J Mol Cell Cardiol. 2026 May 8:S0022-2828(26)00061-1. doi: 10.1016/j.yjmcc.2026.05.002. Online ahead of print.
ABSTRACT
Cardiac injury from lipid overload features cardiomyocyte death, myocardial remodeling, and reduced contractile function. Although L-menthol has reported cardioprotective effects, its mechanisms are poorly defined. We therefore examined the role of transient receptor potential melastatin 8 (TRPM8) in lipid overload-induced cardiac dysfunction and tested whether L-menthol acts via TRPM8. After 12 weeks of high-fat diet, mouse ventricular myocytes showed a marked reduction in TRPM8 protein expression. In vitro, L-menthol reduced cardiomyocyte injury caused by lipid overload, and in vivo it mitigated cardiac injury in high-fat diet fed male mice. These protective effects were largely abolished by TRPM8 knockdown, indicating a TRPM8-dependent mechanism. Mechanistic studies indicate that L-menthol preserves mitochondrial Ca2+ homeostasis via a TRPM8/GRP75/VDAC1 associated pathway, which limits mitochondrial dysfunction and apoptosis during lipid overload. We also found that lipid overload decreased TRPM8 S-palmitoylation at the C707 regulatory site and reduced TRPM8 protein stability. Downregulation of zDHHC13 may contribute to this loss of S-palmitoylation, whereas L-menthol helped maintain TRPM8 S-palmitoylation and protein expression. Together, these results support a TRPM8-dependent protective effect of L-menthol against lipid overload-induced cardiac injury and suggest that TRPM8-related signaling may represent a potential therapeutic target.
PMID:42107764 | DOI:10.1016/j.yjmcc.2026.05.002