Comparative redox and sulfur-metabolic effects of methylsulfonylmethane, N-acetylcysteine, and vitamin C during acute inflammatory stress

Sulfur metabolism is a critical yet underexplored regulator of redox balance, inflammatory signaling, and methylation capacity. Methylsulfonylmethane (MSM) has been proposed to influence these pathways, but its metabolic effects remain poorly defined relative to classical antioxidants. In this study, MSM was compared with N-acetylcysteine (NAC) and vitamin C in a rat model of lipopolysaccharide-induced inflammatory stress, integrating targeted sulfur and one-carbon metabolomics with oxidative, inflammatory, endothelial, and mitochondrial biomarkers.At 18 h post-challenge, MSM produced a distinct sulfur-flux signature characterized by reduced cysteine-S-sulfate and homocysteine without accumulation of oxidized sulfur derivatives, decreased S-adenosylhomocysteine, and an increased S-adenosylmethionine/S-adenosylhomocysteine ratio, consistent with attenuation of sulfite stress and stabilization of methylation balance. In contrast, NAC and vitamin C modulated cysteine and S-adenosylmethionine, but were associated with higher oxidized sulfur species, reflecting direct thiol and electron-donor buffering. Systemic inorganic sulfate levels remained unchanged across groups, indicating tight whole-body regulation; however, MSM-specific upstream shifts suggest enhanced capacity for tissue-level sulfation.Classical markers of endothelial activation and glycocalyx shedding did not differ between groups, likely reflecting the timing of sampling relative to acute shedding kinetics. All interventions reduced urinary free carnitine, consistent with preserved mitochondrial β-oxidation. MSM was associated with modest, coordinated, non-suppressive cytokine changes indicative of adaptive immunomodulation.Collectively, these findings identify MSM as a sulfation-directed metabolic regulator that stabilizes sulfur and methylation pathways under inflammatory stress, distinguishing it mechanistically from conventional antioxidants and expanding redox biology to include sulfur trafficking and sulfation-dependent regulation with relevance to inflammatory and barrier-related disease processes.