This study compared romosozumab and teriparatide for osteoporosis treatment using real-world data. Romosozumab was linked to significantly lower mortality, especially in older adults, without added cardiovascular risk. These findings highlight romosozumab as a potentially safer and more effective option for reducing death risk in patients with osteoporosis. Osteoporosis is a prevalent condition among older adults and significantly increases the risk of fragility fractures, particularly affecting the hip and vertebrae. Pharmacologic therapy remains central to osteoporosis management, with anabolic agents such as romosozumab and teriparatide demonstrating efficacy in increasing bone mineral density and reducing fracture risk. However, direct comparative evidence regarding their impact on mortality is limited. This study aimed to evaluate the differences in all-cause mortality between romosozumab and teriparatide in patients with osteoporosis, utilizing a large real-world dataset. We conducted a retrospective cohort study using electronic medical records from the TriNetX US Collaborative Network, comprising data from over 120 healthcare organizations. Patients aged ≥ 20 years diagnosed with osteoporosis between January 1, 2016, and December 31, 2023, initiating either romosozumab or teriparatide were included. Individuals with malignancies, bone neoplasms, multiple myeloma, parathyroid disorders, or cerebrovascular accidents were excluded. Propensity score matching (1:1) balanced demographic, clinical, and laboratory characteristics between cohorts. The primary outcome was all-cause mortality, with subgroup analyses performed based on age, sex, comorbidities, and treatment settings. Each treatment group included 2470 matched patients. Over the follow-up period, romosozumab was associated with significantly lower all-cause mortality compared to teriparatide (hazard ratio [HR] 0.68, 95

BACKGROUND:Cellular plasticity and epithelial-mesenchymal transition (EMT) promote the initiation and progression of non-small cell lung cancer (NSCLC). Thioredoxin reductase 1 (TXNRD1), a key redox enzyme, has been linked to malignancy, but its mechanism in NSCLC remains unclear. We examined whether TXNRD1 regulates TGF-β1 autocrine signaling to drive EMT and stemness. MATERIALS:Stage-progression gene profiles were analyzed in the TCGA and GEO databases with an emphasis on redox gene families. TXNRD1 was manipulated by overexpression or knockdown in A549, H226, and H1299 cells, followed by migration/invasion, spheroid assays, ELISA for cytokines, and RT-qPCR/Western blot for EMT markers. RNA-seq with pathway enrichment analyses was used to identify downstream programs. An orthotopic lung cancer mouse model was established using TXNRD1-WT cells, TXNRD1-deficient cells, and TXNRD1-deficient cells treated with TRi-1. Tumor progression was monitored by bioluminescence imaging at 6 and 12 weeks after transplantation. RESULTS:TXNRD1 expression was ~2-fold higher in advanced-stage NSCLC and was validated in tumor tissues. CRISPR/Cas9 or siRNA knockdown reduced EMT-associated genes and decreased TGF-β1 production in A549 and H226 cells. TXNRD1 overexpression increased EMT and stemness markers and produced larger, more compact spheres with higher sphere numbers in H1299 cells. RNA-seq indicated the TXNRD1 pathway activates the TGF-β1 pathway to promote EMT, motility, and stemness via an autocrine loop; knockdown or TXNRD1 inhibition suppressed metastatic tumor growth in vivo. CONCLUSIONS:Our study identifies TXNRD1 as a crucial regulator of cellular plasticity and metastasis in NSCLC via the TGF-β1 pathway, suggesting that targeting TXNRD1 may reduce metastatic potential and improve patient survival.

Background: Intravertebral device implantation is a safe and effective treatment for thoracolumbar vertebral fractures. Unilateral intravertebral stenting using a self-expanding implant can achieve anatomic reduction percutaneously through posterolateral transpedicular access. Objectives: This study analyzed clinical and radiological data on patients receiving intravertebral stenting using the expandable vertebral augment (EVA) system and reviewed currently available intravertebral implants. Materials and Methods: This was a retrospective cohort study. A retrospective review of 18 patients with vertebral compression fractures who underwent EVA intravertebral augmentation between 2020 and 2022, with an average of 1-year follow-up, was performed. Data collected pre-, postoperatively, and at final follow-up were patient-reported outcomes, including Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) scores; radiological assessment, including kyphotic angle; vertebral body height (anterior, middle, and posterior), and recovery rate; complications, including postoperative adjacent segment fracture and cement leakage. Results: Twenty levels of the vertebral body were operated on. The mean VAS and ODI scores, the anterior, middle, and posterior vertebral body heights, and the average kyphotic angle all showed significant improvement postoperatively. One postoperative adjacent segment fracture and one cement leakage were noted. No significant changes were found in all parameters during the postoperative period till final follow-up, indicating a sustained and favorable outcome. Conclusions: Intravertebral stenting in the treatment of vertebral compression fractures offers advantages in terms of restoring vertebral body height and kyphotic angle and has a low risk of bone cement leakage. Unilateral application of a single implant requires certain surgical experience due to a more horizontal trajectory.

