Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis

Abstract

Post-exertional malaise (PEM) and cognitive dysfunction (“brain fog”) are among the most disabling features of Long COVID, yet approved disease-modifying treatments remain lacking. Emerging evidence implicates interacting disturbances in mitochondrial bioenergetics, redox regulation and neurovascular inflammation, although much of the supporting data derive from acute COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), mitochondrial disease and mechanistic pharmacology rather than from direct Long COVID studies. This narrative review develops a mechanism-based translational hypothesis: that a pathway-targeted nutraceutical combination may modulate these three axes more effectively than single-agent antioxidant approaches. Candidate modules comprise coenzyme Q10 and alpha-lipoic acid for bioenergetic support; selenium, sulforaphane and resveratrol for Nrf2–thioredoxin redox regulation; and Boswellia serrata, luteolin and eicosapentaenoic acid for prostaglandin and resolution-pathway modulation. The mitochondrial redox modulator sonlicromanol provides pharmacological precedent for combined antioxidant and prostaglandin-directed mechanisms, although the proposed nutraceutical strategy remains clinically untested. We summarise the mechanistic rationale, critically appraise direct versus indirect clinical evidence with explicit certainty grading, outline safety and interaction considerations, and propose a stratified randomised trial framework. This model reframes nutraceuticals as pathway-specific candidate interventions and provides a falsifiable basis for future Long COVID trials.