Topoisomerase Inhibitors and PIM1 Kinase Inhibitors Improve Gene Editing Efficiency Mediated by CRISPR-Cas9 and Homology-Directed Repair.

The CRISPR-Cas9 system has emerged as the most prevalent gene editing technology due to its simplicity, high efficiency, and low cost. However, the homology-directed repair (HDR)-mediated gene knock-in in this system suffers from low efficiency, which limits its application in animal model preparation, gene therapy, and agricultural genetic improvement. Here, we report the design and optimization of a simple and efficient reporter-based assay to visualize and quantify HDR efficiency. Through random screening of a small molecule compound library, two groups of compounds, including the topoisomerase inhibitors and PIM1 kinase inhibitors, have been identified to promote HDR. Two representative compounds, etoposide and quercetagetin, also significantly enhance the efficiency of CRISPR-Cas9 and HDR-mediated gene knock-in in mouse embryos. Our study not only provides an assay to screen compounds that may facilitate HDR but also identifies useful tool compounds to facilitate the construction of genetically modified animal models with the CRISPR-Cas9 system.

A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency.

Small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonists are recognized as promising therapeutics for type 2 diabetes mellitus (T2DM) and obesity. Danuglipron, an investigational small-molecule agonist, has demonstrated high efficacy in clinical trials. However, further development of danuglipron is challenged by a high rate of gastrointestinal adverse events. While these effects may be target-related, it is plausible that the carboxylic acid group present in danuglipron may also play a role in these outcomes by affecting the pharmacokinetic properties and dosing regimen of danuglipron, as well as by exerting direct gastrointestinal irritation. Therefore, this study aims to replace the problematic carboxylic acid group by exploring the internal binding cavity of danuglipron bound to GLP-1R using a water molecule displacement strategy. A series of novel triazole-containing compounds have been designed and synthesized during the structure-activity relationship (SAR) study. These efforts resulted in the discovery of compound 2j with high potency (EC50 = 0.065 nM). Moreover, docking simulations revealed that compound 2j directly interacts with the residue Glu387 within the internal cavity of GLP-1R, effectively displacing the structural water previously bound to Glu387. Subsequent in vitro and in vivo experiments demonstrated that compound 2j had comparable efficacy to danuglipron in enhancing insulin secretion and improving glycemic control. Collectively, this study offers a practicable approach for the discovery of novel small-molecule GLP-1R agonists based on danuglipron, and compound 2j may serve as a lead compound to further exploit the unoccupied internal cavity of danuglipron's binding pocket.

Exploring Symptom Clusters in Chinese Patients with Diabetic Kidney Disease: A Network Analysis.

Purpose: The research on symptom management in patients with diabetic kidney disease (DKD) has shifted from separate symptoms to symptom clusters and networks recently. This study aimed to evaluate the unpleasant symptoms of DKD patients, and to investigate how these symptom clusters could affect patients. Methods: 408 DKD patients were recruited in this cross-sectional study. The symptoms of DKD patients were measured using the modified Dialysis Symptom Index. Network analysis was employed to evaluate the symptom network and the characteristics of individual nodes, while factor analysis was utilized to identify symptom clusters. Results: Blurred vision was the most prevalent symptom among DKD patients. The symptoms identified as the most distressing, severe, and frequent were light headache or dizziness, arteriovenous fistula/catheterization pain, and diarrhea, respectively. Five symptom clusters were obtained from factor analysis, and the most central symptom cluster in the entire symptom network was sexual dysfunction. Conclusion: This study identified five symptom clusters in Chinese DKD patients, with sexual dysfunction emerging as the most central cluster. These findings carry significant clinical implications, underscoring the necessity of assessing symptom clusters and their associations to enhance symptom management in DKD patients. Further research is essential to elucidate the underlying mechanisms of symptoms and to clarify the associations among symptoms in DKD patients across different disease trajectories or treatment modalities.

