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

Qing Chen,1,* Chencheng Xu,1,2,* Jinzhong Fei,3,* Zhengbin Wu,1 Yaoli Wang,1 Yingjie Wang,3 Shifeng Shao1 1Department of ICU, Daping Hospital, Army Medical University, Chongqing, 400042, People’s Republic of China; 2The 955 Hospital of the Chinese People’s Liberation Army Ground Force, Changdu, 854000, People’s Republic of China; 3Department of Post-Graduate School, Army Medical University, Chongqing, 400042, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingjie Wang, Department of Post-Graduate School, Army Medical University, Chongqing, 400042, People’s Republic of China, Email [email protected] Shifeng Shao, Department of ICU, Daping Hospital, Army Medical University, Chongqing, 400042, People’s Republic of China, Email [email protected]: 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.Keywords: sepsis, TP53, ferroptosis, acute lung injury, intestinal barrier dysfunction