New insights into the role of macrophages in cancer immunotherapy.

Macrophages are the main component of the tumor microenvironment, which are differentiated from monocytes in the blood and play an important role in cancer development. Tumor-associated macrophages (TAMs) can promote tumor growth, invasion, metastasis, and resistance to anti-programmed death receptor 1 therapy by regulating programmed cell death ligand 1 expression and interacting with other immune cells in the tumor microenvironment. However, when activated properly, macrophages can also play an anti-tumor role by enhancing the phagocytosis and cytotoxicity of tumor cells. TAM is associated with poor prognosis and drug resistance in patients treated with immunotherapy, indicating that macrophages are attractive targets for combined therapy in cancer treatment. Combination of targeting TAMs and immunotherapy overcomes the drug resistance and achieved excellent results in some cancers, which may be a promising strategy for cancer treatment in the future. Herein, we review the recent findings on the role of macrophages in tumor development, metastasis, and immunotherapy. We focus mainly on macrophage≥centered therapy, including strategies to deplete and reprogram TAMs, which represent the potential targets for improving tumor immunotherapy efficacy.

Nicotinamide mononucleotide maintains cytoskeletal stability and fortifies mitochondrial function to mitigate oocyte damage induced by Triocresyl phosphate.

Triocresyl phosphate (TOCP) was commonly used as flame retardant, plasticizer, lubricant, and jet fuel additive. Studies have shown adverse effects of TOCP on the reproductive system. However, the potential harm brought by TOCP, especially to mammalian female reproductive cells, remains a mystery. In this study, we employed an in vitro model for the first time to investigate the effects of TOCP on the maturation process of mouse oocytes. TOCP exposure hampered the meiotic division process, as evidenced by a reduction in the extrusion of the first polar body from oocytes. Subsequent research revealed the disruption of the oocyte cell cytoskeleton induced by TOCP, resulting in abnormalities in spindle organization, chromosome alignment, and actin filament distribution. This disturbance further extended to the rearrangement of organelles within oocytes, particularly affecting the mitochondria. Importantly, after TOCP treatment, mitochondrial function in oocytes was impaired, leading to oxidative stress, DNA damage, cell apoptosis, and subsequent changes of epigenetic modifications. Supplementation with nicotinamide mononucleotide (NMN) alleviated the harmful effects of TOCP. NMN exerted its mitigating effects through two fundamental mechanisms. On one hand, NMN conferred stability to the cell cytoskeleton, thereby supporting nuclear maturation. On the other hand, NMN enhanced mitochondrial function within oocytes, reducing the excess reactive oxygen species (ROS), restoring meiotic division abnormalities caused by TOCP, preventing oocyte DNA damage, and suppressing epigenetic changes. These findings not only enhance our understanding of the molecular basis of TOCP induced oocyte damage but also offer a promising avenue for the potential application of NMN in optimizing reproductive treatment strategies.

Regulatory mechanisms of autophagy on DHA and carotenoid accumulation in Crypthecodinium sp. SUN.

BACKGROUND: Autophagy is a crucial process of cellular self-destruction and component reutilization that can affect the accumulation of total fatty acids (TFAs) and carotenoids in microalgae. The regulatory effects of autophagy process in a docosahexaenoic acid (DHA) and carotenoids simultaneously producing microalga, Crypthecodinium sp. SUN, has not been studied. Thus, the autophagy inhibitor (3-methyladenine (MA)) and activator (rapamycin) were used to regulate autophagy in Crypthecodinium sp. SUN. RESULTS: The inhibition of autophagy by 3-MA was verified by transmission electron microscopy, with fewer autophagy vacuoles observed. Besides, 3-MA reduced the glucose absorption and intracellular acetyl-CoA level, which resulting in the decrease of TFA and DHA levels by 15.83 and 26.73% respectively; Surprisingly, 3-MA increased intracellular reactive oxygen species level but decreased the carotenoids level. Comparative transcriptome analysis showed that the downregulation of the glycolysis, pentose phosphate pathway and tricarboxylic acid cycle may underlie the decrease of acetyl-CoA, NADPH and ATP supply for fatty acid biosynthesis; the downregulation of PSY and HMGCR may underlie the decreased carotenoids level. In addition, the class I PI3K-AKT signaling pathway may be crucial for the regulation of carbon and energy metabolism. At last, rapamycin was used to activate autophagy, which significantly enhanced the cell growth and TFA level and eventually resulted in 1.70-fold increase in DHA content. CONCLUSIONS: Our findings indicate the mechanisms of autophagy in Crypthecodinium sp. SUN and highlight a way to manipulate cell metabolism by regulating autophagy. Overall, this study provides valuable insights to guide further research on autophagy-regulated TFA and carotenoids accumulation in Crypthecodinium sp. SUN.