Engineered E. coli for D-pantothenic acid production with an acetolactate isomeroreductase mutant.

D-Pantothenic acid, as a momentous vitamin, is extensively applied to feed, medicine, cosmetics and other fields. However, there are still limitations to produce D-pantothenic acid by microbial fermentation at present. In this paper, we constructed a recombinant strain for D-pantothenic acid production by blocking the organic acid pathway, boosting pyruvate biosynthesis, relieving feedback inhibition of acetolactate synthase, improving glucose intake capacity, and modifying essential genes in the metabolic pathway. In addition, a new acetolactate isomeroreductase mutant V412A origin from Escherichia coli (EcAHAIR) encoded by ilvC was obtained to explore its substrate promiscuity. Compared with the wild type, the variant EcAHAIR-V412A has reduced steric hindrance and enhanced intermolecular forces, resulting in a high affinity for 2-acetolactate. Eventually, the fermentation production of the final strain DPAN19/trc-ilvCV412A reached 4.65 g/L, increased by 192.5% compared with strain DPA8 in shake flask cultivation and produced 62.82 g/L D-pantothenic acid in a 5 L bioreactor. The metabolic engineering strategies and enzyme modification approaches described in this paper provide a particular perspective for the bio-manufacturing of D-pantothenic acid, branched-chain amino acids and its derivates.

Synchronous Papillary Thyroid Cancer and Asymptomatic Cervical Lymph Node Sarcoidosis: A Case Report.

Sarcoidosis is a systemic inflammatory disease characterized by the formation of immune granulomas in multiple organs. The cause of this disease is not yet clear. Papillary thyroid cancer (PTC) is the most common malignant endocrine tumor and is often associated with cervical lymph node metastasis. Assessment of risk factors associated with a poor prognosis is crucial in PTC. The coexistence of sarcoidosis and thyroid cancer is rarely reported in the literature. We describe a case of a 54-year-old female diagnosed with PTC and asymptomatic cervical and thoracic hilar lymphadenopathy due to concurrent sarcoidosis. This case will remind clinicians to be aware of the multiple potential causes of lymphadenopathy and realize the importance of the differences in the features of neck lymphadenopathy in patients with suspected head and neck cancer. Overall, careful workup and pretreatment screening enabled us to provide the patient with the most suitable treatment modality and avoid total thyroidectomy.

Characterization of the novel HLA-DRB1*16:76 allele in a Chinese individual.

The HLA-DRB1*16:76 allele differs from HLA-DRB1*16:02:01 by one nucleotide substitution (A > G) at position 37 in exon 1.

Population pharmacokinetics and dose optimization of levofloxacin in elderly patients with pneumonia.

AIMS: Levofloxacin is a quinolone antibiotic with a broad antibacterial spectrum. It is frequently used in elderly patients with pneumonia. The pharmacokinetic profile of elderly patients changes with age, but data on the pharmacokinetics of levofloxacin in these patients are limited. The aim of this study was to establish a population pharmacokinetic model of levofloxacin in elderly patients with pneumonia and to optimize individualized dosing regimens based on this newly developed model. METHODS: This is a prospective, open-label pharmacokinetic study in elderly patients with pneumonia. Blood samples were collected using an opportunistic approach. The plasma concentrations of levofloxacin were determined by high-performance liquid chromatography. A population pharmacokinetic model was established using nonlinear mixed-effect model software. Monte Carlo simulations were used for dose simulation and dose optimization. RESULTS: Data from 51 elderly patients with pneumonia were used for the population pharmacokinetic analysis. A one-compartment model with first-order elimination was most suitable for describing the data, and the estimated glomerular filtration rate was the only covariate that had a significant impact on the model. The final model estimated that the mean clearance of levofloxacin in elderly patients with pneumonia was 5.26 L/h. Monte Carlo simulation results showed that the optimal dosing regimen for levofloxacin was 750 mg once a day in elderly patients with pneumonia, with a minimum inhibitory concentration of 2 mg/L. CONCLUSIONS: The population pharmacokinetic model of levofloxacin in elderly patients with pneumonia was established, and the dose optimization of levofloxacin was completed through Monte Carlo simulation.

