Introduction

Postoperative anxiety is common among patients undergoing major abdominal tumor surgery and is associated with adverse postoperative outcomes, including impaired wound healing, heightened pain perception, nausea, vomiting, and prolonged recovery.1,2 Recent studies indicate that up to 70% of surgical patients experience clinically relevant anxiety during the perioperative period.3 Despite this high burden, effective pharmacologic options remain limited.

Current perioperative treatment emphasizes nonpharmacologic interventions such as education and virtual reality–based preparation, which modestly reduce anxiety but show variable efficacy across trials.4–6 Agents such as dexmedetomidine and melatonin have emerging evidence for perioperative anxiolysis yet no standard therapy has been established for postoperative anxiety.7 Selective serotonin reuptake inhibitors (SSRIs) and serotonin–noradrenaline reuptake inhibitors (SNRIs) are established treatments for chronic anxiety disorders.8 However, their anxiolytic effects develop gradually, limiting the use for postoperative anxiety.9 Benzodiazepines provide rapid anxiolysis and are commonly used as preoperative medication, but the available evidence predominantly concerns preoperative rather than sustained postoperative anxiety.7 However, in the multicenter I-PROMOTE trial, preoperative oral midazolam did not improve global perioperative satisfaction or relieve anxiety in elderly surgical patients.10 Although individual studies have reported reduced early postoperative anxiety with perioperative midazolam, no pharmacological treatment has been established specifically for postoperative anxiety.11

Esketamine, the S-enantiomer of ketamine, has emerged as a promising candidate in this context. Unlike traditional anxiolytics, esketamine possesses a unique pharmacological profile: it is an N-methyl-D-aspartate (NMDA) receptor antagonist with potent anesthetic, analgesic, and rapid antidepressant effects.12 Unlike SSRIs and SNRIs, ketamine-related compounds can produce changes in mood and anxiety symptoms within hours. This rapid onset is potentially relevant to anxiety occurring during the early postoperative period.13,14 Moreover, intravenous administration can be readily incorporated into anesthetic management. In psychiatry, low-dose esketamine has demonstrated robust and rapid antidepressant activity in treatment-resistant depression, leading to its approval by the U.S. FDA in 2019.15–17 Notably, ketamine and esketamine can also produce acute anxiolytic effects. Small trials in refractory anxiety disorders have shown that subanesthetic ketamine infusions yield significant, albeit short-lived, reductions in anxiety symptoms.18 These observations suggest esketamine may simultaneously ameliorate both depression and anxiety, a particularly relevant dual-action in cancer patients.

Early evidence from postoperative settings is encouraging. In surgical patients, subanesthetic esketamine has been associated with improved mood and recovery metrics. For example, a randomized trial in thyroid cancer surgery found that a single intraoperative dose of esketamine (0.5mg kg−1) significantly reduced postoperative anxiety and depression scores compared to placebo.19 Similarly, in patients undergoing hysterectomy, prophylactic esketamine led to lower anxiety and acute stress reactions.20 While in elderly gastrointestinal tumor patients with preoperative anxiety, esketamine only provided short-term anxiety reduction.21 However, esketamine could not alleviate postoperative anxiety after gynecological surgery.22

Despite its high prevalence and impact on recovery, postoperative anxiety remains an undertreated issue in major abdominal tumor surgery. Given the inconsistent evidence and lack of data in major abdominal tumor surgery, we conducted this randomized clinical trial to evaluate the efficacy of esketamine in reducing postoperative anxiety among patients undergoing such procedures.

Materials and Methods

This prospective, double-blind, placebo-controlled study was approved by the Ethical Committee of Zhejiang Cancer Hospital (No. IRB-2024-327 on 8 April, 2024) and registered at ClinicalTrials.gov (NCT06530706 on 31 July, 2024) prior to the commencement of the study. This trial followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines. All participants signed a written informed consent form prior to the study. This study was conducted in accordance with the Declaration of Helsinki.

