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Background <p>Acute kidney injury (AKI) induced by cisplatin (DDP) is a critical complication that elevates patient mortality and worsens clinical outcomes. Recent evidence highlights ferroptosis as a key contributor to AKI pathogenesis. Icariin (ICA), a natural flavonoid glycoside with antioxidant, anti-apoptotic, and anti-ferroptotic properties, holds therapeutic potential. This study aimed to explore ICA’s protective effects against DDP-induced AKI in mice and human renal tubular epithelial (HK-2) cells, focusing on its anti-ferroptotic mechanisms.</p> Methods <p>A DDP-induced AKI mouse model was established using a single intraperitoneal injection of 30&#xa0;mg/kg DDP. In vitro, HK-2 cells were treated with DDP to mimic renal injury. ICA’s effects were evaluated through histopathological analysis, measurement of kidney injury markers (e.g., Scr, BUN), and assessment of oxidative stress (ROS, MDA), apoptosis (Bax, cleaved caspase-3), and ferroptosis-related markers (Fe²⁺, <i>ACSL4</i>, <i>GPX4</i>, <i>FTH1</i>). Mitochondrial morphology was examined via electron microscopy. Protein expression and phosphorylation of JNK signaling components were analyzed using Western blot.</p> Results <p>In mice, ICA alleviated DDP-induced tubular dilation, mucus accumulation, and epithelial shedding, and reduced levels of kidney injury markers. It suppressed apoptosis, as indicated by decreased <i>Bax</i> and cleaved caspase-3, reduced oxidative stress, reflected by lower ROS and MDA levels, and inhibited ferroptosis through a reduction in Fe²⁺. In HK-2 cells, ICA counteracted DDP-induced cytotoxicity, restored mitochondrial integrity, and mitigated ferroptosis, evidenced by decreased <i>ACSL4</i> and increased <i>GPX4</i> and <i>FTH1</i>. Mechanistically, ICA inhibited JNK phosphorylation in both models. Animal studies further confirmed that the renoprotective effects of ICA were mediated through modulation of the JNK pathway.</p> Conclusion <p>ICA alleviates DDP-induced AKI by inhibiting apoptosis, oxidative stress, and ferroptosis, partially through suppression of JNK signaling. These findings underscore ICA’s potential as a therapeutic agent for DDP-associated kidney injury, with ferroptosis and JNK pathways as critical targets.</p>

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Icariin protects against cisplatin-induced renal injury and ferroptosis via JNK pathway in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月30日

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  • Weixing Wang,
  • Zhonggao Wu,
  • Guole Qi,
  • Guohai Xie

摘要

Background

Acute kidney injury (AKI) induced by cisplatin (DDP) is a critical complication that elevates patient mortality and worsens clinical outcomes. Recent evidence highlights ferroptosis as a key contributor to AKI pathogenesis. Icariin (ICA), a natural flavonoid glycoside with antioxidant, anti-apoptotic, and anti-ferroptotic properties, holds therapeutic potential. This study aimed to explore ICA’s protective effects against DDP-induced AKI in mice and human renal tubular epithelial (HK-2) cells, focusing on its anti-ferroptotic mechanisms.

Methods

A DDP-induced AKI mouse model was established using a single intraperitoneal injection of 30 mg/kg DDP. In vitro, HK-2 cells were treated with DDP to mimic renal injury. ICA’s effects were evaluated through histopathological analysis, measurement of kidney injury markers (e.g., Scr, BUN), and assessment of oxidative stress (ROS, MDA), apoptosis (Bax, cleaved caspase-3), and ferroptosis-related markers (Fe²⁺, ACSL4, GPX4, FTH1). Mitochondrial morphology was examined via electron microscopy. Protein expression and phosphorylation of JNK signaling components were analyzed using Western blot.

Results

In mice, ICA alleviated DDP-induced tubular dilation, mucus accumulation, and epithelial shedding, and reduced levels of kidney injury markers. It suppressed apoptosis, as indicated by decreased Bax and cleaved caspase-3, reduced oxidative stress, reflected by lower ROS and MDA levels, and inhibited ferroptosis through a reduction in Fe²⁺. In HK-2 cells, ICA counteracted DDP-induced cytotoxicity, restored mitochondrial integrity, and mitigated ferroptosis, evidenced by decreased ACSL4 and increased GPX4 and FTH1. Mechanistically, ICA inhibited JNK phosphorylation in both models. Animal studies further confirmed that the renoprotective effects of ICA were mediated through modulation of the JNK pathway.

Conclusion

ICA alleviates DDP-induced AKI by inhibiting apoptosis, oxidative stress, and ferroptosis, partially through suppression of JNK signaling. These findings underscore ICA’s potential as a therapeutic agent for DDP-associated kidney injury, with ferroptosis and JNK pathways as critical targets.