Discovery of betulinic acid derivatives as gut-restricted TGR5 agonists: Balancing the potency and physicochemical properties.

The pleiotropic effects of TGR5 make it an appealing target for intervention of metabolic and inflammatory disorders, but systemic activation of TGR5 faces challenges of on-target side effects, especially gallbladder filling. Gut-restricted agonists were proved to be sufficient to circumvent these side effects, but extremely low systemic exposure may not be effective in activating TGR5 since it is located on the basolateral membrane. Herein, to balance potency and physicochemical properties, a series of gut-restricted TGR5 agonists with diversified kinetophores had been designed and synthesized. Compound 22-Na exhibited significant antidiabetic effect, and showed favorable gallbladder safety after 7 days of oral administration in humanized TGR5H88Y mice, confirming that gut-restricted agonism of TGR5 is a viable strategy to alleviate systemic target-related effects.

The impact of pretransplant suspected HLA antibody on the long-term outcome of the graft kidney: A retrospective cohort study.

INTRODUCTION: The preoperative examination of kidney transplantation includes HLA antibody screening to initially determine the presence of preexisting donor-specific antibody (DSA) that mediates hyperacute rejection. Recipients with positive HLA antibodies require further HLA specificity analysis to type the antigen and determine the antigen mismatches between the donor and recipient. However, recipients with suspected antibodies would have no further HLA specificity analysis. It is unclear whether suspected HLA antibodies would affect renal graft function. This study aimed to explore the impact of pretransplant suspected HLA antibody on the long-term outcome of the graft kidney and thus determine the necessity of routinely performing the HLA specificity analysis in recipients with suspected HLA antibodies preoperatively. METHODS: This is a single-center retrospective cohort study. 179 kidney transplant recipients (KTRs) were included and further divided into HLA antibody-negative group (Group 1) and HLA antibody-suspected groups (Group 2) based on the result of the pretransplant HLA antibody screen test. And the antibody-suspected group was further divided into a low-mismatched group (Group A) and a high-mismatched group (Group B) according to the HLA specificity analysis. We tracked the renal function indexes, biochemical indexes, and posttransplant adverse events within 5 years after transplantation and explored the necessity of further HLA specificity analysis in recipients with pretransplant suspected HLA antibodies. RESULTS: There was no statistically significant difference in demographics between HLA antibody-negative group and HLA antibody-suspected groups. At 5 years of follow-up, the KTRs in HLA antibody-negative group had significantly higher eGFR levels, lower serum creatinine levels, and less urinary protein compared to those in antibody-suspected group. Meanwhile, the KTRs in low-mismatched group also had significantly higher eGFR levels, lower serum creatinine levels, and less proteinuria compared to those in high-mismatched group. Correlation analysis showed that the age of KTRs, urinary protein levels and the load capacity of HLA mismatches were associated with eGFR levels of KTRs at 5 year posttransplant. CONCLUSION: KTRs with suspected HLA antibodies before kidney transplantation have worse graft function than the preoperative HLA antibody-negative recipients in the long-term posttransplant follow-up. The specific load capacity of HLA mismatches, the age of the recipient and the urinary protein was found to be negatively correlated with long-term posttransplant renal outcomes. It is necessary to undergo further HLA specificity analysis for recipients with suspected HLA antibodies in HLA antibody screen test to explicit HLA mismatches and improve long-term posttransplant outcomes.

Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones.

