Light controlled self-escape capability of non-cationic carbon nitride-based nanosheets in lysosomes for hepatocellular carcinoma targeting stimulus-responsive gene delivery.

High positive charge-induced toxicity, easy lysosomal degradation of nucleic acid drugs, and poor lesion sites targeting are major problems faced in the development of gene carriers. Herein, we proposed the concept of self-escape non-cationic gene carriers for targeted delivery and treatment of photocontrolled hepatocellular carcinoma (HCC) with sufficient lysosome escape and multiple response capacities. Functional DNA was bound to the surface of biotin-PEG2000-modified graphitic carbon nitride (Bio-PEG-CN) nanosheets to form non-cationic nanocomplexes Bio-PEG-CN/DNA. These nanocomposites could actively target HCC tissue. Once these nanocomplexes were taken up by tumor cells, the accumulated reactive oxygen species (ROS) generated by Bio-PEG-CN under LED irradiation would disrupt the lysosome structure, thereby facilitating nanocomposites escape. Due to the acidic microenvironment and lipase in the HCC tissue, the reversible release of DNA could be promoted to complete the transfection process. Meanwhile, the fluorescence signal of Bio-PEG-CN could be monitored in real time by fluorescence imaging technology to investigate the transfection process and mechanism. In vitro and in vivo results further demonstrated that these nanocomplexes could remarkably upregulate the expression of tumor suppressor protein P53, increased tumor sensitivity to ROS generated by nanocarriers, and realized effective gene therapy for HCC via loading P53 gene.

[Research Progress on Distribution Characteristics and Formation Mechanisms of Microplastics in the Environment].

The extensive application of plastic products leads to the increasingly significant harm of plastic wastes to the ecological environment, which is also a focus of global environmental issues. Due to the lack of a sound plastic waste management system, most plastic waste is still treated by the traditional mode or remains in the environment, with low recycling efficiency, and the plastic life cycle has not yet formed. Plastics in the environment will age and degrade under the actions of physical (wear, waves), chemical (ultraviolet radiation, hydrolysis), and biological (fungi, bacteria) factors for a long time and generate micro (nano) plastics. Due to their small particle size, large specific surface area, and charged characteristics, in addition to their own toxicity, they can also be used as carriers or covert carriers of pollutants (heavy metals, persistent organic pollutants, polycyclic aromatic hydrocarbons, bacteria, etc.) to migrate in the environment through runoff, sewage discharge, and hydrometeorology, causing ecological environmental pollution. MPs pollution has been listed as the second largest scientific problem in the field of environmental and ecological science by the United Nations Environment Programme. MPs are widely distributed, and there are different degrees of MPs pollution in the global water (freshwater, ocean), soil, and atmospheric environment. Traces of MPs have also been found in human placentas, human breastmilk, living lungs, and blood in recent years. Therefore, the formation mechanisms of MPs under the actions of physics, chemistry, and microorganisms, as well as their abundance levels and migration characteristics in water, soil, and atmosphere environment were comprehensively reviewed, with the hope of providing reference for monitoring the pollution levels of MPs in the environment, exploring their transport laws in the environment, proposing the management strategy of MPs pollution, and revealing the degradation mechanisms of MPs under different effects.

