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Summary: The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory mechanisms in relation to cervical cancer remain insufficiently understood. Through bioinformatics analysis, we revealed that ESM1 was highly expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and correlated with dismal clinicopathological features. The activation of ESM1 is facilitated by the presence of oncogenic HPV E6 and E7. HPV E6 and E7 enhance the expression of ESM1 by diminishing the levels of miR-205-5p, which specifically targets the 3′ untranslated region of ESM1 mRNA. In addition, we demonstrated that ESM1 facilitates aerobic glycolysis of cervical cancer cells via the Akt/mTOR pathway. Suppression of ESM1 led to a reduction in the expression of HIF-1α and multiple glycolytic enzymes. Taken together, our findings provide insights into the mechanisms by which HPV infections regulate oncogenes, thereby contributing to cervical carcinogenesis.

Abstract Background Hepatic ischemia–reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. Methods Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. Results Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). Conclusions Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

Most available neutralizing antibodies are ineffective against highly mutated SARS-CoV-2 Omicron subvariants. Therefore, it is crucial to develop potent and broad-spectrum alternatives to effectively manage Omicron subvariants. Here, we constructed a high-diversity nanobody phage display library and identified nine nanobodies specific to the SARS-CoV-2 receptor-binding domain (RBD). Five of them exhibited cross-neutralization activity against the SARS-CoV-2 wild-type (WT) strain and the Omicron subvariants BA.1 and BA.4/5, and one nanobody demonstrated marked efficacy even against the Omicron subvariants BQ.1.1 and XBB.1. To enhance the therapeutic potential, we engineered a panel of multivalent nanobodies with increased neutralizing potency and breadth. The most potent multivalent nanobody, B13-B13-B13, cross-neutralized all tested pseudoviruses, with a geometric mean of the 50% inhibitory concentration (GM IC50) value of 20.83 ng/mL. An analysis of the mechanism underlying the enhancement of neutralization breadth by representative multivalent nanobodies demonstrated that the strategic engineering approach of combining two or three nanobodies into a multivalent molecule could improve the affinity between a single nanobody and spike, and could enhance tolerance toward escape mutations such as R346T and N460K. Our engineered multivalent nanobodies may be promising drug candidates for treating and preventing infection with Omicron subvariants and even future variants.

Three-dimensional (3D) bioprinted cartilage-mimicking substitutes for full-thickness articular cartilage defect repair have emerged as alternatives to in situ defect repair models. However, there has been very limited breakthrough in cartilage regeneration based on 3D bioprinting owing to the lack of ideal bioinks with printability, biocompatibility, bioactivity, and suitable physicochemical properties. In contrast to animal-derived natural polymers or acellular matrices, human-derived Wharton's jelly is biocompatible and hypoimmunogenic with an abundant source. Although acellular Wharton's jelly can mimic the chondrogenic microenvironment, it remains challenging to prepare both printable and biologically active bioinks from this material. Here, we firstly prepared methacryloyl-modified acellular Wharton's jelly (AWJMA) using a previously established photo-crosslinking strategy. Subsequently, we combined methacryloyl-modified gelatin with AWJMA to obtain a hybrid hydrogel that exhibited both physicochemical properties and biological activities that were suitable for 3D bioprinting. Moreover, bone marrow mesenchymal stem cell-loaded 3D-bioprinted cartilage-mimicking substitutes had superior advantages for the survival, proliferation, spreading, and chondrogenic differentiation of bone marrow mesenchymal stem cells, which enabled satisfactory repair of a model of full-thickness articular cartilage defect in the rabbit knee joint. The current study provides a novel strategy based on 3D bioprinting of cartilage-mimicking substitutes for full-thickness articular cartilage defect repair.

