Integrated Network Pharmacology and Molecular Docking to Elucidate the Efficacy and Potential Mechanisms of Tea Ingredients in Sepsis Treatment.

ABSTRACT

Sepsis, a critical health condition induced by an overactive innate immune response and reactive oxygen species (ROS)-driven host damage through apoptosis and ferroptosis, continues to pose a significant mortality risk. Despite accumulating evidence of the potential therapeutic properties of tea ingredients, their specific anti-sepsis potential remains inadequately explored. This study comprehensively investigates the targeted genes of tea ingredients, notably epigallocatechin 3-gallate (EGCG), and their correlation with sepsis signature genes. Our findings elucidate that tea ingredients, especially EGCG, exhibit substantial potential in mitigating inflammation and sepsis-induced damage. Through the inhibition of the MAPK cascade and macrophage activation and by impeding the transcriptional activity of RELA (transcription factor p65) in sepsis, EGCG demonstrates significant anti-sepsis efficacy. Molecular docking analysis further underpins this by revealing the close proximity of EGCG and (-)-catechin gallate binding sites to that of RELA on DNA. Subsequent in vitro assays illuminated EGCG's instrumental role in modulating macrophage M2 polarization, balancing M1 and M2 differentiation of bone marrow-derived macrophages (BMDMs), curtailing inflammatory factor secretion, and inhibiting ROS production. Moreover, EGCG effectively suppresses the expression of ferroptosis/apoptosis markers in LPS-induced macrophages during their early stages. Our study advances our understanding of sepsis prevention and treatment strategies, suggesting that tea ingredients such as EGCG could play a pivotal role in developing future sepsis therapies due to their protective effects.