Gut Microbiota-Derived Tyrosol Alleviates Radiation-Induced Intestinal Injury via Targeting SCD1-MUFA Axis to Suppress ER Stress

Radiation-induced intestinal injury (RIII) represents a major, clinically recalcitrant complication of radiotherapy, with current protective options remaining extremely limited. In this study, we identify tyrosol, a gut-derived phenolic metabolite enriched in the feces of irradiated mice, as a potent radioprotective agent. It reduced intestinal epithelial cell death and improved survival in lethally irradiated mice by preserving mucosal barrier and villus-crypt architecture, and downregulating pro-inflammatory cytokines. Mechanistically, we for the first time reveal that tyrosol directly targets stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in monounsaturated fatty acid (MUFA) biosynthesis. Tyrosol binds to conserved residues (Asn148, Asp156, Asn265) on SCD1, preventing valosin-containing protein (VCP)-mediated proteasomal degradation. This boosts SCD1 activity, increasing MUFAs (e.g., oleic acid, palmitoleic acid) to inhibit ER stress via the p-eIF2α/ATF4/CHOP axis and mitigate radiation-induced cytotoxicity. Importantly, inhibition of SCD1 in animal experiments abolishes tyrosol's protective effects, underscoring the essential role of SCD1. Additionally, MUFA supplementation rescues tyrosol's radioprotection in SCD1-deficient cells. These findings elucidate a novel mechanism whereby gut metabolites confer radioprotection through lipid remodeling and highlight SCD1 activation as a promising therapeutic strategy against gastrointestinal radiation injury.