Physiological repair of large-sized bone defects is great challenging in clinic due to a lack of ideal grafts suitable for bone regeneration. Decalcified bone matrix (DBM) is considered as an ideal bone regeneration scaffold, but low cell seeding efficiency and a poor osteoinductive microenvironment greatly restrict its application in large-sized bone regeneration. To address these problems, we proposed a novel strategy of bone regeneration units (BRUs) based on microgels produced by photo-crosslinkable and microfluidic techniques, containing both the osteogenic ingredient DBM and vascular endothelial growth factor (VEGF) for accurate biomimic of an osteoinductive microenvironment. The physicochemical properties of microgels could be precisely controlled and the microgels effectively promoted adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. BRUs were successfully constructed by seeding BMSCs onto microgels, which achieved reliable bone regeneration in vivo. Finally, by integrating the advantages of BRUs in bone regeneration and the advantages of DBM scaffolds in 3D morphology and mechanical strength, a BRU-loaded DBM framework successfully regenerated bone tissue with the desired 3D morphology and effectively repaired a large-sized bone defect of rabbit tibia. The current study developed an ideal bone biomimetic microcarrier and provided a novel strategy for bone regeneration and large-sized bone defect repair.

Articular cartilage (AC), a bone-to-bone protective device made of up to 80% water and populated by only one cell type (i.e. chondrocyte), has limited capacity for regeneration and self-repair after being damaged because of its low cell density, alymphatic and avascular nature. Resulting repair of cartilage defects, such as osteoarthritis (OA), is highly challenging in clinical treatment. Fortunately, the development of tissue engineering provides a promising method for growing cells in cartilage regeneration and repair by using hydrogels or the porous scaffolds. In this paper, we review the therapeutic strategies for AC defects, including current treatment methods, engineering/regenerative strategies, recent advances in biomaterials, and present emphasize on the perspectives of gene regulation and therapy of noncoding RNAs (ncRNAs), such as circular RNA (circRNA) and microRNA (miRNA).

Stress-induced cell death, mainly apoptosis, and its subsequent tissue repair is interlinked although our knowledge of this connection is still very limited. An intriguing finding is apoptosis-induced proliferation (AiP), an evolutionary conserved mechanism employed by apoptotic cells to trigger compensatory proliferation of their neighboring cells. Studies using Drosophila as a model organism have revealed that apoptotic caspases and c-Jun N-terminal kinase (JNK) signaling play critical roles to activate AiP. For example, the initiator caspase Dronc, the caspase-9 ortholog in Drosophila, promotes activation of JNK leading to release of mitogenic signals and AiP. Recent studies further revealed that Dronc relocates to the cell cortex via Myo1D, an unconventional myosin, and stimulates production of reactive oxygen species (ROS) to trigger AiP. During this process, ROS can attract hemocytes, the Drosophila macrophages, which further amplify JNK signaling cell non-autonomously. However, the intrinsic components connecting Dronc, ROS and JNK within the stressed signal-producing cells remain elusive. Here, we identified LIM domain kinase 1 (LIMK1), a kinase promoting cellular F-actin polymerization, as a novel regulator of AiP. F-actin accumulates in a Dronc-dependent manner in response to apoptotic stress. Suppression of F-actin polymerization in stressed cells by knocking down LIMK1 or expressing Cofilin, an inhibitor of F-actin elongation, blocks ROS production and JNK activation, hence AiP. Furthermore, Dronc and LIMK1 genetically interact. Co-expression of Dronc and LIMK1 drives F-actin accumulation, ROS production and JNK activation. Interestingly, these synergistic effects between Dronc and LIMK1 depend on Myo1D. Therefore, F-actin remodeling plays an important role mediating caspase-driven ROS production and JNK activation in the process of AiP.

