Ferroptosis promotes sepsis-related lung injury via endothelial cell senescence.

This study investigated the role of ferroptosis in vascular cell senescence induced by sepsis and elucidated the regulatory mechanism of the SIRT4-STAT3-ACSL4 signaling axis. The results showed that ferroptosis was significantly activated in pulmonary vascular endothelial cells under septic conditions, leading to the promotion of cellular senescence and exacerbation of lung injury. Inhibition of ferroptosis effectively attenuated cellular senescence and alleviated sepsis-associated lung damage. This study identified ACSL4 as a key regulator of ferroptosis, with its expression markedly elevated in senescent cells and in the lung tissues of septic mice. Further mechanistic studies revealed that SIRT4 suppresses ACSL4 transcription by modulating STAT3 acetylation, while SIRT4 deficiency enhances both ferroptosis and the senescence phenotype. Functional experiments confirmed that SIRT4 overexpression reversed LPS-induced cellular senescence and ferroptosis. This study highlights the critical role of ferroptosis in sepsis-related senescence and proposes that the SIRT4-STAT3-ACSL4 axis serves as a central regulatory mechanism in lung injury. These findings provide new insights into the interplay between ferroptosis and cellular senescence.