Ischemic stroke, a prevalent neurological disorder with substantial global burden, is characterized by high incidence, significant long-term disability and considerable mortality. Precise prognostication of functional outcomes is paramount for timely clinical decision-making and the personalization of care, which holds profound importance for patients with ischemic stroke and their families (Whiteley et al. 2012). Consequently, the identification of prognostic markers following cerebral ischemia is of utmost importance. In the present study, we demonstrated that plasma FTO concentration at admission is independently associated with the 3-month functional outcomes of AIS patients, with a sensitivity of 87.1% and a specificity of 71.7%. Our findings reveal that FTO levels are significantly lower in the group with unfavorable outcomes compared to those with favorable outcomes, and that FTO concentration inversely correlates with 3-month mRS scores. Furthermore, the incorporation of FTO into the clinical model has been shown to markedly enhance the predictive accuracy for ischemic stroke prognosis at the 3-month. These results establish plasma FTO level as a potential biomarker for early prognostic assessment in AIS patients.

Peripheral blood is the most frequently utilized clinical specimen, and routine blood tests are instrumental in diagnosing diseases, monitoring their progression, and assessing prognosis. Due to the presence of the blood–brain barrier (BBB) that impedes the release of brain injury-specific markers into the circulation, blood testing seems to have less diagnostic value for neurological disorders than other systemic diseases (Jickling and Sharp 2015). However, the acute disruption of the BBB following ischemic stroke can lead to the release of brain-derived biomarkers into the peripheral blood, which significantly broadens the application of blood biomarkers in stroke management (Ng et al. 2017). Moreover, increasing evidence suggests that molecular markers in the blood may precede neuroimaging parameters, highlighting the critical importance of detecting proteins, RNAs, metabolites, and lipids in the blood for early warning, diagnosis, and prognosis evaluation of diseases (Jickling and Sharp 2011; Hampel et al. 2023b). Specifically, peripheral blood biomarkers have garnered significant attention as potential diagnostic and prognostic tools for cerebral ischemia. These biomarkers include but are not limited to markers of inflammatory response, nerve damage, oxidative stress, and non-coding RNAs (ncRNAs). Inflammatory responses are pivotal in the pathogenesis of cerebral ischemia, with fluctuations in pro-inflammatory cytokines such as IL-6, IL-8, IL-1β, TNF-α, and anti-inflammatory cytokines such as IL-10, IL-38 being intimately linked to the severity and prognosis of ischemic brain injury (Klimiec-Moskal et al. 2020; Zare Rafie et al. 2021; Jia et al. 2024). Neurological injury markers, including neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) are released into the circulation after brain injury, with their levels reflecting the extent of damage to neurons and glial cells (Glushakova et al. 2016; Ferrari et al. 2023). Oxidative stress markers such as malondialdehyde and superoxide dismutase are indicative of the production and clearance of free radicals, thereby reflecting the oxidative stress state of the body (Kamal et al. 2023). Non-coding RNAs, including lncRNA MALAT1, lncRNA H19, miR-193a-5p, and miR-124, participate in the regulation of cell apoptosis, immune inflammation, and neurogenesis, and hold potential as biomarkers for ischemic brain injury and prognosis (Yang et al. 2017; Wang et al. 2020b; Zhong et al. 2021; Han et al. 2023). Given that a single biomarker may not sufficiently reflect the complexity of stroke pathophysiology, researchers are increasingly exploring panels of multiple biomarkers to enhance the diagnostic and prognostic prediction accuracy (Jickling and Sharp 2015). The identification of these biomarkers provides new ideas for early diagnosis, treatment response monitoring, and prognosis evaluation of ischemic brain injury. Although numerous candidate blood biomarkers for ischemic stroke have been identified, none have yet been adopted for clinical practice, underscoring the need for further research and validation.

