Comment: In-depth cerebrovascular lipidomics profiling for discovering novel biomarkers and mechanisms in moyamoya and intracranial atherosclerotic disease
Year: 2026
Type: article
Abstract: Dear Editor, We read with great interest the recent article by He et al entitled “In-depth cerebrovascular lipidomics profiling for discovering novel biomarkers and mechanisms in moyamoya and intracranial atherosclerotic disease.” Leveraging paired intracranial and extracranial arterial tissues from patients with moyamoya disease (MMD) and intracranial atherosclerotic disease (ICAD), the authors provide one of the most comprehensive lipidomics characterizations in human cerebrovascular tissue to date[1]. Their findings – particularly the identification of diacylglycerol (DG) enrichment and triglyceride (TG) depletion in intracranial MMD arteries and the observed associations with plasma iron parameters – offer valuable insights into potential pathogenic mechanisms and diagnostic signatures. Nevertheless, several methodological and interpretive issues merit further discussion to enhance the translational impact of this important work. First, although the authors highlight marked DG–TG imbalance within intracranial MMD arteries, the study design does not completely rule out the possibility that these lipidomic differences reflect end-stage vascular remodeling rather than causal mechanisms of disease. Intracranial arteries used for analysis were predominantly terminal lesions collected during revascularization. As arterial remodeling in MMD progresses through chronic stenosis, compensatory collateral formation, inflammatory activation, and altered hemodynamics, late-stage tissues may accumulate secondary metabolic signatures not representative of earlier pathogenic steps[2]. The absence of temporal staging – such as Suzuki grading, perfusion severity, or radiographic progression markers – limits the ability to distinguish whether DG accumulation is a driver, amplifier, or simply a by-product of chronic ischemic stress. Future studies integrating lipidomics with radiographic disease staging or leveraging longitudinal sampling (e.g., plasma lipidomic trajectories before and after surgery) would help disentangle causality from consequence. Second, the reported associations between MMD-specific lipid species and systemic iron parameters raise compelling hypotheses, but the mechanistic interpretation remains incomplete. Iron deficiency–mediated angiogenic responses have been proposed as contributors to MMD vasculopathy[3]; however, in the present study, arterial lipid signatures were correlated with peripheral iron markers that may themselves be influenced by surgical status, inflammation, nutritional factors, or chronic disease burden. Moreover, plasma iron measures were cross-sectional and not temporally aligned with tissue acquisition. Without controlling for confounders such as ferritin, transferrin saturation, dietary iron intake, menstrual status, or preoperative anemia management, the strength and specificity of the proposed iron–lipid axis remain uncertain. Incorporating systemic iron regulators (e.g., hepcidin), erythropoietic markers, or local vascular iron content via Perls staining or mass spectrometry imaging could substantially clarify whether iron deficiency plays a mechanistic role in lipid remodeling within MMD arteries. Third, although the authors identify robust lipid panels capable of differentiating MMD from ICAD with high AUC values using machine learning models, the clinical generalizability of these markers warrants caution. The ICAD sample size was notably small (n = 12), raising concerns regarding model overfitting. Lipidomic signatures derived from such imbalanced cohorts may disproportionately reflect group size differences rather than true biological distinctiveness. Additionally, the study population was derived exclusively from a single center in East Asia, where the prevalence of RNF213 p.R4810K mutation is high[4]. Because RNF213 genotype affects endothelial function, angiogenesis, and potentially lipid metabolism, it may confound lipidomic distinctions between MMD and ICAD. Without controlling for RNF213 status, population stratification may partially underlie the observed lipid profile separation. Expanding the dataset to include multiethnic cohorts and genotype-stratified analyses would significantly strengthen the diagnostic value of these lipid biomarkers. To advance the translational potential of this important work, future research should incorporate spatial lipidomics to map DG/TG alterations to specific vascular niches, integrate genomic and epigenomic profiles to elucidate regulatory pathways, and evaluate whether plasma or CSF lipidomic signatures could serve as noninvasive biomarkers. Furthermore, validating the lipidomic signatures in large, multicenter prospective cohorts will be essential for establishing clinical utility. In summary, He et al provide an innovative and methodologically sophisticated exploration of cerebrovascular lipidomics in MMD and ICAD, opening promising avenues for biomarker development and mechanistic discovery. Addressing the aforementioned methodological considerations – particularly regarding disease staging, iron metabolism confounding, and cohort representativeness – will be crucial to strengthening the biological interpretation and clinical applicability of their findings. We commend the authors for their valuable contribution and look forward to future studies building on this impactful work. Consent Not applicable. This article does not involve human participants, patient data, or identifiable personal information. Ethical approval Not applicable. Ethical approval was not required for this study, as it is a narrative review/commentary based on previously published literature.
Source: International Journal of Surgery
Authors: Huang Siyuan, Jiang Yi
Institutions: Chongqing University, Chongqing Emergency Medical Center
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,450
OpenAlex ID: W7124263624