccharide (LPS) in wild-type (WT) and SIRT3 knockout (SIRT3−/−) mice. To evaluate its prophylactic potential, WT mice were pretreated with CHR (20 and 40 mg/kg, i.g.) for three consecutive days prior to a single LPS injection (15 mg/kg, i.p.), while dexamethasone (2.5 mg/kg, i.p.) served as a positive control. Renal function, histopathology, and mitochondrial ultrastructure were evaluated. To assess the inflammatory response, levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured. Additionally, ferroptosis markers, including glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and Fe2+, were determined using biochemical assay kits. NRF2 acetylation and nuclear translocation were further analyzed via Western blot. Pretreatment with CHR substantially attenuated renal dysfunction in AKI mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels. It also mitigated histopathological injury in kidney tissues. This protective effect was characterized by a significant reduction in TNF-α, IL-6, and IL-1β levels and the suppression of ferroptosis via restoring GSH while reducing MDA and Fe2+ deposition. Mechanistically, CHR enhanced SIRT3 expression, culminating in NRF2 deacetylation and its consequent translocation into the nucleus, ultimately promoting the activation of GPX4. Molecular docking experiments suggested a potential interaction between CHR and the active site pocket of SIRT3. Notably, the protective effects of CHR against both AKI and ferroptosis were largely abrogated in SIRT3−/− mice. CHR protects against LPS-induced AKI by inhibiting ferroptosis. This prophylactic process is linked to SIRT3-mediated deacetylation of NRF2, highlighting the potential of CHR as a preventive strategy for sepsis-induced renal injury.

Graphical Abstract