The shortage of cholesterol gallstones treatment intensifies the need to discover of effective small molecule drugs. Clinical follow-up and studies have found that activation of somatostatin receptor subtype 5 (SSTR5) reduce gallbladder contraction and thus increase the risk of cholesterol gallstones, implying that antagonizing SSTR5 may promote gallbladder emptying and reduce the formation of gallstones. Herein, we discovered novel SSTR5 antagonists and firstly investigated its effects on cholesterol gallstone. From loperamide, a reported seed structure with micromole activity, we identified optimal compound 23 as an SSTR5 antagonist exhibiting single-digit nanomolar potency, low hERG inhibition and oral availability. Further in vivo evaluation revealed that 23 significantly promoted gallbladder emptying. Moreover, in a mouse cholesterol gallstone model, 23 (3 mg/kg) effectively reduced the cholesterol gallstones formation, showing better efficacy than the clinical first-line drug UDCA (60 mg/kg), providing a new insight into the development of anti-gallstone drugs.

Molecular mechanism of sex pheromone perception in male Mythimna loreyi revealed by in vitro system.

BACKGROUND: Mythimna loreyi is an important agricultural pest with a sensitive sex pheromone communication system. To clarify the pheromone binding proteins (PBPs) and pheromone receptors (PRs) involved in sex pheromone perception is important for both understanding the molecular olfactory mechanism and developing a new pest control strategy in M. loreyi. RESULTS: First, the electroantennogram (EAG) assay showed that male M. loreyi displayed the highest response to the major sex pheromone component Z9-14:Ac, and higher responses to two minor components, Z7-12:Ac and Z11-16:Ac. Second, the fluorescence competition binding assay showed that PBP1 bound all three pheromones and other tested compounds with high or moderate affinity, while PBP2 and PBP3 each bound only one pheromone component and few other compounds. Third, functional study using the Xenopus oocyte system demonstrated that, of the six candidate PRs, PR2 was weakly sensitive to the major pheromone Z9-14:Ac, but was strongly sensitive to pheromone analog Z9-14:OH; PR3 was strongly and specifically sensitive to a minor component Z7-12:Ac; PR4 and OR33 were both weakly sensitive to another minor component, Z11-16:Ac. Finally, phylogenetic relationship and ligand profiles of PRs were compared among six species from two closely related genera Mythimna and Spodoptera, suggesting functional shifts of M. loreyi PRs toward Spodoptera PRs. CONCLUSION: Functional differentiations were revealed among three PBPs and six PRs in sex pheromone perception, laying an important basis for understanding the molecular mechanism of sex pheromone perception and for developing new control strategies in M. loreyi. © 2023 Society of Chemical Industry.

Ionotropic Receptor IR75q.2 Mediates Avoidance Reaction to Nonanoic Acid in the Fall Armyworm Spodoptera frugiperda (Lepidoptera, Noctuidae).

Ionotropic receptors (IRs) play an important role in olfaction, but little is known in nondrosophila insects. Here, we report in vitro and in vivo functional characterization of IR75q.2 in the invasive moth pest Spodoptera frugiperda. First, 13 IRs (including four coreceptor IRs) were found specifically or highly expressed in adult antennae. Second, these IRs were tested for responding profiles to 59 odorants using the Xenopus oocyte expression system, showing that only SfruIR75q.2 responded to 8-10C fatty acids and their corresponding aldehydes, with SfruIR8a as the only coreceptor. Third, the three acids (especially nonanoic acid) showed repellent effects on moth's behavior and oviposition, but the repellence significantly reduced to the insects with IR75q.2 knockout by CRISPR/Cas9. Taken together, our study reveals the function of SfruIR75q.2 in perception of acid and aldehyde odorants and provides the first in vivo evidence for olfactory function of an odor-specific IR in Lepidoptera.

Stretchable, Adhesive, and Biocompatible Hydrogel Based on Iron-Dopamine Complexes.