Study DesignMeta-Analysis.ObjectivesIntraoperative image-guided spinal navigation provides real-time imaging during surgery and can enhance pathology localization, optimize working channel placement, and facilitate the learning process of Endoscopic lumbar spine surgery (ELSS). This meta-analysis examined whether intraoperative image-guided spinal navigation offers perioperative and clinical advantages in ELSS compared with conventional C-arm fluoroscopy.MethodsWe systematically searched PubMed, Europe PMC, Scopus, Cochrane Library, and ClinicalTrials.gov for studies comparing the perioperative and clinical outcome of intraoperative image-guided spinal navigation with conventional C-arm fluoroscopy in ELSS. Results were summarized using the mean difference (MD) or standardized mean difference (SMD) with accompanying 95% confidence intervals.ResultsA total of 19 studies involving 1390 patients were included for meta-analysis. Intraoperative image-guided spinal navigation in ELSS was significantly associated with a shorter total operation time (MD = -11.18 min, P < 0.01), fewer puncture attempts (MD = -2.94 times, P < .01), shorter cannulation time (MD = -12.59 min, P < 0.01), lower fluoroscopy use frequency (MD = -14.75 times, P < 0.01), lower radiation exposure (SMD = -4.18, P < 0.01), and shorter hospital stay (MD = -0.44 days, P = 0.03) compared with C-arm fluoroscopy. No significant differences in back Visual Analog Scale (VAS) scores, leg VAS scores, or Oswestry Disability Index scores were observed at up to 1 year of follow-up.ConclusionIntraoperative image-guided spinal navigation in ELSS significantly affects perioperative outcomes. However, clinical outcomes are not affected by the type of navigation. Further research is required to evaluate its cost-effectiveness across diverse health-care systems.

OBJECTIVE:To evaluate the effect of spinopelvic parameters on anterior bone graft subsidence and functional outcomes after anterior interbody fusion (AIF) and posterior instrumented fusion (PIF) in pyogenic spondylodiscitis (PS). METHODS:Sixty-five patients who had received AIF+PIF for PS from July 2003 to December 2015 were enrolled. Based on the degree of bone graft subsidence, the patients were divided into groups A (minimal subsidence), B (moderate subsidence), and C (severe subsidence). Comparative analysis was performed evaluating patient demographics, spinopelvic parameters (kyphosis angle, involved segment's intervertebral height, pelvic incidence [PI], pelvic tilt, sacral slope, lumbar lordosis [LL], thoracolumbar kyphosis, and PI minus LL [PI-LL]), and clinical evaluation including Oswestry Disability Index score and visual analog scale (VAS) scores. The data were collected in a patient registry at perioperative, postoperative 3-month, and 2-year to assess clinical and radiological outcomes. Receiver operating characteristic analysis was applied for identification of cutoff points of LL and PI-LL in suggestion of clinical practice. RESULTS:The 65 included patients had a mean follow-up period of 35.09 ± 38.30 months. Generalized estimating equation analysis showed that LL and PI-LL changes in group A were significantly different from those in group C but not in group B, revealing that preoperative LL and postoperative PI-LL are bone graft subsidence type indicators. By contrast, preoperative Oswestry Disability Index, postoperative 3-month VAS-back, preoperative VAS-leg, and postoperative 2-year VAS-leg scores were associated with bone graft subsidence type. Receiver operating characteristic analysis identified preoperative LL < 40.79° and postoperative PI-LL > 15° as significant predictive markers for severe bone graft subsidence, providing valuable thresholds for surgical risk evaluation. CONCLUSIONS:Among spinopelvic parameters, preoperative LL and postoperative PI-LL are important parameters associated with bone graft subsidence severity in patients who had received AIF+PIF for PS.