Participants and Setting

Eligible patients were aged 18 to 70 years, with an American Society of Anesthesiologists (ASA) physical status score of 1 to 3, scheduled for major abdominal tumor surgery including gynecological, colorectal, and gastric tumor surgeries. All patients were screened with Hamilton Anxiety Rating Scale (HAMA) questionnaire one day before the operation if they met the inclusion criteria and only those with a HAMA score > 7 were included. The HAMA is a widely used tool to measure the severity of anxiety symptoms. It consists of 14 items that assess both psychological and somatic aspects of anxiety. Higher scores indicate higher anxiety levels. The exclusion criteria were: (1) Serious mental illness before surgery or use of antipsychotic medications within two weeks before screening; (2) Severe organ dysfunction, such as heart failure (left ventricular ejection fraction < 30%), myocardial infarction, kidney failure (requiring kidney replacement therapy), liver function impairment (Child-Pugh grade C), etc; (3) Patients scheduled to receive general anesthesia combined with epidural anesthesia; (4) Patients unable to communicate, read or write due to visual, auditory, language or other reasons; (5) Allergy to esketamine; (6) Refusal to use a patient-controlled intravenous analgesia (PCIA) pump; (7) Refusal to participate in the study.

Randomization and Blinding

Patients were randomly assigned to either esketamine or placebo group in a 1:1 ratio. A random sequence of treatment allocation was generated before the commencement of the study using a computer-generated randomization program. This sequence was then concealed in opaque, sequentially numbered envelopes by a research assistant who was not involved in the study. An unblinded member of the study team was responsible for preparing the medicine and PCIA pump, while the anesthesiologists involved in patient management and follow-up, the surgeons and the patients were all blinded. Both esketamine and saline were prepared in identical 50-mL syringes.

Study Protocol

After informed consent was obtained, demographic information such as age, sex, weight, past medical history, and concomitant medications was collected. Additionally, information on work, education, marital status, sports habits, income, etc, was gathered. The Patient Health Questionnaire-8 scale (PHQ-8), Quality of Recovery-15 scale (QoR-15), and Athens Insomnia Scale (AIS) were also evaluated. Researchers who collected the questionnaires were trained to reduce bias.

All patients received transversus abdominis plane (TAP) nerve block with 40mL of 0.375% ropivacaine in the pre-anesthesia room. Whether to perform central venous puncture and radial artery puncture was decided by the anesthesiologist based on the surgical procedure. In the operation room, patients were monitored with a three-lead electrocardiogram, pulse oximetry and invasive/non-invasive blood pressure. After preoxygenation, sufentanil 0.3–0.5 μg kg−1, propofol 1.5–2 mg kg−1, and rocuronium 0.9 mg kg−1 were administered to facilitate endotracheal intubation. Anesthesia was maintained with 2–3% sevoflurane in 50% oxygen at a flow rate of 2 L min−1 and remifentanil 0.1–0.2 μg kg−1 min−1, with the minimum alveolar concentration (MAC) value kept at 0.6–0.9 by adjusting inhaled sevoflurane concentration. The esketamine group received an intravenous injection of esketamine (Jiangsu Hengrui Pharmaceutical Co., Ltd). 0.2 mg kg−1 slowly before surgical incision and then a continuous infusion of 0.1 mg kg−1 h−1 until the end of the operation, while the placebo group received an equivalent volume of saline. All patients received standardized hemodynamic monitoring. Hypotension was managed at the discretion of the attending anesthesiologist, with interventions including fluid resuscitation and vasopressor therapy as clinically indicated. Hypertension was treated by deepening anesthesia or with antihypertensive medications. Intraoperative fluid administration was guided by the attending anesthesiologist based on hemodynamic parameters including blood pressure, heart rate, estimated blood loss, and urine output. Dexamethasone 5 mg, haloperidol 1.25 mg, and ondansetron 8 mg were administered to prevent postoperative nausea and vomiting. The use of dexmedetomidine and midazolam was prohibited. To prevent postoperative pain, parecoxib sodium 40 mg and sufentanil 5–10 μg were given at the end of surgery. PCIA was commenced in the operating room upon completion of surgery. Thereafter sugammadex was administered to reverse neuromuscular blockade, and then the tracheal tube was pulled out after adequate muscle strength was established. After transfer to the post-anesthesia care unit (PACU), pain was assessed using the numeric rating scale (NRS). Intravenous rescue analgesia (sufentanil, oxycodone, or acetaminophen) was administered at the physician’s discretion when the NRS score exceeded 3.