Hydrogels' exceptional mechanical strength and skin-adhesion characteristics offer significant advantages for various applications, particularly in the fields of tissue adhesion and wearable sensors. Herein, we incorporated a combination of metal-coordination and hydrogen-bonding forces in the design of stretchable and adhesive hydrogels. We synthesized four hydrogels, namely PAID-0, PAID-1, PAID-2, and PAID-3, consisting of acrylamide (AAM), N,N'-methylene-bis-acrylamide (MBA), and methacrylic-modified dopamine (DA). The impact of different ratios of iron (III) ions to DA on each hydrogel's performance was investigated. Our results demonstrate that the incorporation of iron-dopamine complexes significantly enhances the mechanical strength of the hydrogel. Interestingly, as the DA content increased, we observed a continuous and substantial improvement in both the stretchability and skin adhesiveness of the hydrogel. Among the hydrogels tested, PAID-3, which exhibited optimal mechanical properties, was selected for adhesion testing on various materials. Impressively, PAID-3 demonstrated excellent adhesion to diverse materials and, combined with the low cytotoxicity of PAID hydrogel, holds great promise as an innovative option for biomedical engineering applications.

The Dissolution Behavior of Feldspar Minerals in Various Low-Molecular-Weight Organic Acids.

Feldspar is a high-abundance mineral in the earth's crust, and its natural weathering and dissolution processes are an important phenomenon on the earth's surface. This study focused on the dissolution behavior of silicon (Si) and aluminum (Al) in feldspar minerals (microcline and albite) when exposed to low-molecular-weight organic acids (LMWOAs). Various analytical techniques, including atomic absorption spectrophotometer, X-ray diffraction, scanning electron microscope, and Fourier-transform infrared spectroscopy, were employed to investigate these processes. The results revealed that the concentration of Si and Al released from alkali feldspar increased after treatment with LMWOAs, exhibiting non-stoichiometric dissolution. The Si/Al release ratio from feldspar deviated from the expected value of three. Among the LMWOAs tested, oxalic acid was found to be more effective in dissolving aluminum, while citric acid showed greater efficacy in dissolving silicon. Notably, the composite acid demonstrated the highest capacity for feldspar dissolution, with values of 538 µM (Si) and 287 µM (Al) after treatment for 720 h, respectively. The dissolution data for Si and Al in the organic acid solution was fittingly described by a first-order equation, with high correlation coefficients (R2 ≥ 0.992). The characterization of feldspar powders indicated that the (040) crystal plane of feldspar was particularly susceptible to attack by organic acids. In the presence of these acids, the chemical bonds Si (Al)-O, Si-Si(Al), and O-Si(Al)-O shifted to higher wavenumbers. Additionally, the surface corrosion morphology of feldspar exhibited distinct nanostructures, which became more pronounced with increasing exposure time. It was also observed that the reactivity of feldspar increased over time. These findings provide valuable insights into the natural dissolution process of feldspar and offer a new perspective for the study of this phenomenon.

Efficacy and safety of self-administered acupressure on symptoms, quality of life and nasal mucosal function in patients with perennial allergic rhinitis: study protocol for a randomized controlled exploratory trial.

