This study investigated the protective effects of vitamin D (VD) against lung injury in the prediabetic state and explored the underlying molecular mechanisms, combining in vivo and in vitro approaches. Prediabetes was induced in KKAy mice by six weeks of high-fat diet feeding, confirmed by fasting blood glucose levels and oral glucose tolerance tests. Mice then received vitamin D3 (VD3) supplementation at varying doses for 16 weeks. Metabolic parameters were monitored, and lung architecture was assessed via hematoxylin-eosin and Masson staining. Hydroxyproline content was quantified as a marker of fibrosis, while endoplasmic reticulum stress (ERS) and apoptosis-related proteins were analyzed by Western blotting. Immunofluorescence was used to evaluate NEU1 expression and EGFR pathway activation. In parallel, high glucose (HG)-exposed MLE-12 cells were treated with 10 nM 1,25 (OH)(2)D-3, followed by assessment of cell viability, death markers, epithelial-mesenchymal transition (EMT) markers, and NEU1-EGFR pathway components. While VD3 supplementation had no significant effect on body weight or food intake, it significantly improved glucose and lipid metabolism, reduced insulin resistance, and alleviated pulmonary injury in prediabetic mice (P<.05). Mechanistically, VD3 suppressed NEU1-mediated ERS and apoptosis. These findings were further validated in HG-treated MLE-12 cells, underscoring the therapeutic potential of VD. Collectively, VD supplementation during the prediabetic stage significantly improved glucose intolerance, reduced insulin resistance, and alleviated pulmonary injury in mice, potentially by inhibiting NEU1-mediated ERS and apoptosis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that is difficult to cure. The crucial pathogenic factors of IBD are mainly caused by the overexpression of pro-inflammatory cytokines and the disturbance of gut microbiota triggered by excessive reactive oxygen species (ROS). Herein, the resveratrol-embedded hollow cerium oxide composite nanomaterials with surface modified hyaluronic acid (Res-CeO2@HA) is developed to restore intestinal mucosal immune homeostasis and modulate gut microbiota via effective elimination of ROS-inflammation. The synthetic nanomedicine integrates the enzyme-like activity of CeO2, the antioxidant properties of Res, and the targeting capabilities of HA. Results showed that Res-CeO2@HA had significant advantages in ROS clearance and colon targeting. And it balanced the expression of inflammatory cytokines by inhibiting M1 macrophage polarization, promoting M2 macrophage polarization, and modulating the TLR4/NF-κB signaling pathway to alleviate IBD in mice. Furthermore, it is found that Res-CeO2@HA significantly improved the homeostasis of the intestinal microbiota. This friendly and multifunctional nanomedicine may provide new strategies for the clinical treatment of IBD.

Vitamin D (VD) deficiency is closely associated with metabolic health and cardiac function in prediabetic patients, yet its underlying mechanisms remain unclear. This study investigated the role of VD intervention in prediabetic cardiac injury through in vivo and in vitro models, with particular focus on the ErbB4/ferroptosis axis. Using a high-fat diet-induced KKAy prediabetic mouse model, we observed significant metabolic abnormalities (increased body weight, hyperglycemia, insulin resistance) and cardiac remodeling (cardiac hypertrophy and functional impairment) (P<0.05). Remarkably, 16-week vitamin D (VD3) supplementation substantially ameliorated these pathological changes and reduced serum cardiac injury markers (P<0.05). Mechanistic studies revealed that VD3 downregulated myocardial NRG1 expression, inhibited ErbB4 phosphorylation (p-ErbB4) and YAP activation (p-YAP), while reversing the abnormal expression of ferroptosis-related proteins. In vitro experiments confirmed that high glucose combined with palmitic acid (HGPA) induced ferroptosis in H9c2 cardiomyocytes, which was alleviated by 1,25(OH)2D3 intervention through suppression of ErbB4 phosphorylation. Notably, combined treatment with 1,25(OH)2D3 and the ErbB4 phosphorylation inhibitor dacomitinib demonstrated synergistic protective effects. Our findings not only expand the understanding of the association between prediabetes and VD, but also reveal a relationship between ErbB4 and cardiac ferroptosis in prediabetic conditions.

