Tocotrienol metabolites redirect lipid mediator production in innate immune cells towards inflammation resolution

Restoring homeostasis in persistent inflammation requires suppressing the inflammatory response and promoting resolution. Currently, no clinically used small molecules intentionally achieve both effects. Endogenous long-chain vitamin E metabolites (LCMs) address inflammation at multiple sites, including pro-inflammatory leukotriene production and cytokine release, thus limiting inflammation. Among LCMs, we here identified ω-carboxylates and ω-alcohols that suppress leukotriene biosynthesis while enhancing the biosynthesis of prostaglandin E₂ and specialized pro-resolving mediators, specifically protectins or isomers, proposed to promote inflammation resolution. These LCMs induce a lipid mediator class switch in activated and non-activated human innate immune cells and in a mouse model of self-resolving peritonitis and inhibit ferroptosis. Changes in lipid mediator classes are tightly coordinated between local and systemic sites and follow different kinetics. Mechanistically, LCMs induce polyunsaturated fatty acid release and translocate 15-lipoxygenase-1, a key enzyme in protectin biosynthesis, to particulate locales while also engaging other mechanisms, partially involving cyclooxygenase-2, to increase protectin production. The LCMs also inhibit soluble epoxide hydrolase, reducing the degradation of anti-inflammatory epoxyeicosatrienoic acids, and increase levels of endocannabinoids and dihydroceramides with immunomodulatory and stress-protective functions. These findings provide insights into immunoregulation by tocotrienol metabolites and offer promising lead structures for redirecting lipid mediator profiles from inflammation toward resolution.