B7-H3 and CD47 co-expression in gastric cancer is a predictor of poor prognosis and potential targets for future dual-targeting immunotherapy.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent types of cancer worldwide. B7-H3, an immune checkpoint molecule with promising potential, has been found to be overexpressed in various cancers. CD47 is an anti-phagocytic molecule that interacts with the signal regulatory protein alpha (SIRPα) to affect phagocytes. The relationship between the expression of B7-H3 and CD47, two potential therapeutic targets found in tumor cells, remains unknown. In this study, our objective is to investigate the clinical significance of co-expression of B7-H3 and CD47, as well as the potential therapeutic value of combination therapy in GC. METHODS: We utilized immunohistochemistry (IHC) to assess the expression of B7-H3, CD47, CD68, CD86 and CD163 in tissue microarrays obtained from 268 GC patients who underwent surgeries. Western blotting was employed to assess the protein level of B7-H3 and CD47 in GC tissues. The co-localization of B7-H3/CD47 and CD68 in GC tissues was determined using multiplex immunohistochemistry (m-IHC). We further verified the relationship between B7-H3/CD47 and macrophage infiltration via flow cytometry. To estimate the clinical outcomes of patients from different subgroups, we employed the Kaplan-Meier curve and the Cox model. RESULTS: Among the 268 GC cases, a total of 180 cases exhibited positive expression of B7-H3, while 122 cases showed positive expression of CD47. In fresh GC clinical tissues, B7-H3 and CD47 protein level was also higher in tumor tissue than in adjacent normal tissue. Remarkably, 91 cases demonstrated co-expression of B7-H3 and CD47. We observed a significant correlation between B7-H3 expression and tumor stage (P = 0.001), differentiation (P = 0.045), and depth (P = 0.003). Additionally, there was a significant association between B7-H3 and CD47 expression (P = 0.018). The percentage of B7-H3 and CD47 double positive cells in fresh GC tumor tissues were elevated compared with control adjacent tissues regardless of CD45- or CD45+ cells (P = 0.0029, P = 0.0012). Patients with high B7-H3 or CD47 expression had significantly lower overall survival (OS) rates compared to those with low expression levels (P = 0.0176 or P = 0.0042). Surprisingly, patients with combined high expression of B7-H3 and CD47 exhibited a considerably worse prognosis than others (P = 0.0007). Univariate analysis revealed that cases with high expression of B7-H3, CD47, or both had significantly higher hazard ratios (HR) than cases with low expression of these markers. Furthermore, the results of multivariate analysis indicated that B7-H3/CD47 co-expression and CD47 expression alone are independent prognostic factors for overall survival. Moreover, significant correlations were observed between B7-H3 and CD68 expression, CD47 and CD68 expression, as well as B7-H3/CD47 co-expression and CD68 expression in GC patients (P < 0.001, P = 0.003, and P < 0.001). Flow cytometry test showed that the percentage of CD68-positive cells but not CD86-positive cells among B7-H3-positive or CD47-positive immune cells in GC tumor tissue was elevated significantly compared with adjacent tissue. CONCLUSION: Our findings demonstrated a correlation between B7-H3 expression and CD47 expression in GC patient tissues. Co-expression of B7-H3 and CD47 can serve as an indicator of poor prognosis in GC patients. In GC tumor tissue, but not adjacent tissue, B7-H3 and CD47 expression was accompanied with macrophage infiltration.

The V-shaped curve relationship between fasting plasma glucose and human serum albumin in a large health checkup population in China.

BACKGROUND: This study aimed to investigate the relationship between fasting plasma glucose (FPG) and human serum albumin (HSA) in a large health checkup population in China. METHODS: In this cross-sectional health checkup study, we enrolled a population of 284,635 subjects from Wuhu between 2011 and 2016. All participants completed the physical examination, blood biochemical examination, and blood routine examination. RESULTS: The prevalence of diabetes in men and women was 6.11% and 2.98%, respectively. The average level of HSA and FPG was significantly higher in men than in women (48.44 ± 3.25 vs. 47.14 ± 3.22, P < 0.0001; 5.50 ± 1.26 vs. 5.26 ± 0.94, P < 0.0001). There were significant differences in blood biochemistry and blood routine values by gender. After adjusting for confounding factors, the results showed that FPG and HSA were a V-shaped curve, and the threshold value of HSA was 40.7 mmol/L. FPG and HSA still showed a V-shaped curve after stratification by gender and age. In the male group, FPG decreased with HSA when HSA<42.3 mmol/L, and increased when HSA ≥ 42.3 mmol/L. In the female group, FPG decreased with HSA when HSA<35.7 mmol/L, and increased when HSA ≥ 35.7 mmol/L. In the age<65 group, FPG decreased with HSA when HSA<37.5 mmol/L, and increased when HSA ≥ 37.5 mmol/L. In the age ≥ 65 group, FPG decreased with HSA when HSA<43.2 mmol/L, and increased when HSA ≥ 43.2 mmol/L. CONCLUSIONS: A V-shape relationship exists between fasting plasma glucose and human serum albumin among the Chinese health checkup population studied.

Non-volatile control of topological phase transition in an asymmetric ferroelectric In2Te2S monolayer.