Purpose This study aimed to elucidate the renoprotective mechanism of vitamin D (VD) in diabetic kidney disease (DKD), focused on TREM2 signaling, ferritinophagy, and macrophage polarization. Methods An integrated in vivo and in vitro approach was employed. A DKD rodent model was established using a high-fat diet combined with streptozotocin injections, followed by 10-week intervention with graded doses of vitamin D3 (VitD3). Renal injury was assessed through histopathology, functional assays, and iron deposition quantification. Macrophage polarization and TREM2 expression were profiled by multiplex immunofluorescence and immunoblotting. In parallel, high glucose (HG)-injured RAW264.7 macrophages were used for mechanistic studies. Gain- and loss-of-function experiments with TREM2 siRNA and the ferritinophagy inhibitor 3-MA were applied to dissect the TREM2-ferritinophagy-macrophage polarization axis. Results VitD3 supplementation improved systemic metabolism and renal function, attenuated pathological injury, and reduced renal iron deposition in diabetic rats. These improvements were associated with suppressed ferritinophagy and a corrected M1/M2 macrophage balance, linked to TREM2 modulation. In vitro, 1,25(OH)2D3 promoted M2 polarization and inhibited ferritinophagy in HG-stimulated macrophages. TREM2 knockdown abolished these effects and exacerbated M1 polarization and iron accumulation. Conversely, inhibition of ferritinophagy enhanced M2 polarization and downregulated TREM2, confirming a functional TREM2-ferritinophagy axis. Conclusion VD alleviates diabetic kidney injury by modulating macrophage polarization and ferritinophagy through TREM2. This work provides novel mechanistic insight into VD's immunometabolic actions and supports its potential as an adjunctive therapy for DKD.

Prediabetes is a crucial period for preventing and managing diabetes. This study aimed to explore the effects of CYP2R1/GC gene polymorphisms on vitamin D3 supplementation responsiveness in prediabetes. A total of 240 prediabetic participants received orally 1600 IU of vitamin D3 or placebo daily for 24 weeks. CYP2R1 rs12794714 AA carriers had less increased 25(OH)D3 levels compared with GG carriers after supplementation (3.42 (0.05, 6.79) vs. 8.49 (6.14, 10.83), P = 0.038). Moreover, GC rs4588 GA carriers had less increased 25(OH)D3 levels compared with GG carriers (4.71 (2.64, 6.79) vs. 8.17 (6.37, 9.98), P = 0.033); it also had lower supplementation responsiveness (0.35 (0.14, 0.91), P = 0.032). GC rs4752 AG carriers had higher supplementation responsiveness compared with AA carriers (3.48 (1.05, 11.59), P = 0.042). The results indicated that CYP2R1 rs12794714, GC rs4588, and GC rs4752 polymorphism were associated with vitamin D3 supplementation responsiveness in prediabetes.

BackgroundMetabolic syndrome (MetS) is a significant risk factor for type 2 diabetes and cardiovascular disease. The aim of this study was to identify the characteristics of MetS in northwest China.MethodsThree thousand and one adults were included (1,915 females, 1,086 males). The prevalence of MetS analysis was stratified according to gender, age and the region of residence.ResultsMetS prevalence in females and males was 49.7 ± 9.8% and 32.0 ± 9.0%, respectively (p < 0.001). MetS prevalence in females increased with age and was greater in rural (n = 217) females (53.6%) compared to urban (n = 754) (45.5%) or suburban (n = 818) females (52.0%) (p = 0.003). Regression analysis revealed that rural region, age, half-meat and half-vegetable dietary style, never dieted, weight increase in the previous year and a family history of high blood pressure were independent risk factors for the development of MetS, particularly in women aged ≥50 years.ConclusionMetS prevalence in women was greater than for men, increased with age and occurred more frequently in rural compared to urban and suburban females.