There are limited data examined the correlation between FTO levels and prognosis in patients with ischemic stroke. The present study provides novel insights by demonstrating that elevated plasma FTO levels are independently associated with a favorable prognosis at 3-month after AIS. Moreover, the incorporation of FTO into the conventional risk assessment model substantially improved the model’s discrimination and accuracy. FTO, known as the fat mass and obesity-associated protein, was initially identified as an obesity susceptibility gene through a genome-wide association study (GWAS) of type 2 diabetes (T2DM) patients in Europe (Frayling et al. 2007). Subsequent research confirmed its role as the first m6A mRNA demethylase that belongs to the ALKB family of Fe (II)/α-ketoglutarate-dependent dioxygenases, exhibiting robust demethylase activity towards a variety of methylated RNA substrates (Gerken et al. 2007; Jia et al. 2011). m6A, a prevalent post-transcriptional modification in eukaryotic messenger RNA (mRNA), is notably abundant within the brain and is intricately associated with synaptic plasticity, learning, and memory (Merkurjev et al. 2018; Shi et al. 2018). This modification exerts a significant influence on mRNA dynamics, such as splicing, transport, stability, and translation. Empirical evidence has indicated that both the m6A methylation levels and m6A regulators are altered in the ischemic brain of experimental animal models, within cells subjected to oxygen–glucose deprivation and reoxygenation (OGD/R), and in the peripheral blood samples of patients afflicted with ischemic stroke (Chokkalla et al. 2019; Xu et al. 2020; Fan et al. 2024). The intricate mechanisms underlying m6A methylation’s role in ischemic stroke encompass its influence on atherosclerosis, cerebral ischemia/reperfusion injury, oxidative stress, inflammatory response, and apoptosis. Furthermore, recent studies have delved into the implications of m6A-associated single-nucleotide polymorphisms (SNPs) on stroke susceptibility and identified new causal variants linked to ischemic stroke (Chang et al. 2022). Targeting the m6A modification pathway presents a promising avenue for the development of innovative therapeutic strategies in stroke treatment. Such interventions could potentially facilitate the modulation of gene expression and cellular responses post-stroke, heralding a new era in stroke management.

The precise mechanisms underlying the association between increased plasma concentrations of FTO and favorable outcomes following AIS remain to be elucidated. Recently, accumulating studies have highlighted the role of FTO in the pathophysiology of ischemic stroke, with particular emphasis on its involvement in the m6A RNA modification pathway. A study found that the restoration of FTO levels with an adeno-associated virus 9 (AAV9) reduced m6A methylation in the post-stroke brain, leading to decreased damage to gray and white matter and improved recovery of motor function, cognition, and depression-like behavior in mice of both sexes. These results suggest that FTO is a critical regulator of neuronal function and may exert cerebroprotective effects after experimental stroke (Chokkalla et al. 2023). Another study demonstrated that FTO mitigated neuroinflammation triggered by cerebral ischemia/reperfusion injury through an m6A-dependent reduction in the stability of cGAS mRNA, thereby modulating the Sting/NF-κB signaling pathway (Yu et al. 2023). Overexpression of FTO was found to reduce FYN expression through m6A modification, which subsequently inactivated Drp1 signaling. This led to a decrease in mitochondrial fission, oxidative stress, and ferroptosis, thereby suppressing cerebral ischemia/reperfusion injury in mice. This research sheds light on the potential therapeutic targets for the treatment of ischemic stroke, highlighting the significance of m6A methylation and its regulators as key factors in the pathophysiology of stroke (Zhang and Gong 2024). Another study has highlighted the role of FTO in vascular repair and functional recovery after stroke. It indicates that circular RNA (circRNA) circSCMH1 can enhance vascular repair and reduce ischemic injury by facilitating the transfer of FTO into the cell nucleus, which in turn affected the m6A modification of lipid phosphate phosphatase 3 (Plpp3) mRNA, leading to increased levels of LPP3 protein in endothelial cells (Li et al. 2023). In summary, these studies underscore the significance of the m6A modification pathway and the role of FTO in ischemic stroke, suggesting that they could serve as potential avenues for therapeutic intervention and improve outcomes for stroke patients. For instance, modulating FTO activity could potentially enhance neuroprotection and reduce inflammation. However, further research is warranted to fully elucidate the complex mechanisms involved and to translate these findings into clinical applications.