Objective: Endoscopic lumbar interbody fusion is a novel yet safe approach that provides a clear and expansive endoscopic view, facilitating the preservation of spinal structures. Whether biportal or uniportal incisions should be made for endoscopic interbody fusion is unclear. This study evaluated surgical efficacy and functional outcomes following biportal endoscopic transforaminal lumbar interbody fusion (BE-TLIF) with pedicle screw incisions for the treatment of lumbar spinal pathologies.Methods: Patients who underwent BE-TLIF between October 2019 and June 2023 with a minimum 12-month follow-up were retrospectively included. Functional outcomes were assessed using the visual analogue scale (VAS), Oswestry Disability Index (ODI), EuroQoL-5 Dimensions VAS (EQ5D-VAS), and modified MacNab criteria. Interbody fusion and cage subsidence rates were evaluated using lumbar x-rays.Results: In total, 21 patients (7 men and 14 women) with a mean age of 69.9 years (range, 41–90 years) were included, covering 23 total surgical levels. Compared to their preoperative values, 12-month postoperative mean back and leg VAS and ODI scores were significantly lower (back VAS, 3.3–0.9, p<0.001; leg VAS, 3.4–1.8, p<0.001; ODI, 18–2, p=0.049). In contrast, the EQ5D-VAS scores were significantly higher (79.8–98.2, p=0.009). Most patients (90%) achieved good or excellent modified MacNab criteria outcomes at the 12-month follow-up, and no serious complications were reported. The overall fusion and subsidence rates at 12 months were 87% and 13%, respectively.Conclusion: BE-TLIF via pedicle screw incision provides favorable clinical outcomes, minimizes skin incisions, and is a feasible treatment option for lumbar spine pathologies.

Background: The lack of an accurate coronary artery spasm (CAS) risk prediction model highlights the failure to consider dynamic coronary health and reveals a gap in understanding CAS. Methods: A total of 913 Taiwanese patients (460 women and 453 men) with suspected ischemic heart disease but without angiographic obstructive coronary artery disease were subjected to intracoronary methylergonovine testing during the period 2008-2025. Results: The study included 645 CAS cases (70.6%) and 268 non-CAS controls (29.4%). The multivariable logistic regression model identified 10 variables significantly associated with CAS (p < 0.05): male sex, smoking, low systolic and diastolic blood pressure, reduced B-type natriuretic peptide levels, elevated low-density lipoprotein levels, increased relative wall thickness at end-systole, high left ventricular mass index, low e'(l) values, and high Tei index. Discrimination performance was moderate, with an AUC value of 73.8% that dropped to 72.4% after bootstrapped internal validation, suggesting the potential generalizability of the derived model. The total score ranged from 36 to 98, representing a predicted probability between 12% and 98%, respectively. Conclusions: While a total score of ≥58 with the probability of CAS exceeding 50% indicates a significant chance of undiagnosed CAS, for patients with a total score ≥ 69 and a high probability of CAS ≥ 75%, coronary catheterization with CAS provocation testing is strongly recommended for a definite diagnosis. The simple 10-variable scoring model allows ranking of at-risk populations and is designed to be used as a screening tool rather than a diagnostic adjunct, enabling more efficient diagnostic resource allocation.

Fibroblast growth factor receptor 2 (FGFR2) is frequently overexpressed in gastric cancer and represents a promising therapeutic target. We developed FGFR2-specific single-chain variable fragments (scFvs) using a chicken-derived immune library and a refined cell-based panning strategy incorporating FGFR2-knockdown cells for negative selection. The lead clone, scFv R21, exhibited high binding affinity and strong tumor-inhibitory effects in vitro. To enable therapeutic application, R21 was humanized using three distinct framework strategies: CDR grafting, light chain replacement, and structure-guided back-mutation. Structural modeling by AlphaFold3 indicated that the hR21-Bf variant preserved CDR conformation and overall stability. Despite lower expression, hR21-Bf retained moderate FGFR2 binding affinity (KD) of 38 nM, while other variants showed markedly reduced reactivity. The hR21-Bf construct was further reformatted as a full-length human IgG1 and evaluated in a gastric cancer xenograft model. Mice treated with IgG hR21-Bf showed significant tumor growth inhibition without observable toxicity. Immunohistochemical and biochemical analyses of resected tumors confirmed reduced Ki-67 expression and downregulation of FGFR2-mediated signaling. Our study highlights the impact of scaffold selection on antibody structure and function, supporting a rational approach to antibody humanization using avian-derived libraries for cancer therapy.

