Asthma, a prevalent chronic disease, poses significant health threats and burdens healthcare systems. This study focused on the role of bronchial epithelial cells in asthma pathophysiology.

Bioinformatics was used to identify key asthmarelated genes. An ovalbumin-sensitized mouse model and an IL-13-stimulated Beas-2B cell model were established for further investigation.

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a crucial gene in asthma. CEACAM5 expression was elevated in asthmatic mouse lung tissues and IL-13-stimulated Beas-2B cells, primarily in bronchial epithelial cells. CEACAM5 induced reactive oxygen species (ROS), lipid peroxidation, and ferroptosis. Interfering with CEACAM5 reduced ROS, malondialdehyde levels, and enhanced antioxidant capacity, while inhibiting iron accumulation and autophagy. Overexpression of CEACAM5 in IL-13-stimulated cells activated the JAK/STAT6 pathway, which was necessary for CEACAM5-induced autophagy, ROS accumulation, lipid peroxidation, and ferroptosis.

CEACAM5 promotes ferroptosis and autophagy in airway epithelial cells via the JAK/STAT6 pathway, exacerbating asthma symptoms. It represents a potential target for clinical treatment.

To investigate the role of microvascular pericyte dysfunction in antibody-mediated rejection (ABMR) of transplanted kidneys.

A total of 160 patients who underwent kidney transplantation in our hospital from 2004 to 2020 were enrolled, divided into 4 groups: ABMR group (n = 79), TCMR group (n = 20), mixed rejection group (n = 25) and control group (n = 36). Postoperative renal function indicators were compared, and immunohistochemical and immunofluorescence staining was performed on graft tissues and mice models using the pericyte marker PDGFR-β. An in vitro pericyte dysfunction model was co-cultured with vascular endothelial cells for functional assessment through Western blotting, PCR, and wound healing tests. KEGG pathway analysis from the GEO database identified gene expression changes in pericytes, which were further analyzed using electron microscopy and Western blot techniques.

There were statistically significant differences in creatinine, urea nitrogen, urine protein, and eGFR among the groups over time, with ABMR displaying the poorest outcomes. Immunohistochemistry revealed lower pericyte expression in ABMR, which was confirmed in mouse model studies showing reduced PDGFR-β expression in ABMR. KEGG analysis highlighted decreased autophagy in pericyte dysfunction, supported by electron microscopy and Western blot findings indicating reduced autophagy and pericyte damage, which could be reversed by chloroquine.

ABMR episodes worsened the long-term prognosis of transplanted kidneys. pericyte dysfunction appears to be one of the crucial causes of poor prognosis in ABMR patients. In vitro studies demonstrated that dysfunction of microvascular pericytes can result in damage to vascular endothelial cells, with autophagy impairment being a significant mechanism contributing to pericyte dysfunction.

Congenital Zika virus (ZIKV) infection significantly affects neurological development in infants and subsequently induces neurodevelopmental abnormality symptoms; however, the potential mechanism is still unknown. Therefore, in order to effectively intervene in neurodevelopmental abnormalities in infected infants, it is necessary to identify the main brain regions affected by congenital infection. In this study, we constructed a congenital ZIKV-infected murine model using immunocompetent human STAT2 knock-in mice, which presented long-term neurodevelopmental abnormalities with abnormal neurodevelopmental symptoms. We found that the hippocampus, which regulates cognitive behaviour and processes spatial information and navigation, was the main brain region affected by congenital infection and that hippocampal cells were more prone to autophagy during the growth period of these mice at the transcriptional and pathological levels. These findings highlighted that congenital ZIKV infection could interrupt hippocampal function by activating autophagy, thus providing a theoretical basis for the clinical treatment of congenital ZIKV-infected infants.

Acute central nervous system injuries, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, are a major global health challenge. Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities. Mitochondria are susceptible to damage after acute central nervous system injury, and this leads to the release of toxic levels of reactive oxygen species, which induce cell death. Mitophagy, a selective form of autophagy, is crucial in eliminating redundant or damaged mitochondria during these events. Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries. In this review, we provide a comprehensive overview of the process, classification, and related mechanisms of mitophagy. We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy. In the final section of this review, we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.