Prediabetes represents a pivotal stage in the development and pathogenesis of diabetes, during which notable alterations in the gut microbiota can be observed. Vitamin D (VD) showed anti-diabetic properties, but it is unknown whether the improvement of VD on hyperglycemia is associated with gut microbiota. Thus, our objective was to investigate and verify the effects of VD3 on glucose metabolism in prediabetes, as well as to elucidate the underlying mechanisms. In this study, different concentrations of VD3 were intraperitoneally administered to prediabetic mice induced by high fat diet for 16 weeks. Biochemical analyses, oral glucose tolerance test, 16S rRNA and untargeted metabolomics were used, the mechanism was explored. Then, fecal suspensions collected from the above donors were transplanted into KKay mice for 6 weeks, and the relevant indicators were measured. The results showed that VD3 intervention alleviated glucose metabolism in KKay mice. It increased the protein expression of colon tight junction proteins, alleviated metabolic endotoxemia and inflammation, so that reduced tumor necrosis factor alpha (TNFα) induced toll-like receptor 4/nuclear factor kappa-B (TLR4/NFκB) and improvement of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) insulin signaling pathway. VD3 affected the structure of gut microbiota and metabolites, and functional prediction analysis suggested that VD3 may affect carbohydrate. Besides, the effect of VD3 could be delivered by fecal microbiota transplantation (FMT). Consequently, VD3 ameliorate glucose metabolism by modulating gut microbiota and metabolites in KKay mice, and this ability could be transferred by FMT.

Kawasaki disease (KD), characterized by systematic vasculitis, is a leading cause of pediatric heart disease. Although recent studies have highlighted the critical role of deubiquitinases in vascular pathophysiology, their specific contribution to KD remains largely unknown. Herein, we investigated the function of the deubiquitinase USP7 in both KD patients and a CAWS-induced KD murine model. USP7 expression level is increased both in HCAECs induced by KD sera and cardiac CD31+ endothelial cells of KD mice. Whereas knockout of USP7 increases the cellular proportion of endothelial cells and potentially attenuates the elevated EndoMT, fibrosis, and inflammation in cardiac tissue of KD mice, consistently with the in vitro experiment observed in HCAECs induced by TGF-β2. Mechanistically, USP7 interacts with SMAD2/3, enhancing their protein stability by removing the K48 ubiquitin chain from both proteins and preventing their proteasome degradation, thus increasing the p-SMAD2 levels and nuclear entry. Importantly, intraperitoneal injection of USP7 inhibitor, P22077 elicited a robust anti-EndoMT and anti-vascular inflammation effect in KD model mice. Therefore, our study uncovered a previously unrecognized function of increased USP7 in KD by augmenting TGFβ2/SMAD2/SMAD3 signaling, thus facilitating the transcription of genes implicated in the EndoMT, cardiac fibrosis, and vascular remodeling. Our finding suggests that USP7 could serve as a potential therapeutic target for the prevention and treatment of coronary artery lesions in KD and related vascular diseases.

