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<p>Ferroptosis is increasingly recognized as a key driver of sepsis-induced cardiac dysfunction. Hydroxysafflor yellow A (HSYA), a bioactive flavonoid, shows cardioprotective properties, but its role in ferroptosis remains unclear. Network pharmacology and molecular docking predicted targets of HSYA related to ferroptosis and sepsis-induced cardiac dysfunction. Functional effects were validated in LPS-stimulated H9C2 cells and in cecal ligation and puncture (CLP) septic mice. Cardiac function, biochemical markers, oxidative stress indices, and protein expression of GPX4, xCT, ACSL4, COX-2 and TXN were evaluated. HSYA improved cardiac function and reduced injury in septic mice. It suppressed ferroptosis by lowering Fe²⁺, MDA, ROS, ACSL4 and COX-2, restoring GSH, and upregulating GPX4 and xCT. TXN was screened as a central mediator, and its inhibition abrogated HSYA’s benefits. HSYA protects against septic cardiac dysfunction by inhibiting ferroptosis via TXN activation, highlighting TXN as a novel therapeutic target.</p> Graphical Abstract <p></p>

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Hydroxysafflor Yellow A Attenuates Sepsis-Induced Cardiac Dysfunction by Inhibiting Ferroptosis via Activation of Thioredoxin

  • 期刊论文

  • 发表日期：

    2026年4月13日

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  • Yanke Chen,
  • Xu Cai,
  • Wenbin Nan,
  • Zhenyu Peng

摘要

Ferroptosis is increasingly recognized as a key driver of sepsis-induced cardiac dysfunction. Hydroxysafflor yellow A (HSYA), a bioactive flavonoid, shows cardioprotective properties, but its role in ferroptosis remains unclear. Network pharmacology and molecular docking predicted targets of HSYA related to ferroptosis and sepsis-induced cardiac dysfunction. Functional effects were validated in LPS-stimulated H9C2 cells and in cecal ligation and puncture (CLP) septic mice. Cardiac function, biochemical markers, oxidative stress indices, and protein expression of GPX4, xCT, ACSL4, COX-2 and TXN were evaluated. HSYA improved cardiac function and reduced injury in septic mice. It suppressed ferroptosis by lowering Fe²⁺, MDA, ROS, ACSL4 and COX-2, restoring GSH, and upregulating GPX4 and xCT. TXN was screened as a central mediator, and its inhibition abrogated HSYA’s benefits. HSYA protects against septic cardiac dysfunction by inhibiting ferroptosis via TXN activation, highlighting TXN as a novel therapeutic target.

Graphical Abstract