Postoperative Analgesia Management and Follow-up

Patients received PCIA within 72 hours after surgery. In the PCIA device, sufentanil 3 μg kg−1 (max 200 μg) combined with esketamine 1 mg kg−1 (esketamine group) or sufentanil only 3 μg kg−1 (max 200 μg, placebo group) was diluted with normal saline to a final volume of 150 mL: background infusion 2 mL h−1, bolus 2 mL, lock time 10 mins.

On the 1st, 2nd, and 3rd postoperative days (POD), a follow-up and education on the use of the PCIA pump were conducted by an anesthesiologist who was blinded to the patient grouping. Patients’ pain was assessed using the NRS, and the presence of nausea and vomiting was recorded. The AIS was also evaluated daily from POD1 to POD3. On POD3, additional assessments included HAMA, QoR-15, and PHQ-8 were collected. On POD30, patients were followed up via WeChat video call, during which HAMA, QoR-15, PHQ-8, and AIS were reassessed.

Primary Outcome and Secondary Outcomes

The primary outcome was the response rate on POD3, defined as a ≥50% reduction from the baseline HAMA score.23,24 Secondary outcomes included anxiety status on POD3 and POD30; sleep quality, assessed by the AIS on POD1, POD2, POD3, and POD30; quality of recovery and depression, evaluated using the QoR-15 and PHQ-8 on POD3 and POD30.

Sample Size Calculation

The extent to which esketamine can effectively alleviate anxiety symptoms in surgical patients remained uncertain. The clinically meaningful beneficial effect of esketamine on the anxious symptoms of patients undergoing surgery was unclear. The minimum clinically important difference was supposed to be at least 20%. Therefore, we assumed that the response rate would be 41% on POD3 in the esketamine group and 21% for the placebo group based on our pilot study. The sample size was calculated using the Z-Test with pooled variance for two proportions, with PASS® version 15.0 (NCSS, LLC, Kaysville, UT, USA). A total of 83 patients in each group would provide 80% power with an alpha error of 0.05. To compensate for possible dropouts, the sample size was increased to 180 subjects (90 per group).

Statistical Analysis

All statistical analyses were performed using R software (version 4.2.3). Continuous variables were tested for normality using the Shapiro–Wilk test and described as mean (standard deviation [SD]) or median (interquartile range [IQR]), as appropriate. Categorical variables were summarized as counts and percentages. Between-group comparisons at baseline were conducted using the independent samples t test or Mann–Whitney U-test for continuous variables, and the χ2 or Fisher’s exact test for categorical variables.

For continuous outcomes, between-group differences were evaluated using the Mann–Whitney U-test. Effect sizes were expressed as the adjusted mean difference with corresponding 95% confidence intervals (CIs), estimated by the ANCOVA method. For binary outcomes, relative risks (RR) and 95% CIs were calculated using the Wald method.

For risk-factor modelling of response rate on POD3, logistic regression analyses were performed. Candidate covariates were first screened in univariable models. Variables with P < 0.20 were included in the multivariable model. Final variable selection for the multivariable logistic regression model was performed using a stepwise approach based on the Akaike Information Criterion (AIC). Results are reported as odds ratio (OR) with 95% CIs.

Subgroup analyses were performed by fitting logistic models including an interaction term between treatment group and each subgroup variable. Treatment effects were estimated within each subgroup, and P values for interaction tested whether the esketamine effect differed significantly across subgroups. All statistical tests were two-sided, and a P value < 0.05 was considered statistically significant.

Results Participant Characteristics

Among 4751 patients assessed for eligibility, 180 were randomized to receive either esketamine (n = 90) or placebo (n = 90) from 5 Aug, 2024 to 30 Jun, 2025. The primary analysis included 86 participants in the esketamine group and 87 in the placebo group who had available data for the primary endpoint (Figure 1).

Figure 1 Flow diagram of the study.

Baseline characteristics including sex, age, body mass index, and receipt of neoadjuvant therapies were similar between groups (Table 1). Most participants were women and younger than 60 years. No significant differences were observed in preoperative symptom scales including HAMA, QoR-15, PHQ-8 and AIS scores.