PURPOSE:This study aimed to investigate the anti-inflammatory effects of vitamin D (VD) on adipose tissue in type 2 diabetes mellitus (T2DM), with a particular focus on its regulation of macrophage polarization and the SHP-1/STAT3 signaling pathway. METHODS:A T2DM rat model was induced in 4-week-old Sprague-Dawley rats by feeding a high-fat diet followed by a low-dose streptozotocin injection. After successful model induction, the diabetic rats were treated with varying doses of vitamin D3 (VD3) for 10 weeks to evaluate its effects on adipose tissue inflammation associated with T2DM. To further elucidate the underlying mechanisms, high-glucose (HG)-stimulated RAW264.7 macrophages were employed as an in vitro model to investigate the anti-inflammatory effects of 1,25(OH)2D3, with particular emphasis on the SHP-1/STAT3 signaling pathway. RESULTS:VD3 treatment significantly improved body weight, reduced water intake and urine output, and alleviated hyperglycemia and dyslipidemia in T2DM rats (P < 0.05). Histological analysis revealed restored adipocyte morphology and reduced expression of inflammatory cytokines (TNF-α, IL-6, TGF-β1, MCP-1; P < 0.05). Immunofluorescence and protein analyses demonstrated that VD3 inhibited M1 macrophage polarization and enhanced the M2 phenotype. Moreover, VD3 upregulated SHP-1 expression while downregulating p-STAT3 in adipose tissue (P < 0.05). In vitro, 1,25(OH)2D3 restored cell viability, suppressed pro-inflammatory cytokine production, and promoted M2 polarization under HG conditions (P < 0.05). Inhibition of SHP-1 using TPI-1 abrogated these effects, whereas STAT3 inhibition with stattic further enhanced the anti-inflammatory responses (P < 0.05). CONCLUSION:VD mitigates adipose tissue inflammation and metabolic dysfunction in T2DM by regulating macrophage polarization via the SHP-1/STAT3 signaling pathway.

Alzheimer's disease (AD) is the most common primary progressive neurodegenerative disorder, with inflammatory responses involved in its onset and progression. Vitamin D (VD) is known for its health benefits, including antioxidant effects. Recently, Deglycase protein 1 (DJ-1/PARK7) has been shown to potentially regulate in antioxidant activity and inflammation regulation. In this study, we investigated the therapeutic effects of VD3 (30 IU/g/w) in Dj-1 knockdown APPswe/PS1E9 (APP/PS1) mice. Pathological changes were assessed using the Morris water maze and Barnes maze, as well as immunofluorescence, thioflavin S staining, Nissl staining, TUNEL staining, Western blot, and RT-PCR. The results demonstrated that VD3 significantly ameliorated cognitive deficits and attenuated AD-like pathology in APP/PS1 mice. Moreover, VD3 upregulated DJ-1 expression and suppressed neuroinflammation and neuronal pyroptosis by modulating the NF-κB/NLRP3/caspase-1 and caspase-3/GSDME signaling pathways. Collectively, these findings suggest that DJ-1 mediate these protective effects, as its knockdown reversed VD3-induced improvements in neuroinflammation and neuronal pyroptosis, implicating that DJ-1 is a crucial modulator in the effects of VD3 on Alzheimer's disease pathology.

The aim of this study was to evaluate the effects of vitamin D and/or calcium supplementation on sleep quality in individuals with prediabetes. A 24-week randomized controlled trial (RCT) was conducted in a 212 Chinese population with prediabetes. Participants were randomly assigned to four groups: vitamin D + calcium group (1600 IU/day + 500 mg/day, n = 53), vitamin D group (1600 IU/day, n = 54), calcium group (500 mg/day, n = 51), and control group (placebo, n = 54). The Pittsburgh Sleep Quality Index (PSQI) was used as the primary outcome to assess sleep quality. Questionnaires and fasting blood samples were collected at baseline and post-intervention for demographic assessment and correlation index analysis. After a 24-week intervention, a significant difference was observed in serum 25(OH)D concentration among the four groups (P < 0.05), and the total PSQI score in vitamin D + calcium group was lower compared to the preintervention levels. Subgroup analyses revealed improved sleep quality with calcium supplementation (P < 0.05) for specific groups, including women, individuals with a low baseline 25(OH)D level (< 30 ng/mL), and individuals in menopause. Moreover, correlation analysis revealed a negative correlation between the extent of change in sleep efficiency scores before and after the calcium intervention and the degree of change in insulin efficiency scores (r = − 0.264, P = 0.007), as well as the magnitude of change in islet beta cell function (r = − 0.304, P = 0.002). The combined intervention of vitamin D and calcium, as well as calcium interventions alone, exhibits substantial potential for improving sleep quality in individuals with prediabetes. The trial was registered in August 2019 as ChiCTR190002487.

