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

TL;DR

Tyrosol, a gut microbiota metabolite, protects against radiation-induced intestinal injury by targeting SCD1 and reducing ER stress.

Contribution

This study reveals tyrosol's novel mechanism of radioprotection via SCD1 activation and MUFA production to suppress ER stress.

Findings

Tyrosol reduces intestinal cell death and improves survival in irradiated mice by preserving mucosal architecture.

Tyrosol targets SCD1, preventing its degradation and increasing MUFAs to inhibit ER stress and cytotoxicity.

SCD1 inhibition negates tyrosol's protective effects, confirming its essential role in radioprotection.

Abstract

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.

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