The coupling of topological electronic states and ferroelectricity is highly desired due to their abundant physical phenomenon and potential applications in multifunctional devices. However, it is difficult to achieve such a phenomenon in a single ferroelectric (FE) monolayer because the two polarized states are topologically equivalent. Here, we demonstrate that the symmetry of polarized states can be broken by constructing a Janus structure in a FE monolayer. We illustrate such a general idea by replacing a layer of Te atoms in the In2Te3 monolayer with S atoms. Using first-principles calculations, we show that the In2Te2S monolayer has two asymmetric polarized states, which are characterized by a metal and semiconductor, respectively. Importantly, as the spin-orbit coupling is included, a band gap (50.4 meV) is created in the metallic state, resulting in a non-trivial topological phase. Thus, it proves to be a feasible method to engineer non-volatile FE control of topological order in a single-phase system. We also demonstrate the underlying physical mechanism of topological phase transition, which is unveiled to be related to the weakened intrinsic electric field resulting from charge transfer. These interesting results provide a general way to design asymmetric FE materials and shed light on their potential application in non-volatile multifunctional devices.

Impact of carotid hemodynamics on carotid plaque location: Age difference.

PURPOSE: This study was aimed to investigate the influence of carotid hemodynamics in common carotid artery (CCA) and internal carotid artery (ICA) on carotid plaque location. METHODS: A total of 4444 participants from Anhui Maanshan People's Hospital were selected from December 2013 to December 2018. Doppler ultrasound was used to measure the location of carotid plaque. Patients were divided into four groups according to plaque location: LEFT, RIGHT, BOTH, and NONE. Multiple logistic regression and smooth curve were applied to determine the relationship of carotid plaque location and hemodynamic indexes. RESULTS: Compared with the NONE group, the ratio of artery systolic and diastolic blood flow velocity in right internal carotid (RICA S/D) was a risk factor for LEFT group (OR=1.548) after adjustment; artery systolic and diastolic blood flow velocity ratio of left common carotid artery (LCCA S/D) was a risk factor for RIGHT group (OR=1.250); resistance index of right internal carotid (RICA RI) was a protective factor for BOTH group (OR=0.097), while LCCA S/D and RICA S/D were risk factors for BOTH group (OR=1.201, OR=1.457). Compared with the RIGHT group, artery systolic and diastolic blood flow velocity ratio of right common carotid (RCCA S/D) was the risk factor for the LEFT group (OR=1.463), LCCA S/D and RICA S/D were the risk factors for BOTH group (OR=1.706, OR=2.111). After age stratification, resistance index of right common carotid artery (RCCA RI) and resistance index of left internal carotid artery (LICA RI) were protective factors for BOTH group (OR=0.046, OR=0.042) in group younger than 52. RCCA S/D and RICA S/D were risk factors for BOTH group (OR=1.557, OR=1.843). Resistance index of left common carotid artery (LCCA RI) was a protective factor in the LEFT group compared with the RIGHT group (OR=0.476). In group older than 52, RICA S/D was a risk factor for LEFT group (OR=1.388). LCCA S/D was a risk factor for RIGHT group (OR=1.575). LCCA S/D and RICA S/D were risk factors for BOTH group (OR=1.348, OR=1.311). RICA S/D and RCCA S/D were protective factors in the LEFT group compared with the RIGHT group (OR=0.567, OR=0.680).

Long-term effects of a fat-directed FGF21 gene therapy in aged female mice.

Fibroblast growth factor 21 (FGF21) has been developed as a potential therapeutic agent for metabolic syndromes. Moreover, FGF21 is considered a pro-longevity hormone because transgenic mice overexpressing FGF21 display extended lifespan, raising the possibility of using FGF21 to promote healthy aging. We recently showed that visceral fat directed FGF21 gene therapy improves metabolic and immune health in insulin resistant BTBR mice. Here, we used a fat directed rAAV-FGF21 vector in 17-month-old female mice to investigate whether long-term FGF21 gene transfer could mitigate aging-related functional decline. Animals with FGF21 treatment displayed a steady, significant lower body weight over 7-month of the study compared to age-matched control mice. FGF21 treatment reduced adiposity and increased relative lean mass and energy expenditure associated with almost 100 folds higher serum level of FGF21. However, those changes were not translated into benefits on muscle function and did not affect metabolic function of liver. Overall, we have demonstrated that a single dose of fat-directed AAV-FGF21 treatment can provide a sustainable, high serum level of FGF21 over long period of time, and mostly influences adipose tissue homeostasis and energy expenditure. High levels of FGF21 alone in aged mice is not sufficient to improve liver or muscle functions.