Clinical evolution of antisynthetase syndrome-associated interstitial lung disease after COVID-19 in a man with Klinefelter syndrome: A case report.

BACKGROUND: This study presents a case of rapidly developing respiratory failure due to antisynthetase syndrome (AS) following coronavirus disease 2019 (COVID-19) in a 33-year-old man diagnosed with Klinefelter syndrome (KS). CASE SUMMARY: A 33-year-old man with a diagnosis of KS was admitted to the Department of Pulmonary and Critical Care Medicine of a tertiary hospital in China for fever and shortness of breath 2 wk after the onset of COVID-19. Computed tomography of both lungs revealed diffuse multiple patchy heightened shadows in both lungs, accompanied by signs of partial bronchial inflation. Metagenomic next-generation sequencing of the bronchoalveolar lavage fluid suggested absence of pathogen. A biopsy specimen revealed organizing pneumonia with alveolar septal thickening. Additionally, extensive auto-antibody tests showed strong positivity for anti-SSA, anti-SSB, anti-Jo-1, and anti-Ro-52. Following multidisciplinary discussions, the patient received a final diagnosis of AS, leading to rapidly progressing respiratory failure. CONCLUSION: This study underscores the clinical progression of AS-associated interstitial lung disease subsequent to viral infections such as COVID-19 in patients diagnosed with KS.

Anti-Psoriatic Activity of Black, Green and White Tea Extracts from Southeastern China.

Psoriasis is a common chronic inflammatory disease, but most of its current treatments come with a high risk of side effects. As one of the world's top three beverages, tea has a traditional history of being used as a treatment for skin conditions due to its high safety profile, anti-inflammatory and other properties. In this study, we investigated the anti-psoriasis effects of ethanol extracts of black tea, green tea and white tea from southeastern China. The compositions of the tea extracts (TEs) were first determined by UPLC-Q-Exactive-Orbitrap MS and then genetic analysis, antibacterial, anti-inflammatory, and immunocompetence assays were performed. Imiquimod was used to establish a mouse model of psoriasis-like dermatitis and treating with the extracts to examine their efficacy. A total of 88 chemical components, mainly phenols and organic acids, were identified from the TEs. These TEs ameliorated skin damage and they all reduced the expression of cytokines IL-17 and TNF-α. By analyzing the genes, TEs may affect the inflammatory signaling pathway by regulating the metabolic changes. In addition, TEs can significantly scavenge ROS, NO, and inhibit cellular inflammation. In conclusion, this study examined the inhibitory effects of three TEs on psoriasis and their potential as nutritional supplements for the treatment of skin inflammation.

SARS-CoV-2 Omicron infection augments the magnitude and durability of systemic and mucosal immunity in triple-dose CoronaVac recipients.

The inactivated whole-virion vaccine, CoronaVac, is one of the most widely used coronavirus disease 2019 (COVID-19) vaccines worldwide. There is a paucity of data indicating the durability of the immune response and the impact of immune imprinting induced by CoronaVac upon Omicron infection. In this prospective cohort study, 41 recipients of triple-dose CoronaVac and 14 unvaccinated individuals were recruited. We comprehensively profiled adaptive immune parameters in both groups, including spike-specific immunoglobulin (Ig) G and IgA titers, neutralizing activity, B cells, circulating follicular helper T (cTfh) cells, CD4+ and CD8+ T cells, and their memory subpopulations at 12 months after the third booster dose and at 4 and 20 weeks after Omicron BA.5 infection. Twelve months after the third CoronaVac vaccination, spike-specific antibodies and cellular responses were detectable in most vaccinated individuals. BA.5 infection significantly augmented the magnitude, cross-reactivity, and durability of serum neutralization activities, Fc-mediated phagocytosis, nasal spike-specific IgA responses, memory B cells, activated cTfh cells, memory CD4+ T cells, and memory CD8+ T cells for both the ancestral strain and Omicron subvariants, compared to unvaccinated individuals. Notably, the increase in BA.5-specific immunity after breakthrough infection was consistently comparable to or higher than that of the ancestral strain, suggesting no evidence of immune imprinting. Immune landscape analyses showed that vaccinated individuals have better synchronization of multiple immune components than unvaccinated individuals upon heterologous infection. Our data provide detailed insight into the protective role of the inactivated COVID-19 vaccine in shaping humoral and cellular immunity to Omicron infection. IMPORTANCE: There is a paucity of data indicating the durability of the immune response and the impact of immune imprinting induced by CoronaVac upon Omicron breakthrough infection. In this prospective cohort study, the anti-severe acute respiratory syndrome coronavirus 2 adaptive responses were analyzed before and after the Omicron BA.5 infection. Our data provide detailed insight into the protective role of the inactivated COVID-19 vaccine in shaping humoral and cellular immune responses to heterologous Omicron infection. CLINICAL TRIAL: This study is registered with ClinicalTrials.gov as NCT05680896.