Table 1 Baseline Data of Participants

Intraoperative Data

Blood pressure at intubation was similar between groups except for the heart rate, which was higher in the esketamine group (Table 2). Cumulative inhaled anesthetic exposure was comparable in the esketamine and placebo groups (median [IQR] MAC × hours, 2 [2, 3] in both groups). Participants in the esketamine group received more intraoperative IV fluids (median [IQR], 2,000 [1,500, 2,688] vs 1,500 [1,000, 2,125], P = 0.02). NRS score after extubation was low in both groups (median [IQR], 0 [0–2] in both groups, P = 0.80). Remifentanil use showed similar tendency (median [IQR], 1,152 [796–1,686] vs 1,100 [761–1,520] μg, P = 0.71). Rescue analgesia in PACU was administered to 29 of 86 participants (33.7%) in the esketamine group and 21 of 87 (24.1%) in the placebo group, and there was no statistically significant difference between groups.

Table 2 Intraoperative Data

Efficacy Outcomes

For the primary outcome, treatment response rate on POD3 did not differ between groups (34 [39.5%] vs 37 [42.5%]; RR, 0.93; 95% CI, 0.65 to 1.33; P = 0.81). For the secondary outcomes, HAMA scores were similar in the esketamine and placebo groups on POD3 (median [IQR], 6 [3–10] vs 7 [4–11]; adjusted mean difference, 0; 95% CI, −2 to 1; P = 0.59) and POD30 (median [IQR], 5 [3–8] vs 7 [4–11]; adjusted mean difference, −1; 95% CI, −3 to 1; P = 0.28) (Table 3).

Table 3 Efficacy Outcomes

AIS scores were comparable on POD1–3 but were lower in the esketamine group on POD30, with no statistically significant difference (median [IQR], 6 [4–9] vs 8 [5–11]; adjusted mean difference, −1; 95% CI, −2 to 0; P = 0.052). QoR-15 scores were not different on POD3 (median [IQR], 127 [109–134] vs 130 [115–140]; adjusted mean difference, −2; 95% CI, −7 to 4; P = 0.54) or POD30 (median [IQR], 134 [118–140] vs 128 [115–139]; adjusted mean difference, 4; 95% CI, −2 to 10; P = 0.22). PHQ-8 scores were similar at POD3 (median [IQR], 5 [3–8] in both groups) and modestly lower in the esketamine group on POD30 (median [IQR], 5 [2–8] vs 6 [3–10]; adjusted mean difference, −2; 95% CI, −3 to −1; P = 0.001).

Clinical remission of anxiety (HAMA ≤ 7) did not differ between groups on POD3 (61.6% vs 58.6%; RR, 1.05; 95% CI, 0.82 to 1.34; P = 0.80) but was more frequent with esketamine by POD30 (71.4% vs 51.8%; RR, 1.38; 95% CI, 1.08 to 1.76; P = 0.01) (Table 3). NRS pain scores were low in both groups throughout the postoperative period. Adjusted mean difference of NRS scores at rest and at cough were 0 on POD1–3.

In the multivariate logistic regression analysis, > 9 years of education is associated with treatment response rate (adjusted OR, 2.17; 95% CI,1.07 to 4.38; P = 0.03) (Figure 2). Esketamine use was not independently associated with treatment response rate on POD3 (adjusted OR, 0.97; 95% CI, 0.48 to 1.94; P = 0.93).

Figure 2 Multivariable logistic regression identifying factors associated with HAMA response rate on POD3.

Abbreviations: CI, Confidence Interval; NACT, Neoadjuvant Chemotherapy; OR, Odds Ratio; PHQ-8, Patient Health Questionnaire-8.

Exploratory subgroup analysis was done to determine possible patient groups that could benefit from esketamine administration (Figure 3). Esketamine was found to be less effective in patients older than 60 (OR, 0.05; 95% CI, 0.00 to 0.55; P for interaction = 0.01) and retired patients (OR, 0.08; 95% CI, 0.01 to 0.50; P for interaction = 0.01). Esketamine was more beneficial for patients undergoing laparoscopy than in open surgery (OR, 1.78; 95% CI, 0.75 to 4.23; P for interaction = 0.03).

Figure 3 Subgroup analysis of the effect of esketamine on HAMA response on POD3.

Abbreviations: HAMA, Hamilton Anxiety Rating Scale; NACT, Neoadjuvant Chemotherapy; OR, Odds Ratio; POD, Postoperative Day.

