Acute coronary syndrome (ACS) remains the leading cause of cardiovascular mortality worldwide. Among its subtypes, ST-segment elevation myocardial infarction (STEMI) represents the most critical and life-threatening form. The underlying pathology of STEMI involves rupture of an atherosclerotic coronary plaque, triggering acute thrombosis that abruptly interrupts myocardial blood flow and causes ischemic necrosis of cardiomyocytes (1). Although emergency percutaneous coronary intervention (PCI) effectively restores myocardial perfusion by reopening the infarct-related artery and has markedly reduced acute-phase mortality, the risk of adverse cardiovascular outcomes, such as cardiac death, recurrent myocardial infarction, malignant arrhythmias, and heart failure rehospitalization, remains substantial in the post-procedural period (2). Therefore, in the early emergency stage, identifying reliable biomarkers that can accurately and promptly stratify high-risk patients is of great clinical importance for implementing individualized interventions and improving prognosis.

Currently, clinical assessment of STEMI prognosis primarily relies on risk scoring systems and traditional biomarkers. Risk models such as the Global Registry of Acute Coronary Events (GRACE) score and Thrombolysis in Myocardial Infarction (TIMI) score integrate clinical indicators including age, blood pressure, heart rate, and renal function for risk stratification, but they lack sufficient dynamic sensitivity (3, 4). The conventional biomarker cardiac troponin I (cTnI) serves as a sensitive diagnostic indicator for myocardial infarction; however, its specificity for prognostic prediction is limited (5). Elevated peak cTnI levels can only partially explain the prognostic heterogeneity among STEMI patients and may yield false-positive results under conditions such as renal insufficiency or infection, limiting its value as a stand-alone prognostic marker (6, 7). Consequently, the discovery of novel biomarkers with both high specificity and early detectability has become a key focus in contemporary STEMI research.

In recent years, the roles of molecular signaling pathways in the onset and progression of myocardial infarction have attracted increasing attention. The Wnt/β-catenin signaling pathway, a conserved pathway essential for embryonic cardiac development, plays crucial roles in embryogenesis, tissue repair, and disease pathogenesis (8–10). Previous studies have demonstrated that the Wnt/β-catenin pathway remains largely quiescent in the adult heart (11, 12). However, following acute myocardial ischemic injury, this pathway becomes reactivated and participates extensively in regulating inflammation, apoptosis, fibrosis, and ventricular remodeling (13–15). Key components of this pathway, including Wnt ligands (e.g., Wnt1 and Wnt5a) that initiate signal transduction (16, 17), the central effector β-catenin, and endogenous antagonists such as Dickkopf-related protein 1 (DKK1) and the secreted frizzled-related protein (SFRP) family (18–20), collectively maintain a dynamic balance that may influence the direction and quality of myocardial repair. Moreover, modulation of the Wnt/β-catenin signaling pathway has been shown to mitigate myocardial infarction and improve cardiac outcomes in experimental models (21–23). Nevertheless, comprehensive clinical evidence regarding the expression profiles of key Wnt/β-catenin pathway molecules in STEMI patients and their associations with clinical prognosis remains limited.

Therefore, this study aims to measure serum levels of Wnt1, β-catenin, Wnt5a, SFRP5, and DKK1 in STEMI patients, to delineate their expression characteristics between those with and without major adverse cardiovascular events (MACE). Furthermore, the study sought to evaluate the independent predictive value of these biomarkers for MACE, with the goal of identifying novel and forward-looking biological indicators for risk assessment and prognostic prediction in STEMI patients.

Myocardial repair following STEMI is a highly complex biological process involving intricate regulation by multiple molecular pathways. Among these, the Wnt/β-catenin signaling pathway, an essential regulator of cardiac development during embryogenesis, has recently attracted attention for its role in myocardial injury and repair in the adult heart (12). While prior studies have established associations between individual Wnt pathway components and cardiovascular diseases, the fundamentally novel aspect of this study lies in the systematic, parallel evaluation of a panel of key Wnt pathway biomarkers (including both activators and antagonists) in the acute phase of STEMI, and in the development of a combined predictive model based on their interaction. Our aim was to elucidate the association between these pathway-related biomarkers and the occurrence of MACE, thereby identifying novel prognostic targets and enriching current evidence on the role of the Wnt/β-catenin pathway in acute ischemic heart disease.

We found that serum levels of Wnt1, β-catenin, and Wnt5a were significantly elevated in the MACE group, consistent with previous findings on the involvement of the Wnt/β-catenin pathway in cardiovascular diseases (18). This pathway plays a crucial role in regulating cell proliferation, differentiation, and inflammation. Following acute MI, ischemia, hypoxia, and subsequent inflammation disrupt myocardial homeostasis, leading to reactivation of the otherwise quiescent Wnt/β-catenin signaling (26). On one hand, moderate activation may contribute to early tissue repair; on the other hand, persistent and excessive activation is a key driver of adverse cardiac remodeling. It promotes fibroblast-to-myofibroblast transition, excessive extracellular matrix deposition, and myocardial fibrosis, resulting in increased ventricular stiffness, impaired contractility, and eventual heart failure (21, 27). As the central downstream effector of this pathway, elevated serum β-catenin may reflect both direct release from damaged cardiomyocytes and robust activation of canonical Wnt signaling within the injured microenvironment. Thus, the increased β-catenin observed in the MACE group likely indicates systemic overactivation of a profibrotic and pro-remodeling signaling network, serving as a “danger signal” of maladaptive repair and poor prognosis.