Objectives:Concerns about erythropoietin (EPO) therapy for anemia in patients with end-stage renal disease (ESRD) contributing to potential bone loss and increased fracture risks are growing. This study investigated the impact of EPO administration on the risk of common osteoporotic fractures in ESRD patients. Methods:This population-based retrospective cohort study compared EPO users and non-EPO users among ESRD patients undergoing hemodialysis, diagnosed with ESRD between 2000 and 2014 identified from the National Health Insurance Research Database of Taiwan. The cohorts were matched at a propensity score ratio of 1:1, resulting in equal sample sizes of 2839. Variables related to comorbidities were considered. Results:EPO users exhibited higher cumulative incidences of major osteoporotic fractures, hip fractures, spine fractures, and wrist fractures compared with the non-EPO user (all P < 0.001). In adjusted Cox regression models, higher adjusted subdistribution hazard ratios (aSHRs) were observed for major osteoporotic fractures (2.41, 95% confidence interval [CI] = 2.01-2.89), osteoporotic hip fractures (2.19, 95% CI = 1.69-2.85), spine fractures (2.50, 95% CI = 1.87-3.34), and wrist fractures (2.34, 95% CI = 1.44-3.78) in EPO users than in non-EPO users. The risk of major osteoporotic fractures significantly increased with increasing EPO doses (P for trend < 0.0001), and a similar trend was observed for the risks of osteoporotic spine and wrist fractures. Conclusions:Our findings suggest that EPO treatment in patients with ESRD undergoing hemodialysis is associated with an increased risk of osteoporotic fractures.

Cancer immunotherapy harnesses the immune system to combat tumors and has emerged as a major cancer treatment modality. The PD-1/PD-L1 immune checkpoint modulates interactions between tumor cells and T cells and has been extensively targeted in cancer immunotherapy. However, the monoclonal antibodies known to target this immune checkpoint have considerable side effects, and novel PD-1/PD-L1 inhibitors are therefore required. Herein, a peptide inhibitor to disrupt PD-1/PD-L1 interactions was designed through structure-driven phage display engineering coupled to computational modification and optimization. BetaPb, a novel peptide library constructed by using the known structure of PD-1/PD-L, was used to develop inhibitors against the immune checkpoint, and specific peptides with high affinity toward PD-1 were screened through enzyme-linked immunosorbent assays, homogeneous time-resolved fluorescence, and biolayer interferometry. A potential inhibitor, B8, was preliminarily screened through biopanning. The binding affinity of B8 toward PD-1 was confirmed through computation-aided optimization. Assessment of B8 variants (B8.1, B8.2, B8.3, B8.4, and B8.5) demonstrated their attenuation of PD-1/PD-L1 interactions. B8.4 exhibited the strongest attenuation efficiency at a half-maximal effective concentration of 0.1 μM and the strongest binding affinity to PD-1 (equilibrium dissociation constant = 0.1 μM). B8.4 outperformed the known PD-1/PD-L1 interaction inhibitor PL120131 in disrupting PD-1/PD-L1 interactions, revealing that B8.4 has remarkable potential for modification to yield an antitumor agent. This study provides valuable information for the future development of peptide-based drugs, therapeutics, and immunotherapies for cancer.

Background Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have cardiovascular (CV) benefits, particularly in reducing the risk of heart failure (HF). Pioglitazone (Pio) has shown potential in decreasing the risks of recurrent stroke, non-fatal myocardial infarction (MI), and all-cause mortality but increasing risks of HF. Our study aimed to examine the synergistic effects on CV outcomes in patients with type 2 diabetes mellitus (T2DM) who received the combined treatment of SGLT2i and Pio.Materials and methods A total of 117,850 patients with T2DM and without a history of HF were selected as the observational study cohort from the Chang Gung Research Database (CGRD) in Taiwan between January 1, 2016, and December 31, 2019. The primary composite outcome was 4-point major adverse CV events (4P-MACE), including CV death, non-fatal MI, non-fatal ischemic stroke, and hospitalization for HF. The study was divided into four groups: a combined treatment group in which SGLT2i and Pio were used, two individual groups in which SGLT2i or Pio was used separately, and a reference group (non-study drugs).Results Combined treatment of SGLT2i and Pio had the lowest risk of 4P-MACE (adjusted hazard ratio [aHR], 0.66; 95% confidence interval [CI], 0.54-0.80) compared with the reference group after a mean follow-up of 2.2 years. There was no significant difference in risks of hospitalization for HF (adjusted subdistribution hazard ratio, 0.73; 95% CI, 0.49-1.07) compared with the reference group.Conclusions In T2DM patients without HF, the combined treatment with SGLT2i and Pio may synergistically provide CV benefits without increasing risks of HF.

