S-Methylmethionine (Vitamin U): A Critical Narrative Review of Pharmacological Mechanisms, Evidence Levels, and Translational Barriers

S-methylmethionine (SMM, also known as vitamin U) is a sulfur-containing vitamin-like compound that has been investigated since the 1940s for its gastroprotective and cytoprotective properties. Historically derived from observations of antiulcer activity in plant-derived foods, SMM has been studied in preclinical models and limited clinical settings for its multilevel pharmacological effects. This narrative review critically evaluates the available evidence on SMM’s pharmacological actions across organ systems, with explicit differentiation between preclinical and clinical data. It covers the most consistently reported gastroprotective and antiulcer effects, as well as antioxidant, anti-inflammatory, cytoprotective, and regenerative activities observed predominantly in preclinical studies. Particular attention is paid to organ-specific protection in the nervous system, liver, kidneys, lungs, skin, eyes, and oral tissues, although human evidence remains scarce. Proposed mechanisms are mediated primarily through suppression of oxidative stress, modulation of inflammatory and immune responses, maintenance of glutathione homeostasis, activation of ERK/NF-κB and Nrf2/Keap1 pathways, and regulation of methylation processes. Building on recent descriptive reviews, this work provides a structured critical synthesis that grades evidence quality, compares SMM with the structurally related methyl donor S-adenosylmethionine (SAMe), and analyses the translational and regulatory barriers that have prevented Western drug registration despite over 70 years of investigation. Despite a substantial preclinical evidence base and historical clinical observations, the level of evidence for many indications remains limited. Well-designed Phase II randomized controlled trials and innovative pharmaceutical formulations (especially topical and mucosal delivery systems) are urgently needed to translate preclinical promise into clinical benefits.