Hydroxysafflor Yellow A Mitigates Sepsis-Induced Pulmonary and Intestinal Injury by Inhibiting TP53 Mediated Ferroptosis.

Introduction: Sepsis is a common and life-threatening condition in clinical practice, leading to mortality among intensive care unit (ICU) patients. Due to its unclear pathogenesis, underscoring the urgent need for effective therapeutic strategies. Ferroptosis plays a pivotal role in sepsis progression, and ferroptosis-related genes represent promising intervention targets. Methods: This study performed bioinformatics to identify ferroptosis-related hub genes in sepsis. We used septic mice and lipopolysaccharide (LPS)-treated IECs to detected the role of TP53-mediated ferroptosis in sepsis. Furthermore, in vitro and in vivo experiments were conducted to validate the effect of hydroxysafflor yellow A (HSYA) on TP53-mediated ferroptosis and sepsis. Results: TP53 has been identified as a ferroptosis-related hub gene in sepsis. Inhibition of TP53 with the specific TP53 inhibitor Pifithrin-α markedly reduced ferroptosis both in vitro and in vivo. Meanwhile, inhibition of TP53 significantly reduced inflammation and improved sepsis-induced intestinal barrier dysfunction. Furthermore, this study found that HSAY, a core component of XueBiJing, could stably bind to TP53, reduced the expression of TP53 and TP53-mediated ferroptosis in sepsis and improved animal survival. Conclusion: This study clarified the role of TP53-mediated ferroptosis in sepsis-induced intestinal barrier dysfunction and discovered that HSYA could improve sepsis as an inhibitor of TP53, offering new strategies for the treatment of sepsis.