DKK1, a secreted antagonist that inhibits canonical Wnt activation by binding to LRP5/6 co-receptors (28), may initially rise as a compensatory feedback mechanism. However, growing evidence suggests that persistently high DKK1 levels in chronic inflammatory diseases can induce apoptosis and impair tissue repair. In atherosclerotic plaques, DKK1 overexpression correlates with plaque instability and a higher risk of acute MI (29). Our finding that DKK1 levels were significantly elevated in patients with poor outcomes and positively correlated with MACE risk suggests dysregulated feedback under acute ischemic stress. This observation raises the hypothesis that DKK1 may transition from a compensatory to a potentially detrimental role in the post-STEMI milieu, possibly contributing to pathological processes. However, it is crucial to distinguish this correlative finding from proven causation; our data demonstrate a strong association but do not establish a direct, causal role for DKK1 in MACE pathogenesis. Further mechanistic studies are required to investigate whether elevated DKK1 is merely a marker of severe injury and dysregulated signaling or an active participant in driving adverse outcomes. Conversely, SFRP5, another Wnt antagonist, was markedly reduced in the MACE group, implying diminished inhibition of Wnt signaling and facilitating excessive pathway activation that contributes to adverse outcomes.

Multivariate Cox regression identified β-catenin, DKK1, and cTnI as independent risk factors for MACE. Because single biomarkers often have limited predictive accuracy, we explored the combined prognostic potential of β-catenin (activation marker) and DKK1 (inhibitory marker). This dual-marker strategy achieved superior predictive performance, with an AUC of 0.946—significantly higher than that of individual markers—highlighting their synergistic value in prognostic evaluation. Notably, when β-catenin, DKK1, and cTnI were combined, the AUC increased to 0.969, surpassing both single and dual-marker models. This represents a key novel contribution of our work. This combination suggests that integrating a key pathway activator (β-catenin), its endogenous inhibitor (DKK1), and a terminal injury marker (cTnI) establishes a comprehensive “etiology–compensation–outcome” model, offering a more complete and precise reflection of disease status. This combined model not only outperforms conventional reliance on cTnI alone but also indicates potential for earlier risk detection before irreversible myocardial injury occurs, thereby enabling more accurate risk stratification and personalized intervention.

Nonetheless, several limitations should be acknowledged. First, this was a single-center, retrospective, study with a relatively limited sample size, which may affect generalizability and reduce statistical power for rare outcomes. This design also inherently restricted the availability of certain detailed procedural and anatomical data (e.g., precise time to stent deployment, comprehensive angiographic characteristics) for consistent adjustment in our models. Second, biomarkers were measured at a single time point, preventing assessment of their dynamic changes, which might offer superior prognostic insights. Third, while our modeling strategy mandated adjustment for core demographics and key clinical risk factors, and employed a liberal screening threshold for other confounders, residual confounding from unmeasured or imperfectly captured variables cannot be excluded. Fourth, the precision of hazard ratio estimates for some biomarkers was limited by the number of outcome events, resulting in wider confidence intervals. Fifth, the accuracy of the hazard ratio estimates for individual biomarkers is limited by the number of outcome events, resulting in larger confidence intervals. This highlights the necessity of validation in larger cohorts. Furthermore, the predictive value of our biomarker model was not directly compared with established clinical risk scores such as TIMI or GRACE, which is a necessary step to define its potential incremental utility. Future studies should therefore be prospective in design, enabling the systematic collection of detailed procedural, anatomical, and longitudinal biomarker data. Such multicenter, large-sample cohorts are needed to validate these findings, establish precise cutoff values, and critically evaluate the added predictive value of these biomarkers over existing clinical risk assessment tools.

In conclusion, our findings identify β-catenin and DKK1 within the Wnt/β-catenin pathway as independent risk factors for MACE in STEMI patients. Aberrant activation of this pathway may represent a key pathological mechanism underlying poor prognosis. The combined predictive model based on β-catenin, DKK1, and cTnI significantly improves diagnostic accuracy for MACE, offering a powerful complement to existing assessment systems. More importantly, the novel combined predictive model based on β-catenin, DKK1, and cTnI significantly improves diagnostic accuracy for MACE, offering a powerful complement to existing assessment systems. This model holds promise for earlier risk warning and individualized treatment, providing new biological targets and a theoretical foundation for future precision therapeutic strategies targeting the Wnt/β-catenin signaling pathway.