Comparison of Three Detection Methods for Seoul Virus Causing Hemorrhagic Fever with Renal Syndrome.

BACKGROUND: Seoul virus (SEOV) is a significant causative pathogen of hemorrhagic fever with renal syndrome (HFRS). Accurate discrimination of SEOV infection from other viral or bacterial infections holds vital clinical importance. METHODS: Our study utilized quantitative real-time PCR (qRT-PCR), metagenomic next-generation sequencing (mNGS), and immunological assays to identify the pathogen causing HFRS. RESULTS: For the case, mNGS identified SEOV and suspected host or environmental microorganisms at 5 days from symptom onset. qRT-PCR detected SEOV between 5 to 8 days from symptom onset. Anti-hantavirus IgM antibodies reached positive criteria at 7 days and IgG antibodies at 9 days from symptom onset. CONCLUSIONS: qRT-PCR, mNGS, and immunological assays each have merits and drawbacks. Optimal selection depends on laboratory conditions and clinical requirements.

The plasticity of neuropeptide Y-Y1 receptor system on Tac2 neurons contributes to mechanical hyperknesis during chronic itch.

Rationale: In the physiological states, the act of scratching protects the person from harmful substances, while in certain pathological conditions, the patient suffers from chronic itch, both physically and mentally. Chronic itch sufferers are more sensitive to mechanical stimuli, and mechanical hyperknesis relief is essential for chronic itch treatment. While neuropeptide Y-Y1 receptor (NPY-Y1R) system is known to play a crucial role in modulating mechanical itch in physiological conditions, it is elusive how they are altered during chronic itch. We hypothesize that the negative regulatory effect of Y1Rs on Tac2 neurons, the key neurons that transmit mechanical itch, declines during chronic itch. Methods: We combined transgenic mice, chemogenetic manipulation, immunofluorescence, rabies virus circuit tracing, and electrophysiology to investigate the plasticity of Y1Rs on Tac2 neurons during chronic itch. Results: We found that Tac2 neurons receive direct input from Npy neurons and that inhibition of Npy neurons induces activation of Tac2 neurons. Moreover, the expression of Y1Rs on Tac2 neurons is reduced, and the regulatory effect is also reduced during chronic itch. Conclusion: Our study clarifies the plasticity of Y1Rs on Tac2 neurons during chronic itch and further elucidates the mechanism by which NPY-Y1R system is responsible for modulating mechanical itch. We highlight Y1Rs as a promising therapeutic target for mechanical hyperknesis during chronic itch.

Epithelial IL5RA promotes epithelial-mesenchymal transition in pulmonary fibrosis via Jak2/STAT3 cascade.

Pulmonary fibrosis is a progressive and debilitating lung disease characterized by the excessive accumulation of extracellular matrix (ECM) components within the lung parenchyma. However, the underlying mechanism remains largely elusive, and the treatment options available for pulmonary fibrosis are limited. Interleukin 5 receptor, alpha (IL5RA) is a well-established regulator of eosinophil activation, involved in eosinophil-mediated anti-parasitic activities and allergic reactions. Recent studies have indicated additional roles of IL5RA in lung epithelium and fibroblasts. Nevertheless, its involvement in pulmonary fibrosis remains unclear. In present study, we employed single-cell analyses alongside molecular and cellular assays to unveil the expression of IL5RA in lung epithelial cells. Moreover, using both in vitro and in vivo models, we demonstrated a notable upregulation of epithelial IL5RA during the progression of pulmonary fibrosis. This upregulated IL5RA expression subsequently promotes epithelial-mesenchymal transition (EMT), leading to the generation of mesenchymal phenotype with augmented capability for ECM production. Importantly, our findings uncovered that the pro-fibrotic function of IL5RA is mediated by Jak2/STAT3 signaling cascades. Inhibiting IL5RA has the potential to deactivate Jak2/STAT3 and suppress the downstream EMT process and ECM production, thereby offering a promising therapeutic strategy for pulmonary fibrosis.