BACKGROUND AND AIM:Our aim was to explore the potential relationship between SII and obesity, as well as abdominal obesity. METHODS AND RESULTS:We utilized a weighted multivariable logistic regression model to investigate the relationship between SII and obesity, as well as abdominal obesity. Generalized additive models were employed to test for non-linear associations. Subsequently, we constructed a two-piecewise linear regression model and conducted a recursive algorithm to calculate inflection points. Additionally, subgroup analyses and interaction tests were performed. A total of 7,880 U.S. adult participants from NHANES 2011-2018 were recruited for this study. In the regression model adjusted for all confounding variables, the odds ratios (95% confidence intervals) for the association between SII/100 and obesity, as well as abdominal obesity, were 1.03 (1.01, 1.06) and 1.04 (1.01, 1.08) respectively. There was a non-linear and reverse U-shaped association between SII/100 and obesity, as well as abdominal obesity, with inflection points at 7.32 and 9.98 respectively. Significant positive correlations were observed before the inflection points, while significant negative correlations were found after the inflection points. There was a statistically significant interaction in the analysis of age, hypertension, and diabetes. Moreover, a notable interaction is observed between SII/100 and abdominal obesity within non-Hispanic Asian populations. CONCLUSIONS:In adults from the United States, there is a positive correlation between SII and the high risk of obesity, as well as abdominal obesity. Further large-scale prospective studies are needed to analyze the role of SII in obesity and abdominal obesity.

It has been reported that fucoidan plays a beneficial role in type 2 diabetic mellitus (T2DM). However, it remains obscure if fucoidan has the protective effects on diabetes induced skeletal muscle atrophy. Here, we investigated the effect and mechanism of fucoidan on diabetic muscle atrophy. The results revealed that fucoidan ameliorated the general symptoms of diabetes, alleviated insulin resistance, as well as improved glucose metabolism disorders in vivo and vitro. Moreover, fucoidan also improved the atrophy of skeletal muscle by resisting the reduction of muscle fiber diameter and balance the protein anabolism and catabolism. It is worth noting that these beneficial effects of fucoidan on skeletal muscle atrophy and insulin resistance were abolished by inhibiting PI3K/Akt pathway. Taken together, fucoidan ameliorates diabetic skeletal muscle atrophy at least partially by the PI3K/Akt pathway.

Prediabetes is characterized as a transitional phase between normal blood glucose and diabetes, and the potential role of fucoidan in the progression of diabetes is still debated. The randomized, double-blind, placebo-controlled trial was designed to assess the effect of fucoidan supplementation on glycolipid metabolism, systemic inflammation and gut microbiota in individuals with prediabetes. A total of 70 Chinese participants with prediabetes were randomized to either fucoidan or placebo group, receiving daily doses of 1000 mg fucoidan or placebo capsules for 12 weeks. Glycolipid metabolism and systemic inflammation levels were assessed using standard laboratory techniques, while gut microbiota was analyzed by 16S rRNA sequencing. Following the 12-week intervention period, subjects consuming fucoidan exhibited a lower increase in GSP and a notable reduction in TNF-α, IL-6 and LPS compared to those receiving placebo (P < 0.05). Furthermore, fucoidan supplementation led to an increased abundance of Megamonas and Blautia while decreasing Klebsiella (P < 0.05). These findings suggested that the daily administration of 1000 mg fucoidan may partially modulate glucose metabolism and improve systemic inflammation, potentially linked to its modulation of gut microbiota in Chinese individuals with prediabetes. Thus, fucoidan could be considered as a potential dietary supplement for diabetes prevention.