In conjunction with FTO, our findings indicate that age, onset-to-treatment time, admission NIHSS score, intravenous thrombolysis, diabetes mellitus, coronary heart disease are also associated with the 3-month functional outcomes of AIS patients. These results align with those of previous studies. A significant correlation exists between aging and a poor functional prognosis in patients with AIS, as elderly individuals often exhibit a higher prevalence of comorbidities, greater cognitive impairment, and a higher frailty rate (Candelario-Jalil and Paul 2021; Winkelmeier et al. 2024). Therefore, for elderly patients, the prevention and early identification of stroke are particularly important. Given that neuronal death in stroke is time-dependent, every effort should be directed towards reducing the time from symptom onset to treatment. This includes prompt symptom recognition, swift transportation to a hospital equipped for stroke treatment, and an efficient stroke diagnosis and intervention process (Kurz et al. 2013; di Biase et al. 2022). The admission NIHSS score is a crucial instrument for assessing the prognosis of patients with AIS, and is significantly correlated with functional recovery, mortality rates, and long-term outcomes. It is utilized to gauge stroke severity at the time of admission, with mild stroke defined as an NIHSS score ≤ 8, moderate stroke as an NIHSS score between 9 and 15, and severe stroke as an NIHSS score > 16. By employing NIHSS scoring, clinicians can anticipate a patient’s recovery trajectory and tailor treatment plans accordingly (Adams et al. 1999; Ordies et al. 2022). Intravenous thrombolysis is the primary pharmacological intervention for AIS, ideally administered within the first golden hour after stroke onset (< 4.5 h). This treatment significantly salvages the ischemic penumbra, mitigates neurological deficits, and improves the prognosis for AIS patients (Psychogios and Tsivgoulis 2022). A substantial proportion of ischemic stroke patients are afflicted with diabetes mellitus, a condition that is associated with increased brain damage, impaired neurological function, heightened risk of recurrence, and higher mortality rates. Stringent blood sugar control is of paramount importance for the prevention of stroke and the amelioration of post-stroke prognoses (Lau et al. 2019). Clinically, atherosclerotic ischemic stroke or transient ischemic attack (TIA) often coexists with coronary heart disease. Compared to those without coronary heart disease, the majority of ischemic stroke patients who also have coronary heart disease present with more severe conditions, an elevated risk of death, and a poorer prognosis (Chen et al. 2017).

It is essential to recognize some limitations inherent in this study. Firstly, the relatively small sample size with 201 AIS participants in single center may constrain the generalizability of our findings. An independent validation cohort was not employed in this analysis. Therefore, large-scale, multicenter clinical studies are warranted to further substantiate the predictive significance of FTO on the prognosis of AIS patients. Secondly, this study lacked data on certain risk factors that could potentially influence stroke outcomes, including Body Mass Index (BMI), lifestyle factors (e.g., smoking history, alcohol consumption, physical activity), and key clinical variables such as infarct volume. Notably, early neurological improvement (ENI), early neurological deterioration (END), and recurrent stroke events, were not captured during follow-up, which merit consideration in future investigations. Thirdly, considering the heterogeneity and complexity of ischemic stroke, the current design does not address the temporal trajectory of plasma FTO levels post-stroke onset. Early-phase changes in FTO concentrations (e.g., within 24 h vs. 72 h), associations between FTO fluctuations and treatment response (e.g., thrombolysis and mechanical thrombectomy), as well as longitudinal FTO profiles in relation to recurrent stroke risk, necessitate further research. These limitations highlight the need for further validation and mechanistic exploration to establish FTO as a reliable prognostic biomarker in AIS.