AAV-BDNF gene therapy ameliorates a hypothalamic neuroinflammatory signature in the Magel2-null model of Prader-Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) exhibit several metabolic and behavioral abnormalities associated with excessive food-seeking activity. PWS is thought to be driven in part by dysfunctional hypothalamic circuitry and blunted responses to peripheral signals of satiety. Previous work described a hypothalamic transcriptomic signature of individuals with PWS. Notably, PWS patients exhibited downregulation of genes involved in neuronal development and an upregulation of neuroinflammatory genes. Deficiencies of brain-derived neurotrophic factor (BDNF) and its receptor were identified as potential drivers of PWS phenotypes. Our group recently applied an adeno-associated viral (AAV)-BDNF gene therapy within a preclinical PWS model, Magel2-null mice, to improve metabolic and behavioral function. While this proof-of-concept project was promising, it remained unclear how AAV-BDNF was influencing the hypothalamic microenvironment and how its therapeutic effect was mediated. To investigate, we hypothalamically injected AAV-BDNF to wild type and Magel2-null mice and performed mRNA sequencing on hypothalamic tissue. Here, we report that (1) Magel2 deficiency is associated with neuroinflammation in the hypothalamus and (2) AAV-BDNF gene therapy reverses this neuroinflammation. These data newly reveal Magel2-null mice as a valid model of PWS-related neuroinflammation and furthermore suggest that AAV-BDNF may modulate obesity-related neuroinflammatory phenotypes through direct or indirect means.

Protocol to minimize the confounding effect of cold stress on socially isolated mice using thermoneutral housing.

Social isolation, a risk factor for mortality and various disease states, in mice remains poorly understood, due in part to under-consideration of housing temperature and the murine thermoneutral zone. Here, we present a housing protocol to minimize the confounding effect of chronic cold stress on socially isolated mice that are unable to socially thermoregulate. We describe steps for allocating mice to group housing or social isolation conditions, housing mice in thermoneutral cabinets, feeding mice with high-fat diet, and measuring body weight, food intake, and metabolic indicators. For complete details on the use and execution of this protocol, please refer to Queen et al..1.

Gender-based relationship between serum creatinine and carotid plaque stability: A cross-sectional study in China.

OBJECTIVE: Carotid plaque instability is a risk factor for ischemic stroke, and changes in serum creatinine are associated with carotid plaque. However, the relationship between serum creatinine and carotid plaque stability is not well explained. This study aimed to interpret this relationship for clinical treatment of carotid plaque. METHODS: A total of 4363 subjects aged 29-86 from December 2013 to December 2018 were included in this study. The stability of carotid plaque was determined based on ultrasound echoes and divided into two groups: carotid plaque stable group and carotid plaque unstable group. The relationship between serum creatinine and carotid plaque stability was determined using curve fitting methods as well as logistic regression. RESULTS: After age stratification, there was an inverted U-shaped curve between the stability of right carotid plaque and serum creatinine in males, When serum creatinine levels were less than 84 µmol/L, the probability of carotid plaque instability gradually increased, and the carotid plaque became stable when creatinine levels were greater than 84 µmol/L. The relationship between left carotid female plaque stability and serum creatinine showed a U-shaped curve. When serum creatinine levels were less than 80 µmol/L, the carotid plaque stability stabilized, and the probability increased when creatitine levels were more than 80 µmol/L, as the carotid plaque instability rose. CONCLUSION: There was an inverted U-shaped relationship between the stability of carotid plaque in the right carotid artery and serum creatinine in males, and a U-shaped relationship between the stability of carotid plaque in the left carotid artery and serum creatinine in females.

Surgical Management and Outcome of Entero-Urinary Fistula Complicating Crohn's Disease: A Single Center Study.

