Triptolide alleviates acute lung injury by reducing mitochondrial dysfunction mediated ferroptosis through the STAT3/p53 pathway

Abstract

Acute lung injury (ALI) represents a severe clinical condition marked by intense pulmonary inflammation and complex pathogenic mechanisms. Triptolide, a potent anti-inflammatory agent derived from the plant Tripterygium wilfordii Hook. f., remains to be fully elucidated for its therapeutic efficacy in ALI. This study aimed to investigate the potential of triptolide in mitigating ALI by modulating ferroptosis and preserving mitochondrial function. Utilizing an ALI model induced by lipopolysaccharide (LPS) both in mice and BEAS-2B cells, we evaluated the impact of triptolide on lung injury, inflammatory cytokines, oxidative stress, and mitochondrial function. RNA sequencing, network pharmacology, molecular docking, and a thermal stability assay for cellular proteins (CETSA) were utilized to identify triptolide targets and pathways. Triptolide significantly alleviated LPS-induced pulmonary pathological changes, downregulated inflammatory cytokines including IL-6, IL-1β, and TNF-α, and reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels while increasing glutathione (GSH) and superoxide dismutase (SOD) activity. RNA sequencing revealed that triptolide upregulated SLC7A11 and inhibited ferroptosis. Network pharmacology and molecular docking identified the STAT3/p53 pathway as a key mediator of triptolide's action. CETSA confirmed that triptolide binds to and enhances the thermal stability of STAT3 and p53 proteins. This study is the first to elucidate that triptolide mitigates ALI by targeting the STAT3/p53 pathway, preserving mitochondrial function, and inhibiting ferroptosis. Collectively, these results propose that triptolide may serve as an effective therapeutic option for the treatment of ALI.

Keywords: Acute lung injury; Ferroptosis; Mitochondrial function; Oxidative stress; STAT3/p53 pathway; Triptolide.