Molecular mechanisms of ferroptosis in renal ischemia-reperfusion injury and novel therapeutic perspectives

doi:10.3877/cma.j.issn.2095-3216.2026.02.006

Abstract

Abstract:

Renal ischemia-reperfusion injury is often irreversible, and effective clinical treatments remain scarce. Recent studies have demonstrated that ferroptosis is a critical mechanism mediating renal tubular epithelial cell death in renal ischemia-reperfusion injury, making it a prominent research hotspot. This review summarizes the molecular mechanisms of ferroptosis and the progress in identifying novel targets in renal ischemia-reperfusion injury, and also discusses the current status and future prospects of developing drugs that target ferroptosis.

Key words: Ferroptosis, Ischemia-reperfusion injury, Acute kidney injury

Xu Li, Yufeng Qiao. Molecular mechanisms of ferroptosis in renal ischemia-reperfusion injury and novel therapeutic perspectives[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2026, 15(02): 100-107.

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References 67

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调控水平	主要靶点	主要机制	参考文献
转录水平	PPARγ	过表达可抑制肾小管上皮细胞炎症与铁死亡	[42]
	长链非编码RNA血红素加氧酶1	长链非编码RNA血红素加氧酶1与miR-3587结合并促进血红素加氧酶1的表达，抑制铁死亡	[43]
	趋化素	激活AMP活化蛋白激酶，诱导Nrf2核转位，上调SLC7A11的表达，促进谷胱甘肽生物合成	[44]
蛋白水平	FBXW7	泛素化降解GPX4，促进铁死亡	[45]
	MARCH6	促进ACSL4和p53的降解来减轻脂质过氧化，抑制铁死亡	[46]
	ZNRF2	靶向GPX4和SLC7A11，调节ACSL4和LPCAT3，促进铁死亡	[47]
	RTN3	破坏GPX4与热休克同源蛋白70的相互作用，促进GPX4自噬，促进铁死亡	[48]
代谢水平	S1P	抑制可恢复肾小管上皮细胞中沉默信息调节因子3表达和超氧化物歧化酶2活性，并降低线粒体活性氧水平	[49]
	RIG-I	激活c-Myc，调节铁蛋白重链转录，抑制GPX4表达，促进铁死亡	[50]
	CYP7B1	抑制CYP7B1表达，引起27-羟基胆固醇积累，激活雌激素受体α，上调血红素加氧酶1表达，促进脂质过氧化和铁死亡	[51]

调控水平	主要靶点	主要机制	参考文献
转录水平	PPARγ	过表达可抑制肾小管上皮细胞炎症与铁死亡	[42]
	长链非编码RNA血红素加氧酶1	长链非编码RNA血红素加氧酶1与miR-3587结合并促进血红素加氧酶1的表达，抑制铁死亡	[43]
	趋化素	激活AMP活化蛋白激酶，诱导Nrf2核转位，上调SLC7A11的表达，促进谷胱甘肽生物合成	[44]
蛋白水平	FBXW7	泛素化降解GPX4，促进铁死亡	[45]
	MARCH6	促进ACSL4和p53的降解来减轻脂质过氧化，抑制铁死亡	[46]
	ZNRF2	靶向GPX4和SLC7A11，调节ACSL4和LPCAT3，促进铁死亡	[47]
	RTN3	破坏GPX4与热休克同源蛋白70的相互作用，促进GPX4自噬，促进铁死亡	[48]
代谢水平	S1P	抑制可恢复肾小管上皮细胞中沉默信息调节因子3表达和超氧化物歧化酶2活性，并降低线粒体活性氧水平	[49]
	RIG-I	激活c-Myc，调节铁蛋白重链转录，抑制GPX4表达，促进铁死亡	[50]
	CYP7B1	抑制CYP7B1表达，引起27-羟基胆固醇积累，激活雌激素受体α，上调血红素加氧酶1表达，促进脂质过氧化和铁死亡	[51]