The fabrication of biphasic cartilage-bone integrated scaffolds is an attractive alternative for osteochondral repair but has proven to be extremely challenging. Existing three-dimensional (3D) scaffolds are insufficient to accurately biomimic the biphasic cartilage-bone integrated microenvironment. Currently, photo-crosslinkable hydrogels based on tissue-specific decellularized extracellular matrix (dECM) have been considered as an important technique to fabricate biomimetic scaffolds, but so far there has been no breakthrough in the photo-crosslinkable hydrogel scaffolds with biphasic cartilage-bone biomimetic microenvironment. Here, we report a novel strategy for the preparation of biomimetic cartilage-bone integrated scaffolds based on photo-crosslinkable cartilage/bone-derived dECM hydrogels, which are able to reconstruct biphasic cartilage-bone biomimetic microenvironment. The biphasic cartilage-bone integrated scaffolds provided a 3D microenvironment for osteochondral regeneration. The cartilage biomimetic scaffolds, consisting of cartilage-derived dECM hydrogels, efficiently regulated chondrogenesis of bone marrow mesenchymal stem cells (BMSCs). The bone biomimetic scaffolds, composed of cartilage/bone-derived dECM hydrogels, first regulated chondrogenesis of BMSCs, followed by endochondral ossification over time. Taken together, the biphasic cartilage-bone integrated tissue could be successfully reconstructed by subcutaneous culture based on cartilage-bone bilayered structural design. Furthermore, the biphasic cartilage-bone biomimetic scaffolds (cell-free) achieved satisfactory cartilage-bone integrated regeneration in the osteochondral defects of rabbits’ knee joints.

Δ1-Pyrroline-5-carboxylate synthetase (P5CS) acts as the rate-limiting enzyme in the biosynthesis of proline in plants. Although P5CS plays an essential role in plant responses to environmental stresses, its biological functions remain largely unclear in pear (Pyrus betulifolia). In the present study, 11 putative pear P5CSs (PbP5CSs) were identified by comprehensive bioinformatics analysis and classified into five subfamilies. Segmental and tandem duplications contributed to the expansion and evolution of the PbP5CS gene family. Various cis-acting elements associated with plant development, hormone responses, and/or stress responses were identified in the promoters of PbP5CS genes. To investigate the regulatory roles of PbP5CS genes in response to abiotic and biotic stresses, gene expression patterns in publicly available data were explored. The tissue-specific expressional dynamics of PbP5CS genes indicate potentially important roles in pear growth and development. Their spatiotemporal expression patterns suggest key functions in multiple environmental stress responses. Transcriptome and real-time quantitative PCR analyses revealed that most PbP5CS genes exhibited distinct expression patterns in response to drought, waterlogging, salinity-alkalinity, heat, cold, and infection by Alternaria alternate and Gymnosporangium haraeanum. The results provide insight into the versatile functions of the PbP5CS gene family in stress responses. The findings may assist further exploration of the physiological functions of PbP5CS genes for the development and enhancement of stress tolerance in pear and other fruits.

Backfat thickness (BF) is closely related to the service life and reproductive performance of sows. The dynamic monitoring of sows’ BF is a critical part of the production process in large-scale pig farms. This study proposed the application of a hybrid CNN-ViT (Vision Transformer, ViT) model for measuring sows’ BF to address the problems of high measurement intensity caused by the traditional contact measurement of sows’ BF and the low efficiency of existing non-contact models for measuring sows’ BF. The CNN-ViT introduced depth-separable convolution and lightweight self-attention, mainly consisting of a Pre-local Unit (PLU), a Lightweight ViT (LViT) and an Inverted Residual Unit (IRU). This model could extract local and global features of images, making it more suitable for small datasets. The model was tested on 106 pregnant sows with seven randomly divided datasets. The results showed that the CNN-ViT had a Mean Absolute Error (MAE) of 0.83 mm, a Root Mean Square Error (RMSE) of 1.05 mm, a Mean Absolute Percentage Error (MAPE) of 4.87% and a coefficient of determination (R-Square, R2) of 0.74. Compared to LviT-IRU, PLU-IRU and PLU-LviT, the CNN-ViT’s MAE decreased by more than 12%, RMSE decreased by more than 15%, MAPE decreased by more than 15% and R² improved by more than 17%. Compared to the Resnet50 and ViT, the CNN-ViT’s MAE decreased by more than 7%, RMSE decreased by more than 13%, MAPE decreased by more than 7% and R2 improved by more than 15%. The method could better meet the demand for the non-contact automatic measurement of pregnant sows’ BF in actual production and provide technical support for the intelligent management of pregnant sows.