Adverse Events

Intraoperative hypotension and vasopressor use were similar between groups (Table 4). Hypertension occurred in 16.5% (13 of 79) of participants in the esketamine group and 7.3% (6 of 82) in the placebo group (RR, 2.25; 95% CI, 0.90 to 5.62). Antihypertensive therapy was used more frequently in the esketamine group (12.8% [11 of 86] vs 3.4% [3 of 87]; RR, 3.71; 95% CI, 1.07 to 12.84). Postoperative nausea and vomiting rates were comparable between groups. No serious adverse events were reported in either group.

Table 4 Adverse Events

Discussion

In this randomized clinical trial, esketamine use did not significantly improve treatment response on POD3. The proportion of participants achieving anxiety remission (HAMA ≤ 7) was higher in the esketamine group on POD30. Overall, the data did not support an early anxiolytic benefit after major abdominal tumor surgery. While the primary endpoint was negative, we observed that the esketamine group was associated with lower PHQ-8 scores at POD30, which may suggest that esketamine could alleviate postoperative depression. This finding warrants further investigation.

Perioperative anxiety is linked to sympathetic activation, stress-hormone release, and worse surgery recovery.1,25–28 In oncologic and major abdominal surgery cohorts, preoperative anxiety is consistently associated with more postoperative pain, poorer sleep and longer hospital stay.29–31 To our knowledge, this is among the first trials to target postoperative anxiety as a primary outcome in abdominal tumor surgery. While pharmacologic and psychological interventions can reduce preoperative anxiety, sustained postoperative benefit has rarely been demonstrated.32,33 Unlike many previous perioperative studies in which anxiety was evaluated as a secondary outcome, this trial used the POD3 HAMA response rate as the primary outcome. The negative primary finding helps define the limits of the short-term anxiolytic effect of this perioperative esketamine regimen.

Our findings did not demonstrate an acute anxiolytic effect of esketamine, a finding that aligns with recent trials showing modest or delayed benefits of this agent. Several studies have demonstrated that esketamine lacks sustained efficacy for postoperative anxiety and depression during postoperative period. Esketamine reduced anxiety on POD1 but not from POD2 to POD7 in elderly gastrointestinal tumor patients with preoperative anxiety.21 Similarly, esketamine relieved depressive symptoms in patients undergoing abdominal tumor resection on POD1 but not POD3.34 In patients undergoing non-cardiac thoracic surgery, high-dose esketamine reduced postoperative anxiety and depression on POD1 and POD3, while no significant differences were observed in the low-dose esketamine group.12 By contrast, a meta-analysis further confirmed that while esketamine shows promise for reducing anxiety,35 and the effectiveness may depend on individual patient profiles and surgical settings. Another study reported relief of depression and anxiety on POD7 following cardiac valve surgery.36 A noteworthy ICU trial investigating the long-term mood effects of ketamine sedation: post-cardiac surgery patients exhibited significantly reduced anxiety and depression scores at 2 weeks and even 6 months after ICU discharge.37 These discrepancies likely reflect heterogeneity in dosing, timing, baseline psychiatric status and the specific surgical populations evaluated across these studies.

With respect to secondary outcomes, we assessed depressive symptoms (PHQ-8) and quality of recovery (QoR-15). Prior trials have reported mixed results with some demonstrating early postoperative depression reduction,25,36,38 while some found no benefit at POD3.34 PHQ-8 scores were similar at POD3 and lower at POD30 in the esketamine group. A change of 2 to 3 points was considered minimally clinical important difference for PHQ-8,39,40 but the difference was 2 points in the present study, so the effect was limited. As esketamine was not primarily used as an antidepressant, its effect on long-term depressive symptoms needs further verification. QoR-15 did not differ at either time point, which was consistent with the previous study.41 Although several studies found esketamine was associated with reduced postoperative insomnia,12,42 the AIS score was not different between the two groups in the present study, which might be explained by the limited power to detect small differences.

