Prognostic value and cardioprotective mechanisms of 5-methoxytryptophan in patients with acute myocardial infarction

5-Methoxytryptophan (5-MTP) is an endogenous tryptophan metabolite with anti-inflammatory and anti-fibrotic properties. Its clinical significance in acute myocardial infarction (AMI) and underlying mechanisms remain largely unknown. In a prospective cohort, 407 AMI patients undergoing successful percutaneous coronary intervention (PCI) were enrolled. Plasma 5-MTP was measured by ELISA. SYNTAX score was used to assess coronary artery disease complexity. In-hospital heart failure (HF) and 1-year major adverse cardiovascular events (MACE) were recorded. Associations were assessed using logistic/Cox regression, restricted cubic splines (RCS) and propensity score matching (PSM). In parallel, H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) and treated with 5-MTP (10 μM); cell viability, apoptosis and NF-κB pathway activation were evaluated. Primary rat cardiac fibroblasts were stimulated with TGF-β1 with or without 5-MTP; migration, α-SMA, collagen I and MMP-9 were measured. Plasma 5-MTP was inversely correlated with SYNTAX score (r = − 0.431, P < 0.001). Higher 5-MTP was independently associated with lower SYNTAX score (medium vs. low: OR 0.40, 95% CI 0.24–0.66, P < 0.001; high vs. low: OR 0.14, 95% CI 0.08–0.23, P < 0.001). Higher 5-MTP levels predicted reduced in-hospital HF (OR 0.20, 95% CI 0.08–0.52, P < 0.001) and 1-year MACE (HR 0.39, 95% CI 0.19–0.79, P = 0.009). RCS analyses confirmed a linear dose–response pattern across all outcomes (all P for nonlinear > 0.05). In vitro, 5-MTP attenuated H/R-induced cardiomyocyte apoptosis, suppressed IκBα phosphorylation, p65 nuclear translocation and reduced IL-1β, IL-6, TNF-α, MCP-1 and COX-2 expression. In fibroblasts, 5-MTP inhibited TGF-β1-induced migration, α-SMA/collagen I expression and MMP-9 secretion. Low plasma 5-MTP is independently associated with severe coronary artery disease, in-hospital HF and worse 1-year outcomes after AMI. Its cardioprotective effects may be mediated, at least in part, through inhibition of NF-κB-driven inflammation in cardiomyocytes and suppression of TGF-β1-induced fibroblast activation. These findings suggest that 5-MTP may serve as a prognostic biomarker and a potential therapeutic target in AMI, pending further validation.