Prediabetes is a crucial stage for prevention and treatment of diabetes, and vitamin D (VD) has been found to be linked to the development of prediabetes and diabetes. Thus, we aimed to identify the effect of VD supplementation on glucose metabolism in prediabetic participants and mice. A 1:1 paired design of randomized, placebo-controlled trial with 1600 IU/day VD 3 or placebo was administered to individuals with prediabetes, two-way repeatedmeasures ANCOVA was used to analyze glycolipid and inflammatory factors. A high-fat diet induced prediabetic KKay mice were utilized to evaluate the effects of VD 3 with 16 weeks supplementation. Generalized estimation equation, one way ANOVA were used to analyze continuous monitoring indexes and terminal indexes, respectively. Exercise capacity, skeletal muscle pathological features and relevant proteins were examined. The clinical results showed that VD 3 could improve insulin secretion and decrease inflammation. Results of KKay mice exhibited that VD 3 not only ameliorate glycolipid metabolism and inflammatory indicators, but also regulated pathological changes of skeletal muscle and exercise capacity. Mechanistically, our results demonstrated that VD 3 could inhibit the TLR4/NF kappa B and activate PI3K/AKT signaling pathway. Collectively, the study indicated that VD 3 exerts its beneficial effects by inhibiting TLR4/NF kappa B to decrease inflammatory response, and activating PI3K/AKT signaling pathway to regulate glucose homeostasis. (c) 2024 Published by Elsevier Inc.

Diabetic nephropathy (DN) is a serious public health problem worldwide, and ferroptosis is deeply involved in the pathogenesis of DN. Prediabetes is a critical period in the prevention and control of diabetes and its complications, in which kidney injury occurs. This study aimed to explore whether ferroptosis would induce kidney injury in prediabetic mice, and whether vitamin D (VD) supplementation is capable of preventing kidney injury by inhibiting ferroptosis, while discussing the potential mechanisms. High-fat diet (HFD) fed KKAy mice and high glucose (HG) treated HK-2 cells were used as experimental subjects in the current study. Our results revealed that serious injury and ferroptosis take place in the kidney tissue of prediabetic mice; furthermore, VD intervention significantly improved the kidney structure and function in prediabetic mice and inhibited ferroptosis, showing ameliorated iron deposition, enhanced antioxidant capability, reduced reactive oxygen species (ROS) and lipid peroxidation accumulation. Meanwhile, VD up-regulated Klotho, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, and down-regulated p53, transferrin receptor 1 (TFR1) and Acyl-Coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Moreover, we demonstrated that HG-induced ferroptosis is antagonized by treatment of VD and knockdown of Klotho attenuates the protective effect of VD on ferroptosis in vitro. In conclusion, ferroptosis occurs in the kidney of prediabetic mice and VD owns a protective effect on prediabetic kidney injury, possibly by via the Klotho/p53 pathway, thus inhibiting hyperglycemia-induced ferroptosis.

Background There is a correlation between obesity and 25-hydroxyvitamin D (25OHD) that tends to be negative. However, this relationship varies among different races. In this study, Asian adults with and without obesity were compared in terms of their levels of 25OHD. Methods We carried out a cross-sectional analysis on 2664 non-Hispanic Asian adults who participated in the National Health and Nutrition Examination Survey (NHANES) conducted between 2011 and 2018. To examine the connection between obese status, body mass index (BMI), waist circumference (WC) and weight, and 25OHD, we ran multivariate linear regression models and multivariate logistic regression models. Results After adjusting for all confounding factors, obesity status shows a significant positive correlation with vitamin D deficiency (model 3: OR = 2.318, 95% CI:1.317, 4.082). This positive correlation remains significant in males (males: OR = 2.713, 95% CI: -13.398, 5.217). In all three models, a negative association was observed between obesity status and 25OHD (model 1: β = -4.535, 95% CI: -6.987, -2.083; model 2 β = -4.249, 95% CI: -6.549, -2.039; model 3 β = -1.734, 95% CI: -7.285, 3.816). After controlling for covariates, there was a significant negative correlation between WC and 25OHD when stratified by gender and obesity status in both males with and without obesity (males with obesity: β = -1.461, 95% CI: -2.485, -0.436; males without obesity: β = -0.855. 95% CI: -1.499, -0.210). In males with obesity, there was a very strong positive connection between body weight and 25OHD (β = 0.912, 95% CI: 0.227, 1.597). In addition, neither gender’s obese individuals showed a significant link between BMI and 25OHD. Conclusion This study demonstrated a positive correlation between obesity and vitamin D deficiency and a negative correlation between obesity and 25OHD in Asian American adults. Additionally, among male obese individuals, there was a significant negative correlation between WC and 25OHD, an observation that needs to be validated in further prospective studies.