Impact of thermal treatment on proanthocyanidin-pectin binary complexes: Insights from structural, rheological, antioxidant, and astringent properties.

In this study, the effects of thermal treatments on the structural, rheological, water mobility, antioxidant, and astringency properties of proanthocyanidin (PA)-pectin binary complexes were investigated. Thermal treatments (25, 63, or 85 °C) significantly decreased the particle size but increased the molecular weight of PA-pectin complexes, which indicated that heating altered the intermolecular and intramolecular interactions between PA and pectin. The thermal treatments reduced the apparent viscosity of both pectin and PA-pectin complexes, but the presence of proanthocyanidins (PAs) increased the apparent viscosity and water mobility of the PA-pectin complexes. Antioxidant activity analysis showed that the presence of pectin slightly reduced the antioxidant activity of the PAs, but there were no significant changes in the total phenolic content and antioxidant activity after thermal treatment. Finally, we found that pectin reduced the astringency of the PAs by forming PA-pectin complexes. Moreover, the thermal treatments also significantly reduced the astringency of the PA-pectin complexes.

Degree of methyl esterification: A key factor for the encapsulation of icaritin with pectin.

Pectin is a promising nano-carrier. The degree of methyl esterification (DM) influences the physiochemical properties of pectin. However, the effect of DM on the encapsulation capacity of pectin remains unclear. In this work, low methyl-esterified pectin (LMP) and high methyl-esterified pectin (HMP) were prepared. The molecular weight, rheological properties of these pectins with various DM levels were determined. Then icaritin/pectin micelles (IPMs) were prepared using HMP and LMP. Notably, higher loading capacities (18.75-20.12 %) were observed in HMP-IPMs compared to LMP-IPMs (15.72-16.64 %). Furthermore, LMP-IPMs demonstrated a DM-dependent reduction in particle sizes, ranging from 449 to 527 nm. In contrast, the particle sizes of HMP-IPMs varied between 342 and 566 nm, with smaller particle sizes observed in HMP-IPMs at higher DM levels. A significant positive correlation was found between DM and the formation of IPMs, including encapsulation efficiency, loading capacity, Zeta potential, and polydispersity index. Alkali de-esterification showed a weak impact on the pectin structure. Hydroxyl groups like 7-OH and 5-OH of icaritin might be involved in the formation of IPMs. The hydrogen-bond interactions between pectin and icaritin could be enhanced as DM increased.

Correlation Between Bariatric Surgery and the Risk of Multiple Myeloma: Results from an Evidence-Based Strategy.

OBJECTIVE: We conducted a meta-analysis of current literature to assess whether bariatric surgery(BS) has a positive effect on reducing the risk of multiple myeloma(MM). METHODS: Relevant studies meeting the criteria were systematically reviewed using databases such as PubMed, Web of Science, Embase (Ovid platform), MEDLINE, and the Cochrane Library. The meta-analysis utilized hazard ratios (RR) and 95% confidence intervals (CI) to analyze the correlation between BS and the risk of MM. STATA software (version 12.0) was employed for the meta analysis. RESULTS: The meta-analysis included 10 eligible studies, involving 2,452,503 patients with obesity. The results demonstrated a significant reduction in the risk of multiple myeloma in patients with obesity after bariatric surgery compared to non-surgical patients with obesity (RR = 0.51, 95%CI: 0.31-0.84). Subgroup analyses revealed a decreased probability of developing multiple myeloma in European patients with obesity and North American patients with obesity who underwent bariatric surgery. Studies with a sample size greater than or equal to 100,000 indicated a significantly reduced risk of multiple myeloma in patients with obesity undergoing bariatric surgery compared to the non-surgical group (RR: 0.45, 95%CI: 0.23-0.88, P < 0.02). Two publications before 2010 showed no significant difference in the incidence of multiple myeloma between the surgical and non-surgical groups (RR: 0.61, 95% CI: 0.14-2.63, P = 0.504), while publications after 2010 demonstrated a reduced incidence in the surgical group (RR: 0.51, 95% CI: 0.30-0.86, P = 0.012). CONCLUSION: Our meta-analysis results suggest a reduced risk of multiple myeloma in patients with obesity following bariatric surgery. PROSPERO REGISTRATION: CRD42023485668.