BACKGROUND: Entero-urinary fistulas (EUF) are a rare complication of Crohn's disease (CD), observed in 1.6 to 7.7%. The management of EUF complicating CD is challenging. We aimed to report the outcome and surgical management of EUF in CD. METHODS: A retrospective chart review was performed in all CD patients with EUF who underwent surgery in our center between January 2012 and December 2021. Patient demographics, preoperative optimization, surgical management, postoperative complications, and follow-up information were collected from a prospectively maintained database. RESULTS: A total of 74 eligible patients were identified. The median interval between CD diagnosis and EUF diagnosis was 2 (0.08-6.29) years. Patients with EUF presented with pneumaturia (75.68%), urinary tract infections (72.97%), fecaluria (66.22%), and hematuria (6.76%). Fistulae originated most commonly from the ileum (63.51%), followed by the colon (14.86%), the rectum (9.46%), the cecum (2.70%), and multiple sites (9.46%). The EUF symptoms, weight, nutritional status, laboratory results were significantly improved after preoperative optimization. The absence of EUF symptoms was observed in 42 patients after the optimization and only 9 of which required bladder repair. However, 19 of 32 patients whose symptoms did not resolve required bladder repair (P = 0.001). Only 1 patient developed a bladder leakage in the early postoperative period and 3 patients experienced recurrent bladder fistula. CONCLUSIONS: Surgical management of EUF complicating CD is effective and safe, with a low rate of postoperative complication and EUF recurrence. Preoperative optimization, which is associated with the resolution of urinary symptoms and improved surgical outcomes, should be recommended.

Effects of Air Pollution Exposure during Preconception and Pregnancy on Gestational Diabetes Mellitus.

This study aimed to investigate the association between air pollution and gestational diabetes mellitus (GDM) in small- and medium-sized cities, identify sensitive periods and major pollutants, and explore the effects of air pollution on different populations. A total of 9820 women who delivered in Handan Maternal and Child Health Hospital in the Hebei Province from February 2018 to July 2020 were included in the study. Logistic regression and principal component logistic regression models were used to assess the effects of air pollution exposure during preconception and pregnancy on GDM risk and the differences in the effects across populations. The results suggested that each 20 µg/m3 increase in PM2.5 and PM10 exposure during preconception and pregnancy significantly increased the risk of GDM, and a 10 µg/m3 increase in NO2 exposure during pregnancy was also associated with the risk of GDM. In a subgroup analysis, pregnant women aged 30-35 years, nulliparous women, and those with less than a bachelor's education were the most sensitive groups. This study provides evidence for an association between air pollution and the prevalence of GDM, with PM2.5, PM10, and NO2 as risk factors for GDM.

Development of a nomogram for the early prediction of PACU VAS in patients undergoing laparoscopic radical resection of colorectal cancer with fentanyl.

Introduction: To make early predictions of PACU VAS before surgery, we created a novel nomogram for the early prediction of PACU VAS in patients having laparoscopic radical excision of colorectal cancer with fentanyl. Methods: From July 2018 to December 2020, a total of 101 patients in Zhongshan Hospital Affiliated to Fudan University who underwent laparoscopic radical resection of colorectal cancer were enrolled in this study. For feature selection, a stepwise regression model was utilized. Multivariable logistic regression analysis was used to establish a prediction model. We incorporated age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype, and this was presented with a nomogram. The nomogram's performance was evaluated in terms of discrimination and clinical utility. Results: The signature, which comprised of seven carefully chosen characteristics, was linked to the PACU VAS for the development dataset. Predictors contained in the individualized prediction nomogram included age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype. With an area under the ROC curve of 0.877 (95% CI, 0.6874-1.0000), the model showed good discrimination. The nomogram still had good discrimination. Decision curve analysis demonstrated that the nomogram was clinically useful. Conclusions: The nomogram presented in this study incorporates age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype and can be conveniently used to facilitate the individualized prediction of PACU VAS in patients undergoing laparoscopic radical resection of colorectal cancer with fentanyl.

Darovasertib, a novel treatment for metastatic uveal melanoma.

The FDA granted orphan drug designation to darovasertib, a first-in-class oral, small molecular inhibitor of protein kinase C (PKC), for the treatment of uveal melanoma, on 2 May 2022. Primary uveal melanoma has a high risk of progressing to metastatic uveal melanoma, with a poor prognosis. The activation of the PKC and mitogen-activated protein kinase pathways play an essential role in the pathogenesis of uveal melanoma, and mutations in the G protein subunit alpha q (GNAQ), and G protein subunit alpha11 (GNA11) genes are considered early events in the development of uveal melanoma. Compared to other PKC inhibitors, such as sotrastaurin and enzastaurin, darovasertib is significantly more potent in inhibiting conventional (α, ß) and novel (δ, ϵ, η, θ) PKC proteins and has a better tolerability and safety profile. Current Phase I/II clinical trials indicated that darovasertib, combined with the Mitogen-activated protein kinase/Extracellular (MEK) inhibitors, binimetinib or crizotinib, produced a synergistic effect of uveal melanoma. In this article, we summarize the development of drugs for treating uveal melanomas and discuss problems associated with current treatments. We also discuss the mechanism of action, pharmacokinetic profile, adverse effects, and clinical trial for darovasertib, and future research directions for treating uveal melanoma.

