Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by chronic stenosis or occlusion of the internal carotid arteries leading to the development of abnormal vascular networks near the base of the brain (1, 2). The etiology of MMD remains elusive, may involve a combination of genetic, immune, inflammatory, and environmental factors. However, the RNF213 gene has demonstrated a significant association with MMD. Research indicated that variations in the RNF213 gene, particularly the p.R4810K mutation, were closely linked to an increased risk of developing MMD in East Asian populations (3, 4). Its clinical presentation can range from ischemic stroke to hemorrhagic events, frequently resulting in neurological deficits (5). The current treatment options are primarily surgical, aimed at revascularization to improve cerebral perfusion (6), and perioperative medical decision-making and the selection of surgical modality are crucial for patient outcomes (7).

Despite advancements in surgical techniques, predicting short-term postoperative outcomes in patients with MMD remains a challenge. Clinicians have tried to stratify these patients based on clinical aspects, and recent studies suggest that several biomarkers and medical imaging technology may be helpful in predicting postoperative outcomes (8–12). However, the potential role of Alkaline Phosphatase (ALP) has not been elucidated.

ALP, a hydrolase enzyme responsible for dephosphorylating compounds, has been implicated in multiple metabolic processes including bone metabolism, liver function, and vascular calcification (13–16). While ALP has traditionally been associated with hepatic and biliary pathology, emerging evidence suggests that elevated ALP levels are associated with atherosclerosis and cardiovascular disease (17–20). Previous studies have demonstrated that serum ALP levels may serve as a prognostic biomarker for stroke, post-stroke recurrence, and postoperative stroke (19, 21–23). Currently, there is limited research on the association between ALP levels and clinical outcomes in patients with MMD.

In this study, we aimed to explore the predictive value of ALP levels in determining short-term postoperative outcomes in MMD patients undergoing revascularization surgery. Through retrospective analysis and prospective observation, we sought to elucidate whether preoperative ALP levels correlated with postoperative complications and overall functional recovery. By establishing a link between ALP and postoperative outcomes, we propose a novel biomarker that can aid in the prognostication of MMD and potentially guide therapeutic strategies for the postoperative management of patients with MMD.

The role of biomarkers in predicting postoperative outcomes in patients with MMD is of interest. ALP has been traditionally recognized for its relevance to bone and liver metabolism, and recent studies have suggested that it is also associated with cardiovascular diseases and atherosclerosis (16, 28). This study identified a positive correlation between ALP and postoperative stroke in patients with MMD undergoing surgical treatment with univariate and multivariate Cox model analyses, suggesting it as a potential indicator of vascular-related prognoses. In particular, a nomogram was constructed to reflect the indicators that may affect the postoperative outcomes of patients with MMD, and is feasible for clinical use.

Recent clinical studies have elucidated the level of ALP is associated with vascular calcification, metabolic syndrome and the increased incidence of mortality (16). It was thought to through mechanisms such as reflecting inflammation, endothelial dysfunction and affecting vascular homeostasis (23). Recent study have also shown that serum ALP was associated with cerebral small vessel disease and impaired cerebral microcirculation (29). Besides, ALP played a crucial role in promoting angiogenesis during the fracture healing process, and ALP and VEGF exhibit a complex and coordinated relationship in promoting osteogenesis and angiogenesis (30). Hence, ALP may contribute to the pathogenesis of MMD. Emerging evidence in cardiovascular research has revealed that ALP may play a broader and more complex role than its traditional functions. Elevated ALP levels have been implicated in vascular calcification and atherosclerosis, suggesting a link between ALP activity and cardiovascular diseases (31, 32). In the context of atherosclerotic disease, ALP contributes to the ossification of vascular smooth muscle cells, leading to arterial stiffening and potential plaque instability (33, 34). Similar enzymatic processes may be relevant in the cerebral vasculature of patients with MMD, where fragile collateral networks are inherently prone to disturbances in hemodynamic forces. The association between ALP and vascular inflammation, calcification, and endothelial dysfunction suggests its involvement in pathways that could exacerbate cerebrovascular risk, particularly following surgical treatment (35, 36).