Anti-obesity effects of mulberry leaf extracts on female high-fat diet-induced obesity: Modulation of white adipose tissue, gut microbiota, and metabolic markers.

Mulberry leaves (MLs) are reported to have beneficial effects in modulating obesity in male models. However, the impact of different types of mulberry leaf extracts (MLEs) on female models, specifically their influence on adipocytes, gut microbiota, and related metabolic markers, remains poorly understood. In this study, we observed a strong correlation between the total phenolic content (TPC), antioxidant and adipocyte modulation effects of water extracted MLEs. HB-W (water-extracted baiyuwang) and HY-W (water-extracted Yueshen) demonstrated remarkable inhibition effects on adipocytes in 3 T3-L1 adipocytes model. Moreover, MLEs effectively reduced the levels of triglycerides (TG), non-esterified fatty acids (NEFA), and total cholesterol (T-CHO) in adipocytes in vitro. In vivo experiments conducted on female mice with high fat diet (HFD)-induced obesity revealed the anti-obesity effects of HB-W and HY-W, leading to a significant decrease in weight gain rates and notable influence on the ratios of adipose tissue, particularly white adipose tissue (WAT). Gene expression analysis demonstrated the up-regulation of WAT-related genes (Pla2g2a and Plac8) by HB-W, while HY-W supplementation showed beneficial effects on the regulation of blood sugar-related genes. Furthermore, both HB-W and HY-W exhibited modulatory effects on obesity-related gut microbiota (Firmicutes-to-Bacteroidetes ratio) and short chain fatty acid (SCFA) contents. Importantly, they also mitigated abnormalities in liver function and uncoupling protein 1 (UPC1) expression. Overall, our findings underscore the anti-obesity effects of MLEs in female rats with high-fat diet-induced obesity.

Identification of the first selective bioluminescent probe for real-time monitoring of carboxylesterase 2 in vitro and in vivo.

Carboxylesterase (CES), a main hydrolysis enzyme family in the human body, plays a crucial role in drug metabolism. Among them, CES1 and CES2 are the primary subtypes, and each exhibits distinct distribution and functions. However, convenient and non-invasive methods for distinguishing them and the real-time monitoring of CES2 are relatively rare, hindering the further understanding of physiological functions and underlying mechanisms. In this study, we have designed, synthesized, and evaluated the first selective bioluminescent probe (CBP 1) for CES2 with high sensitivity, high specificity and rapid reactivity. This probe offers a promising approach for the real-time detection of CES2 and its dynamic fluctuations both in vitro and in vivo.

Serum iron status and the risk of lung cancer: a two-sample Mendelian-randomization study.

Background: Previous epidemiological studies have reported controversial findings about the potential causal association between iron status and lung cancer. This study sought to assess the potential causality of serum iron status and lung cancer using the Mendelian-randomization (MR) method. Methods: We selected the genetic variables for iron status from the Genetics of Iron Status (GIS) consortium comprising 48,972 samples from European populations. The following two analysis strategies for instrumental variables (IVs) were applied: a conservative approach (instruments related to four iron status markers), and a liberal approach (instruments related to each iron status marker). The summary-level data for lung cancer were obtained from the International Lung Cancer Consortium comprising 27,209 individuals from European populations. The causality between serum iron status and lung cancer was examined. Results: Using the conservative approach, a higher serum iron status was found to be causally correlated with lower risks of lung squamous cell carcinoma. The odds ratios of lung squamous cell carcinoma per standard deviation (SD) unit increment in the four iron status markers were 0.73 [95% confidence interval (CI): 0.60-0.89; P=0.002] in serum iron, 0.50 (95% CI: 0.33-0.77; P=0.002) in ferritin, 1.35 (95% CI: 1.09-1.67; P=0.006) in transferrin, and 0.80 (95% CI: 0.69-0.92; P=0.001) in transferrin saturation based on the inverse variance-weighted method. Similar results were found using the liberal approach. Conclusions: Genetically, a high serum iron status was inversely associated with the risk of lung squamous cell carcinoma. More research needs to be conducted to explore the underlying mechanisms and to determine the potential application value about preventing the occurrence of cancer.

Intelligent Electrochemical Point-of-Care Test Method with Interface Control Based on DNA Pyramids: Aflatoxin B1 Detection in Food and the Environment.