Cisplatin is a widely used chemotherapeutic agent in the treatment of non-small cell lung cancer (NSCLC), but cisplatin resistance remains a significant clinical challenge. Lysosomal transmembrane protein 5 (LAPTM5) is a lysosomal membrane protein implicated in macroautophagy/autophagy, although its precise mechanism has yet to be fully elucidated.In this study, we demonstrated that LAPTM5 promotes cisplatin resistance in NSCLC by maintaining lysosomal membrane stability and preserving autophagic flux. Mechanistic investigations showed that LAPTM5 competes with LAMP1 for binding to WWP2, thereby inhibiting LAMP1 ubiquitination and degradation, which ultimately preserves lysosomal membrane stability. LAPTM5 knockdown increases lysosomal membrane permeability, leading to the release of cathepsin D (CTSD), which elevates intracellular reactive oxygen species (ROS) levels; further destabilizing the lysosomal membrane and accelerating cell death. Our findings elucidate the mechanism by which LAPTM5 contributes to cisplatin resistance through lysosomal membrane stabilization and identify LAPTM5 as a potential therapeutic target for overcoming cisplatin resistance in NSCLC.

Steatosis is characterized by an increase in free fatty acids, such as palmitic acid (PA), in hepatocytes and the accumulation of triglycerides in the liver. However, the role of intracellular autophagy in PA accumulation-induced hepatotoxicity is not clearly understood. Therefore, in this study, we investigated the effects of PA on autophagy in hepatocytes and its underlying mechanism of action. Treatment of HepG2 cells with PA induced a significant increase in intracellular p62 and LC3-II levels, suggesting inhibition of autophagy. Furthermore, PA inhibited autophagic flux in HepG2 cells, as monitored using GFP-RFP-LC3. Mechanistically, PA increased the phosphorylation of the Ser12 and Thr29 residues of LC3, which are autophagy inhibition markers, through protein kinase A (PKA) and protein kinase C (PKC) signaling. Finally, PKA and PKC inhibitors restored PA-induced autophagic flux inhibition, reduced intracellular lipid accumulation, and rescued the altered expression of lipogenic genes, such as SREBP-1c, in HepG2 cells. Thus, our study demonstrates the mechanism of autophagy inhibition by PA in hepatocytes and provides a potential therapeutic approach for preventing and treating hepatic steatosis.

Cerebral ischemia is a prevalent cerebrovascular disorder, with the restoration of blocked blood vessels serving as the current standard clinical treatment. However, reperfusion can exacerbate neuronal damage and neurological dysfunction, resulting in cerebral ischemia-reperfusion (I/R) injury. Presently, clinical treatment strategies for cerebral I/R injury are limited, creating an urgent need to identify new effective therapeutic targets. The PI3K/AKT signaling pathway, a pro-survival pathway associated with cerebral I/R injury, has garnered significant attention. We conducted a comprehensive review of the literature on the PI3K/AKT pathway in the context of cerebral I/R. Our findings indicate that activation of the PI3K/AKT signaling pathway following cerebral I/R can alleviate oxidative stress, reduce endoplasmic reticulum stress (ERS), inhibit inflammatory responses, decrease neuronal apoptosis, autophagy, and pyroptosis, mitigate blood-brain barrier (BBB) damage, and promote neurological function recovery. Consequently, this pathway ultimately reduces neuronal death, alleviates brain tissue damage, decreases the volume of cerebral infarction, and improves behavioral impairments. These results suggest that the PI3K/AKT signaling pathway is a promising therapeutic target for further research and drug development, holding significant potential for the treatment of cerebral I/R injury.

Lysosomotropic autophagy inhibitors were identified from a structurally diverse library of diazatricycloundecanes. Structure activity relationship (SAR) studies on the three side chain substituents (R1-R3) of diazatricycloundecane identified compound 1e as the most potent inducer of LC3-II protein accumulation. Mechanistic analysis revealed that compound 1e functions as a lysosomotropic agent, increasing lysosomal pH and inhibiting autophagy through lysosomal dysfunction. Furthermore, compound 1e was less cytotoxic compared to previously reported lysosomotropic agents and exhibited excellent drug-like physicochemical properties, surpassing those of classical lysosomotropic agents such as chloroquine and hydroxychloroquine.