Knee osteoarthritis (OA) involves articular cartilage degradation driven mainly by inflammation. Kaempferol (KM), known for its anti-inflammatory property, holds potential for OA treatment. This study investigated the potential of hyaluronic acid (HA)-coated gelatin nanoparticles loaded with KM (HA-KM GNP) for treating knee OA. KM was encapsulated into gelatin nanoparticles (KM GNP) and then coated with HA to form HA-KM GNPs. Physical properties were characterized, and biocompatibility and cellular uptake were assessed in rat chondrocytes. Anti-inflammatory and chondrogenic properties were evaluated using IL-1β-stimulated rat chondrocytes, compared with HA-coated nanoparticles without KM (HA GNP) and KM alone. Preclinical efficacy was tested in an anterior cruciate ligament transection (ACLT)-induced knee OA rat model treated with intra-articular injection of HA-KM GNP. Results show spherical HA-KM GNPs (88.62 ± 3.90 nm) with positive surface charge. Encapsulation efficiency was 98.34 % with a sustained release rate of 18 % over 48 h. Non-toxic KM concentration was 2.5 μg/mL. In IL-1β-stimulated OA rat chondrocytes, HA-KM GNP significantly down-regulated RNA expression of IL-1β, TNF-α, COX-2, MMP-9, and MMP-13, while up-regulating SOX9 compared to HA GNP, and KM. In vivo imaging demonstrated significantly higher fluorescence intensity within rat knee joints for 3 hours post HA-KM GNP injection compared with KM GNP (185.2% ± 34.1% vs. 45.0% ± 16.7%). HA-KM GNP demonstrated significant effectiveness in reducing subchondral sclerosis, attenuating inflammation, inhibiting matrix degradation, restoring cartilage thickness, and reducing the severity of OA in the ACLT rat model. In conclusion, HA-KM GNP holds promise for knee OA therapy.

Ovarian clear cell carcinoma (OCCC) frequently develops resistance to platinum-based therapies, which is regarded as an aggressive subtype. However, metabolic changes in paclitaxel resistance remain unclear. Herein, we present the metabolic alternations of paclitaxel resistance in bioenergetic profiling in OCCC. Paclitaxel-resistant OCCC cells were developed and metabolically active with oxygen consumption rates (OCR) compared to parental cells. Metabolite profiling analysis revealed that paclitaxel-resistant OCCC cells reduced intracellular ATP and GTP influx rates, increasing the NADH/NAD+ ratio. We further demonstrated that paclitaxel-resistant OCCC cells led to characteristic alternations of metabolite levels in energy-requiring and energy-releasing steps of glycolysis and their corresponding glycolytic enzymes. Copy number alterations and RNA sequencing analysis demonstrated that ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporter genes involved in glycolysis metabolism and molecular transport were enriched in paclitaxel-resistant OCCC cells. We first identified that Hexokinase 2 (HK2) expression is upregulated in paclitaxel-resistant OCCC cells to determine the quantity of glucose entering glycolysis. Utilizing proteolysis-targeting chimera (PROTAC) HK2 degraders, we also found that paclitaxel sensitivity, viability, and oxygen consumption rates under paclitaxel treatment were restored by HK2 degraders treatment, and decreased downstream expression of the ABC and SLC transporters was shown in OCCC cells. Taken together, these findings highlight the paclitaxel resistance in OCCC elucidates metabolic alternation, including ABC- and SLC- drug transporters, thereby affecting glycolysis metabolism in response to paclitaxel resistance, and HK2 may become a novel potential therapeutic target for paclitaxel resistance.