Sensitive, intelligent point-of-care test (iPOCT) methods for small molecules like aflatoxin B1 (AFB1) are urgently needed for food and the environment. The challenge remains of surface control in iPOCT. Herein, we developed an electrochemical sensor based on the DNA pyramid (DNP), combining a smartphone, app, and mobile electrochemical workstations to detect AFB1. The DNP's structure can reduce local overcrowding and entanglement between neighboring probes, control the density and orientation of recognition probes (antibodies), produce uniform and orientational surface assemblies, and improve antigen-antibody-specific recognition and binding efficiency. Simultaneously, the hollow structure of the DNP enhances the electron transfer capacity and increases the sensitivity of electrochemical detection. In this work, the biosensor based on DNP was first combined with electrochemical (Ec) iPOCT to simultaneously achieve ordered interface modulation of recognition probes and intelligent detection of AFB1. Under optimal conditions, we found a detection limit of 3 pg/mL and a linear range of 0.006-30 ng/mL (R2 = 0.995). Further, using peanut, soybean, corn, and lake water as complex matrices, it recorded recoveries of 82.15-100.53%, excellent selectivity, acceptable stability, and good reproducibility. Finally, this Ec iPOCT provides consistent results compared to the high-performance liquid chromatography-tandem mass spectrometry method.

USP10 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells.

Cisplatin-based chemotherapy is the main treatment option for advanced or metastatic esophageal squamous cell carcinoma (ESCC). However, most ESCC patients develop drug resistance within 2 years after receiving cisplatin chemotherapy. Ubiquitin-specific protease 10 (USP10) is abnormally expressed in a variety of cancers, but the mechanistic roles of USP10 in ESCC are still obscure. Here, the effects of USP10 on the migration and cisplatin resistance of ESCC in vivo and in vitro and the underlying mechanisms have been investigated by bioinformatics analysis, RT-PCR, western blotting, immunoprecipitation, immunohistochemistry, cell migration and MTS cell proliferation assays, deubiquitination assay, and mouse tail vein injection model. USP10 was significantly up-regulated in ESCC tissues compared with adjacent normal tissues in both public databases and clinical samples and was closely associated with overall survival. Subsequent results revealed that USP10 contributed to the migration and cisplatin resistance of ESCC cells, while knocking down USP10 in cisplatin-resistant cells exhibited opposite effects in vitro and in vivo. Further Co-IP experiments showed that integrin ß1 and YAP might be targets for USP10 deubiquitination. Moreover, deficiency of USP10 significantly inhibited the migrative and chemo-resistant abilities of ESCC cells, which could be majorly reversed by integrin ß1 or YAP reconstitution. Altogether, USP10 was required for migration and cisplatin resistance in ESCC through deubiquinating and stabilizing integrin ß1/YAP, highlighting that inhibition of USP10 may be a potential therapeutic strategy for ESCC.

Si3C Monolayer as an Efficient Metal-Free Catalyst for Nitrate Electrochemical Reduction: A Computational Study.

Nitrate electroreduction reaction to ammonia (NO3ER) holds great promise for both nitrogen pollution removal and valuable ammonia synthesis, which are still dependent on transition-metal-based catalysts at present. However, metal-free catalysts with multiple advantages for such processes have been rarely reported. Herein, by means of density functional theory (DFT) computations, in which the Perdew-Burke-Ernzerhof (PBE) functional is obtained by considering the possible van der Waals (vdW) interaction using the DFT+D3 method, we explored the potential of several two-dimensional (2D) silicon carbide monolayers as metal-free NO3ER catalysts. Our results revealed that the excellent synergistic effect between the three Si active sites within the Si3C monolayer enables the sufficient activation of NO3- and promotes its further hydrogenation into NO2*, NO*, and NH3, making the Si3C monolayer exhibit high NO3ER activity with a low limiting potential of -0.43 V. In particular, such an electrochemical process is highly dependent on the pH value of the electrolytes, in which acidic conditions are more favorable for NO3ER. Moreover, ab initio molecular dynamics (AIMD) simulations demonstrated the high stability of the Si3C monolayer. In addition, the Si3C monolayer shows a low formation energy, excellent electronic properties, a superior suppression effect on competing reactions, and high stability, offering significant advantages for its experimental synthesis and practical applications in electrocatalysis. Thus, a Si3C monolayer can perform as a promising NO3ER catalyst, which would open a new avenue to further develop novel metal-free catalysts for NO3ER.