Postoperative anxiety is multifactorial and may arise from the interaction of psychological vulnerability with surgical stress, pain, sleep disturbance, inflammation, and autonomic activation. Esketamine is a noncompetitive NMDA receptor antagonist.12 At subanesthetic doses, blockade of NMDA receptors on γ-aminobutyric acid–mediated inhibitory interneurons has been proposed to transiently disinhibit glutamate release and enhance postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signaling. AMPA receptor activation may promote the synthesis and release of brain-derived neurotrophic factor (BDNF), followed by activation of tropomyosin receptor kinase B (TrkB) and mTORC pathways that support synaptic protein synthesis and neuroplasticity. These pathways have been implicated primarily in the rapid and sustained antidepressant effects of ketamine and esketamine, but their contribution to postoperative anxiety remains uncertain.43–46

Esketamine may also influence postoperative emotional symptoms indirectly through analgesia and modulation of perioperative stress responses. Previous perioperative studies have reported increases in peripheral BDNF, 5-hydroxytryptamine, and dopamine concentrations occurring concurrently with short-term improvements in mood symptoms.36,47,48 However, these associations do not establish that changes in these biomarkers mediate the clinical effect. The POD30 improvements on depression symptoms warrant confirmation in the future mechanistic studies.

Even the incidence of hypertension was comparable between the two groups, antihypertensive therapy was used more frequently in the esketamine group, primarily due to its central sympathetic activation. These hemodynamic changes are usually mild to moderate and generally well-tolerated in patients without severe cardiovascular comorbidities.

In the exploratory multivariable analysis, more than 9 years of education was associated with higher odds of achieving the POD3 anxiety response. Education may reflect differences in health literacy, understanding of perioperative information, and communication with healthcare professionals. Previous studies have suggested that perioperative education and counseling may influence anxiety outcomes.49 Exploratory subgroup analyses also suggested potential heterogeneity of treatment effect according to age, retirement status, and surgical approach. Age and retirement status are closely related and may represent overlapping patient characteristics. Laparoscopic and open procedures differ in surgical stress, postoperative pain, and recovery. Nevertheless, these analyses involved small subgroups and therefore require further validation. For its established anesthetic and analgesic indications, esketamine may still be used according to patient characteristics and local clinical practice, with appropriate monitoring for hemodynamic and psychotomimetic adverse effects.

The study has several limitations. First, the 30-day follow-up was conducted via WeChat video rather than face-to-face, which may introduce bias. Face-to-face follow-up is quite challenging as many patients may drop out. Therefore, we chose to use WeChat video for follow-up. Although all data collectors received training on the scales to minimize bias, the scales are subjective, so some degree of bias may still exist. Second, no blood samples were collected during the surgery. Therefore, no neurotrophic, neurotransmitter and inflammatory biomarkers were measured. Consequently, the study cannot determine the mechanisms underlying the potential effect of esketamine on postoperative anxiety and depression. Third, the observed response rates (42.5% in the placebo group) deviated substantially from our pilot-based assumptions (21%). Post-hoc sensitivity analysis indicates that to detect a 20% absolute difference (62.5% vs 42.5%) from the observed placebo response rate of 42.5%, 94 patients per group would be required to achieve 80% power with an alpha error of 0.05. Our enrolled sample of 90 patients per group provides approximately 78.5% power for this effect size. Thus, the sample size was not the primary limitation; rather, the absence of a clinically meaningful treatment effect (observed −3% vs hypothesized +20%) precluded statistical significance. Finally, this was a single-center study involving a predominantly female population, largely because gynecological procedures constituted the majority of included surgeries. The inclusion of gynecological, colorectal, and gastric procedures also introduced clinical heterogeneity in anatomical site, surgical extent, operative duration, and perioperative management. These factors, together with the follow-up period of only 30 days, limit the generalizability of the findings. Larger multicenter studies involving more diverse surgical populations are needed to validate these findings.

Conclusion

In summary, esketamine did not reduce anxiety in patients with preoperative anxiety undergoing major abdominal tumor surgery on POD3 and POD30. These findings should be confirmed by larger multicenter trials. The secondary outcome showed that the esketamine group might be associated with lower depressive symptoms at POD30, but this finding warrants further investigation in adequately powered studies.

Data Sharing Statement

Data will be available from the corresponding author (from Dr. Wen Zhang) upon reasonable request.

Acknowledgments

The authors thank the staff of the Department of Anesthesiology, Department of Gastric Surgery, Department of Colorectal Surgery, and Department of Gynecologic Oncology, Zhejiang Cancer Hospital, China, for their help and cooperation in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by grant LTGD24H090004 from Zhejiang Provincial Basic Public Welfare Research Program (Dr. Wen Zhang) and grant 2025SZRJJ2248 from Hangzhou Natural Science Foundation (Dr. Pingbo Xu).

Disclosure

The authors report no conflicts of interest in this work.

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