BACKGROUND:Despite abundant evidence on the epidemiological risk factors of metabolic diseases related to hyperuricemia, there is still insufficient evidence regarding the nonlinear relationship between triglyceride-glucose (TyG) index and hyperuricemia. Thus, the purpose of this research is to clarify the nonlinear connection between TyG and hyperuricemia.METHODS:From 2011 to 2018, a cross-sectional study was carried out using data from the National Health and Nutrition Examination Survey (NHANES). This study had 8572 participants in all. TyG was computed as Ln [triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The outcome variable was hyperuricemia. The association between TyG and hyperuricemia was examined using weighted multiple logistic regression, subgroup analysis, generalized additive models, smooth fitting curves, and two-piecewise linear regression models.RESULTS:In the regression model adjusting for all confounding variables, the OR (95% CI) for the association between TyG and hyperuricemia was 2.34 (1.70, 3.21). There is a nonlinear and reverse U-shaped association between TyG and hyperuricemia, with a inflection point of 9.69. The OR (95% CI) before the inflection point was 2.64 (2.12, 3.28), and after the inflection point was 0.32 (0.11, 0.98). The interaction in gender, BMI, hypertension, and diabetes analysis was statistically significant.CONCLUSION:Additional prospective studies are required to corroborate the current findings, which indicate a strong positive connection between TyG and hyperuricemia among adults in the United States.

PURPOSE:Recently, a significant negative correlation has been found between vitamin D (VD) and metabolic associated fatty liver disease (MAFLD), suggesting a potential beneficial role of VD in preventing of MAFLD, while underscoring the importance of exploring its mechanisms. METHODS:The experiment comprised two parts: male C57BL/6J mice (6 weeks) were fed a high-fat diet (HFD) and intraperitoneally injected with vitamin D3 (VD3) (1.68 IU/g/week) for 16 weeks. Meanwhile, palmitic acid (PA)-induced HepG2 cells were treated with 1,25(OH)2D3 (10 nM). The general conditions of the mice were evaluated by measuring body weight, liver/body weight, serum biochemical parameters, and inflammation indices. Additionally, injury-associated indices and histopathology were used to assess the severity of liver injury. Furthermore, indicators of ferroptosis, including lipid peroxidation, iron aggregation, and the aberrant expression of related proteins, were determined using Prussian blue staining, ELISA assay, and Western blot. RESULTS:Long-term VD3 administration significantly reduced body weight gain and the liver/body weight ratio of HFD-induced MAFLD mice, while also improving serum lipid metabolism dysregulation and enhancing insulin sensitivity. The changes in the expressions of liver injury indices and histological manifestations due to VD3 treatment indicated that VD3 may exerts beneficial effects on liver injury through inhibiting inflammatory cell infiltration and vacuolation. Importantly, VD3 supplementation also inhibited ferroptosis by enhancing the body's antioxidant capacity, reducing local iron aggregation, and modulating the expression levels of ferroptosis-related proteins. These findings were further confirmed in a PA-induced HepG2 steatosis cell model, highlighting the pharmacological effects of VD. CONCLUSIONS:VD shows promise in mitigating HFD -induced liver injury by improving metabolic dysregulation and inhibiting ferroptosis, suggesting therapeutic potential in MAFLD.