TRPM8-driven thermogenesis by menthol: mechanisms of cold injury prevention

Cold injury presents a significant health challenge, causing tissue damage due to prolonged exposure to low temperatures. This study examines menthol's protective effects against cold injury, focusing on its activation of transient receptor potential cation channel subfamily M member 8 (TRPM8), a "cold-sensing" receptor, to stimulate thermogenesis in brown adipose tissue (BAT). Male C57BL/6J mice were treated with menthol for 21 days and exposed to -20 °C. Core body temperature, activity levels, and cold injury severity were measured. Network pharmacology methods identified TRPM8 as a potential target, confirmed through molecular docking and pathway analysis. Further experiments inhibited TRPM8 to evaluate its role in menthol-induced thermogenesis and cold tolerance. Menthol significantly raised core body temperature, improved cold tolerance, and reduced cold injury severity in treated mice. Network pharmacology analysis highlighted TRPM8 as a key regulator of BAT thermogenesis through the PKA/UCP1 pathway. TRPM8 inhibition diminished menthol's effect, underscoring its essential role in menthol-mediated thermogenesis. This study demonstrates that menthol activates TRPM8 in BAT, enhancing thermogenesis to prevent cold injury. These findings suggest menthol as a promising natural agent for cold injury prevention, with TRPM8 as a potential therapeutic target.