Our findings align with and extend previous clinical observations demonstrating the prognostic value of serum ALP levels in cerebrovascular diseases. Multiple cohort studies have established that elevated ALP levels are independently associated with an increased risk of incident stroke, with meta-analyses showing a dose-response relationship between ALP levels and stroke incidence across diverse populations (37). Importantly, our results corroborate emerging evidence that ALP elevation predicts poor post-stroke outcomes, including higher risks of stroke recurrence, mortality, and functional disability (19, 21, 22). The consistency between our findings in MMD patients and these previous observations in general stroke populations suggests that ALP may represent a biomarker in MMD patients.

Emerging evidence suggests that ALP contributes to cerebrovascular pathology by mediating vascular calcification, inflammatory responses, and endothelial dysfunction. The dual role of ALP in vascular biology—promoting both pathological calcification and compensatory angiogenesis through VEGF interaction—creates a complex dynamic in MMD progression and postoperative recovery (30, 32). While ALP-mediated angiogenesis may support collateral circulation formation, excessive ALP activity appears to dominate in the postoperative period, potentially leading to graft dysfunction and recurrent ischemic events. Mechanistically, ALP may disrupt inorganic pyrophosphate (PPi) metabolism—a potent endogenous inhibitor of vascular calcification—thereby promoting calcium deposition in cerebral vessels and exacerbating arteriosclerosis and ischemic events (32, 38). These pathological processes may also explain why elevated ALP levels correlate with cerebral small vessel disease and post-bypass cerebrovascular complications, suggesting its potential as both a pathogenic factor and prognostic biomarker in MMD.

Vascular calcification may be a key factor for cerebrovascular events (39). ALP plays a critical role in the metabolism of organic pyrophosphate, a key inhibitor of vascular calcification (32). Organic pyrophosphate acts as a physiological regulator, preventing the excessive deposition of calcium and phosphate in the vascular walls (32). Cerebral vascular calcification contributes to the pathogenesis of arteriosclerosis, which subsequently leads to cerebral ischemic events. In addition, ALP was associated with cerebrovascular events after stroke and cerebral artery stenosis bypass grafting surgery (19, 23). Hence, increasing ALP levels may be a risk factor or a new biomarker for cerebrovascular events after MMD bypass surgery.

Previous studies have demonstrated that RNF213 was associated with the progression of MMD, but no significant correlation has been found with either long-term or short-term prognosis. Therefore, it was not included as a variable in the construction of the nomogram. The nomogram offers key statistical and practical advantages. First, it integrates multiple predictors into a single, easy-to-use visualization, converting complex statistical models into an intuitive tool. Second, it provides individualized, quantitative risk predictions—offering absolute probabilities rather than only relative risks, thereby supporting more precise clinical decisions. Finally, it retains more predictive information compared to categorical staging systems and is more accessible than digital calculators, making it both accurate and practical for clinical use.

Although our study provides novel insights into the role of ALP in MMD, there are still limitations that require further research. As a prospective study, long-term follow-up data and more comprehensive test results are required, and. Furthermore, the homogeneity of our sample, stemming from a single center, imposes restrictions on generalizability. Prospective multicenter studies with larger and more diverse populations are required. Despite our efforts to mitigate confounding through multivariate adjustment and model selection, the potential for residual confounding remains. Although we accounted for major clinical and demographic variables, unmeasured or unknown factors not included in the analysis may still influence the outcomes, which unmeasured confounding factors could distort the true association between serum ALP and post-operative stroke, complicating causal inference. Finally, the dichotomization of ALP levels may represent a significant limitation, as it fails to capture the prognostic continuum within the normal range. A more granular analysis of ALP gradients is needed to validate and extend our findings. Future studies with more comprehensive data collection are warranted to further validate these findings.

This study demonstrated that serum ALP could be a potential predictive marker for postoperative stroke events in patients with MMD. It may be helpful to construct a more integrative approach to perioperative assessment, encompassing biochemical and clinical data, to optimize risk prediction. Further investigations are necessary to elucidate the pathophysiological mechanisms underlying this association. ALP, a modifiable risk factor, may be a tailored strategy for managing patients with MMD in the perioperative period.