There is a potential link between autoimmune diseases and Epstein-Barr virus (EBV) infections, with EBV playing a substantial role in the onset of Sjogren's syndrome (SjS). Some EBV proteins could mimic host self-antigens post-infection, leading to molecular mimicry. This similarity may cause the immune system to attack its tissues mistakenly. Among the various proteins associated with EBV, nuclear antigen 1 (EBNA-1) is essential for the latent replication of infected cells and is prevalent in all EBV-related diseases. In the study, single-chain variable fragment (scFv) antibodies targeting EBNA-1 were isolated using phage display technology from a primary SjS patient who also had a chronic active EBV infection. The specific clones were enriched after panning, and the binding activity of selected scFvs targeting EBNA-1 was confirmed. Sequence analysis indicated that the scFvs exhibiting positive signals could be grouped into five clones, all of which used homologous heavy chain V regions derived from germline Vh4-39, and two types of light chain V regions stemming from germline V lambda 1-44 and V lambda 3-15. These scFvs were found to exhibit a high degree of somatic mutations, likely indicative of antigen selection. Of the scFvs, P1-3 demonstrated the strongest binding affinity to EBNA-1, exhibiting a determined value of 7.3 x 10_8 M, and showed cross-reactivity to the SjS associated La/SSB self-antigen. The experimental results combined with AlphaFold 3 predictions revealed a potential epitope for scFv P1-3 binding to EBNA-1. Additionally, scFv P1-3 could also cross-bind to the modeled structure of La/SSB. We inferred a possible structural correlation between EBNA-1 and La/SSB involving an X2AX6PG epitope motif. This research contributes to our understanding of the structural basis of the interactions between antibodies and EBNA-1, shedding light on the VH and VL gene usage of anti-EBNA-1 antibodies in EBV-infected SjS patients and the potential origins of autoantibodies.

Transforaminal lumbar interbody fusion (TLIF) is a commonly used technique for treating lumbar degenerative diseases. In this study, we developed a fully computer-supported pipeline to predict both the cage height and the degree of lumbar lordosis subtraction from the pelvic incidence (PI-LL) after TLIF surgery, utilizing preoperative X-ray images. The automated pipeline comprised two primary stages. First, the pretrained BiLuNet deep learning model was employed to extract essential features from X-ray images. Subsequently, five machine learning algorithms were trained using a five-fold cross-validation technique on a dataset of 311 patients to identify the optimal models to predict interbody cage height and postoperative PI-LL. LASSO regression and support vector regression demonstrated superior performance in predicting interbody cage height and postoperative PI-LL, respectively. For cage height prediction, the root mean square error (RMSE) was calculated as 1.01, and the model achieved the highest accuracy at a height of 12 mm, with exact prediction achieved in 54.43% (43/79) of cases. In most of the remaining cases, the prediction error of the model was within 1 mm. Additionally, the model demonstrated satisfactory performance in predicting PI-LL, with an RMSE of 5.19 and an accuracy of 0.81 for PI-LL stratification. In conclusion, our results indicate that machine learning models can reliably predict interbody cage height and postoperative PI-LL.

AbstractControversies regarding the benefits of statin treatment on clinical outcomes in coronary artery spasm (CAS) without obstructive coronary artery disease (CAD) persist due to limited data. In this retrospective nationwide population‐based cohort study from the Taiwan National Health Insurance Research Database during the period 2000–2012, the matched cohorts consisted of 12,000 patients with CAS. After propensity score matching with 1:1 ratio, 2216 patients were eligible for outcome analysis in either statin or nonstatin group, with the mean follow‐up duration of 4.8 and 4.6 years, respectively. Statin users versus nonusers had a significantly reduced risk of major adverse cardiovascular events (MACEs) (6.7% vs. 9.5%, hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.55–0.84) and all‐cause mortality (6.0% vs. 7.6%; HR 0.77; 95% CI 0.61–0.96). While the results of MACEs were mainly contributed by cardiovascular death (1.9% vs. 3.2%; HR 0.56; 95% CI 0.38–0.83) and ischemic stroke (3.8% vs. 5.4%; subdistribution HR 0.69; 95% CI 0.52–0.91), they were primarily driven by reductions in ischemic but not hemorrhagic stroke. The benefit of statins was significantly pronounced in patients with hypertension and diabetes. Nevertheless, the effect on MACEs was consistent irrespective of age, sex, dyslipidemia, and mental disorder. Statins significantly reduced the risk of MACEs and all‐cause mortality in CAS patients. The benefit of statin therapy in reducing MACEs appeared to be linear, with greater risk reduction with higher doses and longer duration without upper threshold, reflecting the dose‐dependent relationship of statins with MACEs in CAS patients.