Ferroptosis-related TFRC: a potential therapeutic target in sepsis and regulatory effect of γ-Tocotrienol

Ferroptosis, an iron-dependent regulated cell death, plays a critical role in the pathophysiology of sepsis. This study aimed to identify core targets and therapeutic agents related to ferroptosis in sepsis.

Differential analysis of peripheral blood RNA-sequencing data from 19 patients with sepsis and 10 healthy controls was performed. Ferroptosis-related hub genes were identified via a PPI network and validated by Mendelian randomization, protein cohort studies, and survival/meta-analyses. Single-cell sequencing localized core genes, and in vitro/in vivo experiments explored targeted drugs.

High TFRC expression correlated with poor sepsis prognosis. TFRC was predominantly expressed in monocytes and B cells, with more monocytes in non-survivors. γ‑Tocotrienol (γ‑T3) treatment was associated with reduced TFRC expression, lower ROS and IL‑1β levels, and improved survival in septic zebrafish and mice.

TFRC is a potential therapeutic target for ferroptosis in sepsis. γ‑T3 alleviates LPS-induced TFRC upregulation and improves survival in septic mice, suggesting its potential as a therapeutic agent.

ChiCTR1900021261 (Chinese Clinical Trial Registry), registered February 4, 2019.

retrospective observational study using archived biological samples.