Peritoneal fibrosis (PF), a common complication in patients receiving peritoneal dialysis (PD), is primarily caused by the epithelial-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs). PF is the main reason for patients on PD to withdraw from PD. Effective treatment is unavailable for this complication at present. Elabela (ELA) is a polypeptide hormone secreted by the vascular endothelium and kidney. Peptide hormones ELA and apelin (APLN) have various protective effects on the cardiovascular and urinary systems and have potential therapeutic effects on organ fibrosis. ELA and APLN are less studied in PD population. Here, we aimed to investigate the clinical significance of ELA in patients on PD and to evaluate the therapeutic effect of ELA on EMT of HPMCs. Compared with those in patients with stage 5 chronic kidney disease who are not on dialysis, serum ELA levels in patients on PD increased with the improvement of residual renal function at PD duration

Cholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic cholestasis with liver injury in response to α-naphthylisothiocyanate (ANIT) not to bile duct ligation (BDL) induced-extrahepatic cholestasis. ANIT (80 mg/kg) increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBiL), total bilirubin (TBiL), and total bile acids (TBA) which was attenuated by DCHT treatment in a dose-dependent manner. DCHT treatment at high dose of 1.875 g/kg restored bile acid homeostasis, as evidenced by the recovery of the transcription of genes implicated in bile acid biosynthesis, uptake and efflux. DCHT treatment (1.875 g/kg) reversed ANIT-evoked disordered glutathione homeostasis (as determined by GSH/GSSG ratio) and increased in the mRNA levels for Il6, Il1b and Tnfa associated with liver inflammation. Using network pharmacology-based approaches, we identified 22 putative targets involved in DCHT treatment for intrahepatic cholestasis not extrahepatic cholestasis. In addition, as evidenced by dual-luciferase reporter assays, compounds from DCHT with high affinity of PPARα increased luciferase levels from a PPARα-driven reporter. PPARα agonist fenofibrate was able to mimic the cytoprotective effect of DCHT on intrahepatic cholestasis, which was abolished by the PPARα antagonist GW6471. KEGG enrichment and western blot analyses showed that signaling axes of JNK/IL-6/NF-κB/STAT3 related to PPARα might be the principal pathway DCHT affects intrahepatic cholestasis. Taken together, the present study provides compelling evidence that DCHT is a promising formula against acute intrahepatic cholestasis with hepatotoxicity which works via PPARα activation.

Myocardial infarction (MI) causes peripheral organ injury, in addition to cardiac dysfunction, including in the liver, which is known as cardiac hepatopathy. Aerobic exercise (AE) can effectively improve liver injury, although the mechanism and targets are currently not well established. Irisin, mainly produced by cleavage of the fibronectin type III domain-containing protein 5 (FNDC5), is a responsible for the beneficial effects of exercise training. In this study, we detected the effect of AE on MI-induced liver injury and explored the role of irisin alongside the benefits of AE. Wildtype and Fndc5 knockout mice were used to establish an MI model and subjected to AE intervention. Primary mouse hepatocytes were treated with lipopolysaccharide (LPS), rhirisin, and a phosphoinositide 3-kinase (PI3K) inhibitor. The results showed that AE significantly promoted M2 polarization of macrophages and improved MI-induced inflammation, upregulated endogenous irisin protein expression and activated the PI3K/ protein kinase B (Akt) signaling pathway in the liver of MI mice, while knockout of Fndc5 attenuated the beneficial effects of AE. Exogenous rhirisin significantly inhibited the LPS-induced inflammatory response, which was attenuated by the PI3K inhibitor. These results suggest that AE could effectively activate the FNDC5/irisin-PI3K/Akt signaling pathway, promote the polarization of M2 macrophages, and inhibit the inflammatory response of the liver after MI.