铁死亡抑制剂功能	核心作用靶点	代表药物	主要机制	治疗与应用潜力
恢复GPX4功能	GPX4表达活性	铁死亡抑制素-1	自由基捕获抗氧化剂，清除活性氧，上调GPX4表达	经典铁死亡抑制剂，广泛用于基础研究
	GPX4降解	托法替布为代表的乙酰辅酶A羧化酶抑制剂	阻断GPX4的降解，增强抗氧化能力
	Nrf2通路	黄芩	阻断谷胱甘肽消耗和GPX4降解，激活Nrf2通路上调GPX4表达	多酚类天然化合物
抑制脂质过氧化	ALOXs	黄芩素	ALOXs抑制剂，抑制ALOX介导的过氧化物形成
	ACSL4	曲格列酮(ACSL4抑制剂)	抑制5-脂氧合酶，减少脂质过氧化来发挥作用
	磷脂	外源性单不饱和脂肪酸或氘代多不饱和脂肪酸	从磷脂中取代易氧化的多不饱和脂肪酸，减少脂质过氧化积累
控制铁利用	游离铁	去铁胺、环吡酮	铁螯合剂，螯合游离铁，阻断芬顿反应，抑制OH形成	去铁胺在临床被应用于铁过载疾病

铁死亡抑制剂功能	核心作用靶点	代表药物	主要机制	治疗与应用潜力
恢复GPX4功能	GPX4表达活性	铁死亡抑制素-1	自由基捕获抗氧化剂，清除活性氧，上调GPX4表达	经典铁死亡抑制剂，广泛用于基础研究
	GPX4降解	托法替布为代表的乙酰辅酶A羧化酶抑制剂	阻断GPX4的降解，增强抗氧化能力
	Nrf2通路	黄芩	阻断谷胱甘肽消耗和GPX4降解，激活Nrf2通路上调GPX4表达	多酚类天然化合物
抑制脂质过氧化	ALOXs	黄芩素	ALOXs抑制剂，抑制ALOX介导的过氧化物形成
	ACSL4	曲格列酮(ACSL4抑制剂)	抑制5-脂氧合酶，减少脂质过氧化来发挥作用
	磷脂	外源性单不饱和脂肪酸或氘代多不饱和脂肪酸	从磷脂中取代易氧化的多不饱和脂肪酸，减少脂质过氧化积累
控制铁利用	游离铁	去铁胺、环吡酮	铁螯合剂，螯合游离铁，阻断芬顿反应，抑制OH形成	去铁胺在临床被应用于铁过载疾病

铁死亡相关药物	核心作用靶点	代表药物	主要机制	治疗与应用潜力	参考文献天然化合物
	SLC7A11	芍药苷	上调SLC7A11和GPX4；抑制TNF-α、IL-1β和IL-6等炎症因子	天然化合物来源广，作用温和，具有抗炎、抗氧化特性	[55]
	铁自噬	水飞蓟宾	破坏核受体共激活因子4/铁蛋白重链1相互作用，抑制铁自噬，减少铁释放		[56]
	Nrf2/血红素加氧酶-1	龙血素C、黄酮	促进Nrf2核易位，上调GPX4，抑制Fe^2＋积累，激活Nrf2/血红素加氧酶-1通路，改善线粒体功能		[57，58]
	铁死亡标志物	虫草素	减轻氧化应激损伤，减少铁积累，上调铁死亡标志物		[59]
已知药物再研究	巨噬细胞极化	利拉鲁肽	促进巨噬细胞向M2表型极化，缓解症损伤和铁死亡	GLP-1受体激动剂，临床上用于减重和糖尿病	[60]
	GPX4	塞曲司特	自由基捕获抗氧化剂，抑制脂质过氧化	血栓烷A2受体抑制剂，临床上运用于哮喘	[61]
	ACSL4	右美托咪定	通过抑制ACSL4表达，减轻脂质过氧化和铁死亡	选择性α2-肾上腺素能受体激动剂，临床上运用于镇静	[62]

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