Targeting FAR1 to inhibit intestinal macrophage ferroptosis: repurposing irinotecan as a novel sepsis therapy.

Intestinal barrier breakdown is a key driver of sepsis-related multiple organ dysfunction; however, the metabolic mechanisms underlying this process remain poorly understood. In this study, by integrating multiomic analysis with machine learning on clinical and experimental data, we identified fatty acyl-CoA reductase 1 (FAR1) as a critical regulator that promotes ferroptotic susceptibility in sepsis. FAR1 was markedly upregulated in septic macrophages, promoting polyunsaturated ether phospholipid remodeling and lipid peroxidation involving the ACSL4/GPX4 metabolic-regulatory network. We repurposed irinotecan as a FAR1-targeting compound through pharmacological sensitivity screening and subsequent validation. Beyond its canonical function as a topoisomerase I inhibitor, irinotecan exhibited a noncanonical activity by directly interacting with FAR1 in a Gly252-dependent manner. This interaction suppresses FAR1-associated ether lipid metabolic remodeling, thereby attenuating ferroptotic responses and preserving the "gatekeeper" function of intestinal macrophages. In preclinical sepsis models, low-dose irinotecan attenuated macrophage ferroptotic responses, restored mitochondrial integrity, alleviated intestinal barrier dysfunction, and improved survival. Our findings provide evidence supporting a "target-drug-mechanism" framework and highlight the potential repurposing of irinotecan as a host-directed therapeutic strategy for sepsis, particularly in contexts associated with elevated FAR1 expression.