Fruit color is one of the most important external qualities of pear (Pyrus pyrifolia) fruits. However, the mechanisms that control russet skin coloration in pear have not been well characterized. Here, we explored the molecular mechanisms that determine the russet skin trait in pear using the F1 population derived from a cross between russet skin (‘Niitaka’) and non-russet skin (‘Dangshansu’) cultivars. Pigment measurements indicated that the lignin content in the skin of the russet pear fruits was greater than that in the non-russet pear skin. Genetic analysis revealed that the phenotype of the russet skin pear is associated with an allele of the PpRus gene. Using bulked segregant analysis combined with the genome sequencing (BSA-seq), we identified two simple sequence repeat (SSR) marker loci linked with the russet-colored skin trait in pear. Linkage analysis showed that the PpRus locus maps to the scaffold NW_008988489.1: 53297-211921 on chromosome 8 in the pear genome. In the mapped region, the expression level of LOC103929640 was significantly increased in the russet skin pear and showed a correlation with the increase of lignin content during the ripening period. Genotyping results demonstrated that LOC103929640 encoding the transcription factor MYB36 is the causal gene for the russet skin trait in pear. Particularly, a W-box insertion at the PpMYB36 promoter of russet skin pears is essential for PpMYB36-mediated regulation of lignin accumulation and russet coloration in pear. Overall, these results show that PpMYB36 is involved in the regulation of russet skin trait in pear.

Background: Child maltreatment (CM) is correlated with suicidality risk among adolescents. Additionally, exposure to bisphenol AF (BPAF) may increase this risk. However, the combined effect of CM and BPAF exposure remains unknown and should be further investigated. Methods: In this study, 1,475 early adolescents (mean age = 12.48 years) from the Chinese Early Adolescents Cohort were enrolled. Data were collected at three time points with an interval of 12 months between 2019 and 2021. Participants’ history of CM and suicidality (including suicidal ideation and suicidal attempts) were evaluated using a self-report questionnaire. Blood samples were obtained from participants to measure serum BPAF concentrations at baseline. Group-based trajectory modeling was employed to identify different developmental trajectories of suicidality across the three waves. After adjusting for potential confounders, the association between CM and BPAF exposure on suicidal ideation and suicidal attempts was assessed using logistic regression and Poisson regression analyses. Results: Participants with CM were associated with a risk of one- and two-year incident suicidality (all ps < 0.05), and BPAF levels were positively associated with two-year incident suicidal ideation (adjusted OR = 1.68, 95% CI: 1.13–2.50). Additionally, middle and high levels of BPAF exposure synergistically increase the risk for one- and two-year incident suicidal ideation among participants with CM (adjusted ORs = 2.00–3.83). Similarly, participants exposed to high-level BPAF as well as CM were at a greater risk of one- and two-year incident suicidal attempts than those with low-level BPAF exposure and no CM (adjusted incidence rate ratio [IRRs] = 2.82–4.34). Moreover, compared with participants with a low developmental trajectory of suicidality across the three waves, high BPAF exposure exhibited a significant synergistic effect on participants with CM in the persistently high suicidal ideation trajectory and the increasing suicidal attempts trajectory (all ps < 0.05). Sex subgroup analysis revealed that females were more susceptible to the synergistic effect of BPAF and CM exposure on suicidality than males. Conclusions: Environmental factors and the psychological status of individuals may synergistically increase their susceptibility to suicidality. These results offer novel insights into enhancing our understanding of suicidality among adolescents.