INTRODUCTION: Allergic rhinitis is a global health problem that can potentially be managed through acupressure. Our clinical observations have identified Allergic Rhinitis Acupressure Therapeutic (ARAT) as a novel acupressure treatment acting on specific acupoints, which may enhance the effectiveness of acupressure. Therefore, we propose a three-arm randomized controlled trial will be conducted to investigate the efficacy and safety of ARAT for perennial allergic rhinitis (PAR). METHODS/DESIGN: In this trial, eligible 111 participants diagnosed with PAR will be randomly assigned to one of three groups: the ARAT group, the non-specific acupoints group, or the blank control group. The primary outcome will be the change in the total nasal symptom score, and the secondary outcomes will include: 1) changes in the scores of the standard version of Rhinoconjunctivitis Quality of Life Questionnaire (RQLQs); 2) acoustic rhinometry and anterior rhinomanometry; 3) changes in the scores of relief medication usage; 4) incidence of adverse events. Additionally, we will measure and compare the changes in cytokine levels (IL-5, IL-13, IFN-γ, and TSLP) in nasal secretions. The RQLQs and primary outcomes will be assessed at the beginning, middle, and end stages of the treatment period, with monthly follow-ups conducted over a total of three months. The secondary outcomes and biomarkers in nasal secretions will be measured at the beginning and end of the treatment period. Any adverse events or need for rescue medication will be carefully noted and recorded. DISCUSSION: This study may produce a new acupressure treatment prescription that is easy to learn, more targeted, and adaptable. This trial represents the first clinical investigation comparing ARAT treatment for PAR with the non-specific acupoints group and blank control group. Our data is expected to provide evidence demonstrating the safety and efficacy of ARAT for PAR patients, while also exploring the functional mechanism underlying ARAT treatment, moreover, the results offer valuable insights for healthcare professionals in managing PAR symptoms. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2300072292. Registered on June 08, 2023.

Vitamin D supplementation reduced blood inflammatory cytokines expression and improved graft function in kidney transplant recipients.

Background: Chronic allograft dysfunction(CAD) is the leading cause of graft loss in kidney transplant recipients (KTRs). Inflammatory process is believed to be one of the major contributors to CAD. The aim of this study is to explore the anti-inflammatory effect of vitamin D (VD) supplementation in KTRs and its role in the graft function improvement(protection). Methods: A retrospective cohort of 39 KTRs with chronic antibody mediated rejection(CAMR)or stable renal function and a prospective cohort of 42 KTRs treated or untreated with VD were enrolled. Serum levels of vitamin D metabolism and serum inflammatory cytokines, renal graft function, and routine blood biomarkers were tested and dynamically tracked within 12 months post-transplant. Results: Compared with the stable group, the CAMR group exhibited significantly elevated serum levels of inflammatory cytokines IL-1ß, IFN-γ, IL-2, IL-10, IP-10, and HMGB1 (P <0.05). The supplementation of vitamin D effectively increased the serum concentration of vitamin D in kidney transplant recipients (KTRs) in the treated group. During the course of treatment, the treated group exhibited a gradual increase in eGFR levels, which were significantly higher than those observed in the untreated group at 12 months post-transplant (p<0.05). Notably, as eGFR improved, there was a significant decrease in levels of IL-1ß, IFN-γ, IL-2, IL-10, IP-10 and HMGB1 in the treated group compared to the untreated group (P<0.05). Conclusion: This study confirmed that immune-inflammation is a crucial factor in the development of CAD in KTRs.VD deficiency impairs its anti-inflammatory activity. By assisting in the regulation of excessive immune inflammation and restoration of immune homeostasis, effective VD supplementation contributes to protection and maintenance of graft function in KTRs.

Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists.

Danuglipron is the most representative small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) and has received considerable attention due to positive results in the treatment of type 2 diabetes mellitus (T2DM) and obesity in clinical trials. However, hERG inhibition, lower activity than endogenous GLP-1, and a short action time represent limitations in terms of feasible application. In this study, we report a new class of 5,6-dihydro-1,2,4-triazine derivatives that serve to eliminate potential hERG inhibition caused by the piperidine ring of danuglipron. Applying systematic in vitro to in vivo screening, we have identified compound 42 as a highly potent and selective GLP-1R agonist, which delivers improved (7-fold) efficacy in stimulating cAMP accumulation compared with danuglipron and which exhibits acceptable drug-like properties. Furthermore, 42 significantly reduces glucose excursion and inhibits food intake of hGLP-1R Knock-In mice. These effects are longer-lasting than that shown by danuglipron, demonstrating feasibility in the treatment of T2DM and obesity.

11-epi-Sinulariolide Acetate-induced Apoptosis in Oral Cancer Cells Is Regulated by FOXO Through Inhibition of PI3K/AKT Pathway.