Type-I Photosensitizer-Triggered Controllable Carbon Monoxide Release for Effective Treatment of Staph Skin Infection.

Staphylococcus aureus (S. aureus) infection is a major infectious skin disease that is highly resistant to conventional antibiotic treatment and host immune defense, leading to recurrence and exacerbation of bacterial infection. Herein, we developed a photoresponsive carbon monoxide (CO)-releasing nanocomposite by integrating anion-π+ type-I photosensitizer (OMeTBP) and organometallic complex (FeCO) for the treatment of planktonic S. aureus and biofilm-associated infections. After optimizing the molar ratio of FeCO and OMeTBP, the prepared nanoparticles, OMeTBP@FeCONPs, not only ensured sufficient loading of CO donors and efficient CO generation but also showed negligible free ROS leakage under light irradiation, which helped to avoid tissue damage caused by excessive ROS. Both in vitro and in vivo results demonstrated that OMeTBP@FeCONPs could effectively inhibit S. aureus methicillin-resistant S. aureus (MRSA), and bacterial biofilm. Our design has the potential to overcome the resistance of conventional antibiotic treatment and provide a more effective option for bacterial infections.

Metronomic capecitabine with rapamycin exerts an immunosuppressive effect by inducing ferroptosis of CD4+ T cells after liver transplantation in rat.

Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor recurrence after liver transplantation is the key to determining the long-term prognosis of patients with HCC after liver transplantation. In our previous study, we found that capecitabine (CAP), an effective drug for the treatment of HCC, could exert an immunosuppressive effect after liver transplantation by inducing T cell ferroptosis. Recent studies have shown that ferroptosis is highly associated with autophagy. In this study, we confirmed that the autophagy inducer rapamycin (RAPA) combined with metronomic capecitabine (mCAP) inhibits glutathione peroxidase 4 (GPX4) and promotes ferroptosis in CD4+ T cells to exert immunosuppressive effects after rat liver transplantation. Compared with RAPA or mCAP alone, the combination of RAPA and mCAP could adequately reduce liver injury in rats with acute rejection after transplantation. The CD4+ T cell counts in peripheral blood, spleen, and transplanted liver of recipient rats significantly decreased, and the oxidative stress level and ferrous ion concentration of CD4+ T cells significantly increased in the combination group. In vitro, the combination of drugs significantly promoted autophagy, decreased GPX4 protein expression, and induced ferroptosis in CD4+ T cells. In conclusion, the autophagy inducer RAPA improved the mCAP-induced ferroptosis in CD4+ T cells. Our results support the concept of ferroptosis as an autophagy-dependent cell death and suggest that the combination of ferroptosis inducers and autophagy inducers is a new research direction for improving immunosuppressive regimens after liver transplantation.

The cGAS-STING-YY1 axis accelerates progression of neurodegeneration in a mouse model of Parkinson's disease via LCN2-dependent astrocyte senescence.

Recent studies provide clues that astrocyte senescence is correlated with Parkinson's disease (PD) progression, while little is known about the molecular basis for astrocyte senescence in PD. Here, we found that cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) was upregulated in senescent astrocytes of PD and aged mice. Strikingly, deletion of astrocytic cGAS significantly prevented senescence of astrocytes and neurodegeneration. Furthermore, we identified LCN2 as the effector of cGAS-STING signal by RNA-Seq analysis. Genetic manipulation of LCN2 expression proved the regulation of cGAS-STING-LCN2 axis in astrocyte senescence. Additionally, YY1 was discovered as the transcription factor of LCN2 by chromatin immunoprecipitation. Binding of STING to YY1 impedes nuclear translocation of YY1. Herein, we determine the involvement of the cGAS-STING-YY1-LCN2 signaling cascade in the control of astrocyte senescence and PD progression. Together, this work fills the gap in our understanding of astrocyte senescence, and provides potential targets for delaying PD progression.