Background In early adolescence, youth are highly prone to suicidal behaviours. Identifying modifiable risk factors during this critical phase is a priority to inform effective suicide prevention strategies.Aims To explore the risk and protective factors of suicidal behaviours (ie, suicidal ideation, plans and attempts) in early adolescence in China using a social-ecological perspective.Methods Using data from the cross-sectional project ‘Healthy and Risky Behaviours Among Middle School Students in Anhui Province, China’, stratified random cluster sampling was used to select 5724 middle school students who had completed self-report questionnaires in November 2020. Network analysis was employed to examine the correlates of suicidal ideation, plans and attempts at four levels, namely individual (sex, academic performance, serious physical illness/disability, history of self-harm, depression, impulsivity, sleep problems, resilience), family (family economic status, relationship with mother, relationship with father, family violence, childhood abuse, parental mental illness), school (relationship with teachers, relationship with classmates, school-bullying victimisation and perpetration) and social (social support, satisfaction with society).Results In total, 37.9%, 19.0% and 5.5% of the students reported suicidal ideation, plans and attempts in the past 6 months, respectively. The estimated network revealed that suicidal ideation, plans and attempts were collectively associated with a history of self-harm, sleep problems, childhood abuse, school bullying and victimisation. Centrality analysis indicated that the most influential nodes in the network were history of self-harm and childhood abuse. Notably, the network also showed unique correlates of suicidal ideation (sex, weight=0.60; impulsivity, weight=0.24; family violence, weight=0.17; relationship with teachers, weight=−0.03; school-bullying perpetration, weight=0.22), suicidal plans (social support, weight=−0.15) and suicidal attempts (relationship with mother, weight=−0.10; parental mental illness, weight=0.61).Conclusions This study identified the correlates of suicidal ideation, plans and attempts, and provided practical implications for suicide prevention for young adolescents in China. Firstly, this study highlighted the importance of joint interventions across multiple departments. Secondly, the common risk factors of suicidal ideation, plans and attempts were elucidated. Thirdly, this study proposed target interventions to address the unique influencing factors of suicidal ideation, plans and attempts.

Abstract Aims Previous cross-sectional and case–control studies have proposed that decreased vitamin D levels are positively correlated with the risk of suicidality in adults. However, limited studies have examined the association between vitamin D and suicidality in adolescents. This study aimed to investigate the relationship between serum vitamin D and suicidality risk among early adolescents. Methods Data were obtained from a Chinese early adolescent cohort. In this cohort, seventh-grade students from a middle school in Anhui Province were invited to voluntarily participate in the baseline assessments and provide peripheral blood samples (in September 2019). The participants were followed up annually (in September 2020 and September 2021). Serum 25-hydroxyvitamin D [25(OH)D] and vitamin D–related single-nucleotide polymorphisms at baseline were measured in November 2021. Traditional observational and Mendelian randomization (MR) analyses were performed to examine the relationship between serum 25(OH)D at baseline and the risk of baseline and incident suicidality (i.e., suicidal ideation [SI], plans and attempts). Results Traditional observational analysis did not reveal a significant linear or non-linear association of serum 25(OH)D concentration with the risks of baseline and 2-year incident suicidality in the total sample (P > .05 for all). Sex-stratified analysis revealed a non-linear association between the 25(OH)D concentration and the risk of baseline SI in women (Poverall = .002; Pnon-linear = .001). Moreover, the risk of baseline SI in the 25(OH) insufficiency group was lower than that in the 25(OH) deficiency group in the total sample (odds ratio [OR] = 0.69, 95% confidence interval [CI] = 0.51–0.92, P = .012). This difference remained significant in women (OR = 0.59, 95% CI = 0.40–0.87, P = .008) but not in men (OR = 0.78, 95% CI = 0.53–1.15, P = .205). Additionally, both linear and non-linear MR analyses did not support the causal effect of serum 25(OH)D concentration on the risk of baseline, 1-year and 2-year incident suicidality (P > .05 for all). Conclusions This study could not confirm the causal effect of vitamin D on suicidality risk among Chinese early adolescents. Future studies must confirm these findings with a large sample size.