BACKGROUND/AIM: Oral cancer is a general term for carcinomas that occur around the oral tissues, and most are squamous cell carcinoma. Oral cancer is a common disease among Taiwanese males and poses a great threat to national health owing to its high mortality rate. In this study, we used the CAL-27 oral cancer cell lines as in vitro models to investigate the pathways involved in 11-epi-sinulariolide acetate (11-epi-SA)-induced apoptosis. MATERIALS AND METHODS: There have been no previous studies of the anticancer activity of 11-epi-SA isolated from Sinularia flexibilis against oral cancer. We used MTT assay, cell morphologic analysis, DNA fragmentation, TUNEL/DAPI assay, and JC-1 fluorescence staining to analyze the inhibitory effect of 11-epi-SA against the CAL-27 oral cancer cell line and assessed the potential molecular mechanism of apoptosis using western blot. RESULTS: Our results showed that 11-epi-SA inhibited CAL-27 cell proliferation, and its effect on cell growth was mediated through an apoptotic pathway mechanism. 11-epi-SA inhibited the PI3K/AKT pathway, allowing downstream FOXO to separate from 14-3-3 and return to the nucleus. We also observed that 11-epi-SA disrupted mitochondrial Bcl family protein homeostasis and activated caspase-3 and caspase-9, which led to apoptosis. CONCLUSION: A low concentration of 11-epi-SA can effectively induce apoptosis in oral cancer cells through the PI3K/AKT/FOXO pathway. 11-epi-SA has great potential as a new drug for the treatment of oral cancer.

Effect of esketamine on postoperative depressive symptoms in patients undergoing thoracoscopic lung cancer surgery: A randomized controlled trial.

Background: Depressive symptoms are common among patients with lung cancer. We aimed to assess the effects of esketamine on postoperative depressive symptoms after thoracoscopic lung cancer surgery. Methods: In this randomized, double-blind, placebo-controlled trial, 156 patients undergoing thoracoscopic lung cancer surgery were randomly allocated in a 1:1 ratio to receive intravenous esketamine (intraoperatively and in patient-controlled analgesia until 48 h postoperatively) or normal saline placebo. The primary outcome was the proportion of patients with depressive symptoms at 1 month postoperatively, assessed using the Beck Depression Inventory-II (BDI-II). Secondary outcomes included depressive symptoms at 48 h postoperatively, hospital discharge and 3 months postoperatively, BDI-II scores, anxious symptoms, Beck Anxiety Inventory scores, Quality of Recovery-15 (QoR-15) scores, and 1- and 3-month mortality. Main results: A total of 151 patients (75 in the esketamine group and 76 in the normal saline group) completed the 1-month follow-up. The esketamine group had a significantly lower incidence of depressive symptoms at 1 month compared to the normal saline group (1.3% vs. 11.8%; risk difference = -10.5, 95%CI = -19.6% to -0.49%; p = 0.018). After excluding patients without lung cancer diagnosis, the incidence of depressive symptoms was also lower in the esketamine group (1.4% vs. 12.2%; risk difference = -10.8, 95%CI = -20.2% to -0.52%; p = 0.018). The secondary outcomes were similar between groups, except that the esketamine group had higher QoR-15 scores at 1 month postoperatively (median difference = 2; 95%CI = 0 to 5; p = 0.048). The independent risk factors for depressive symptoms were hypertension (odds ratio = 6.75, 95%CI = 1.13 to 40.31; p = 0.036) and preoperative anxious symptoms (odds ratio = 23.83, 95%CI = 3.41 to 166.33; p = 0.001). Conclusion: Perioperative administration of esketamine reduced the incidence of depressive symptoms at 1 month after thoracoscopic lung cancer surgery. History of hypertension and preoperative anxious symptoms were independent risk factors for depressive symptoms.Clinical trial registration: Chinese Clinical Trial Registry http://www.chictr.org.cn, Identifier (ChiCTR2100046194).