Stroke poses a threat to the elderly, being the second leading cause of death and the third leading cause of disability worldwide. Ischemic stroke (IS), resulting from arterial occlusion, accounts for ~85% of all strokes. The pathophysiological processes involved in IS are intricate and complex. Currently, tissue plasminogen activator (tPA) is the only Food and Drug Administration‑approved drug for the treatment of IS. However, due to its limited administration window and the risk of symptomatic hemorrhage, tPA is applicable to only ~10% of patients with stroke. Additionally, the reperfusion process associated with thrombolytic therapy can further exacerbate damage to brain tissue. Therefore, a thorough understanding of the molecular mechanisms underlying IS‑induced injury and the identification of potential protective agents is critical for effective IS treatment. Over the past few decades, advances have been made in exploring potential protective drugs for IS. The present review summarizes the specific mechanisms of various forms of programmed cell death (PCD) induced by IS and highlights potential protective drugs targeting different PCD pathways investigated over the last decade. The present review provides a theoretical foundation for basic research and insights for the development of pharmacotherapy for IS.

This study aims to investigate the mechanism of hydroxychloroquine (HCQ) immunoregulation therapy in improving adverse pregnancy outcomes of recurrent miscarriages (RM) caused by antiphospholipid syndrome (APS).

(i) Immunofluorescence staining was used to analyse the potential targets of antiphospholipid antibodies at the maternal-fetal interface in normal early pregnancy; (ii) Immunohistochemical and immunofluorescence techniques were used to compare and analyse the placenta vascular remodeling, villus tissue synthetic secretion function, trophoblastic autophagy and apoptosis levels in first trimester decidual tissue between normal and APS caused recurrent miscarriages (APS-RM) cases; (iii) HTR8/SVneo and BeWo cell lines were treated with serum from normal and APS-RM cases, and quantified by RT-PCR and Western blot to analysis the expression levels of cell invasion, secretion, autophagy and apoptosis-related molecules; (iv) After adding 0.1 μg/ml HCQ to the serum-treated cell line, the expression of autophagy and invasion-related proteins were detected, and invasion and tube formation of HTR8/SVneo cells was assessed by transwell experiments and tube formation assay.

(i)β2-glycoprotein Ⅰ antigen is expressed in all types of trophoblasts at the maternal-fetal interface in first trimester; (ii) The extravillous trophoblast cells (EVTs) have excessive autophagy in the decidual tissue of the APS-RM cases, and the uterine spiral artery was remodelled insufficiently; (iii) APS-RM cases serum can lead to cell excessive autophagy, and decrease cell invasion and tube formation in vitro; (iv) 0.1 μg/ml HCQ could rescue abnormal cell status caused by APS cases serum in HTR8/SVneo cells in vitro; (v) APS cases serum mainly affects the invasion and tube formation of EVTs, but has little effect on the function of villous trophoblast cells.

Antiphospholipid antibodies can lead to excessive autophagy in EVTs, thereby affecting ability of invasion and remodeling of spiral arteries, which is one of the mechanisms leading to adverse pregnancy outcomes. HCQ can rescue adverse pregnancy outcomes in APS patients by inhibiting excessive autophagy.

Recurrent spontaneous abortion (RSA) is a significant challenge encountered by couples of reproductive ages, with inadequate trophoblast invasion identified as a primary factor in RSA pathogenesis. However, the precise molecular mechanisms through which trophoblast cell dysfunction leads to RSA remain incompletely understood. Research has highlighted the critical role of integrins in embryo implantation and development. Although integrin α-3 (ITGA3) is recognized for its promotion of invasion in cancer cells, its involvement in miscarriage remains poorly characterized. This investigation initially assessed ITGA3 expression in villous tissues obtained from patients with RSA and patients with induced abortion. The findings demonstrated a notable reduction in ITGA3 levels in the villous tissues of patients with RSA compared with the control group. Subsequent in vitro analyses indicated that ITGA3 knockdown inhibited the migration, invasion, and proliferation of trophoblast cells. Through RNA sequencing and subsequent experimentation, it was revealed that ITGA3 regulated Unc51-like kinase 1 (ULK1)-mediated autophagy to influence trophoblast cell invasion, migration, and proliferation. Furthermore, utilizing a miscarriage animal model, the diminished expression of ITGA3 and ULK1 in the placentas of RSA mice was confirmed. In conclusion, the study findings suggest that the downregulation of ITGA3 suppresses ULK1 expression, consequently impeding autophagy to initiation and impeding trophoblast cell invasion and migration, thereby contributing to the pathological progression of RSA.NEW & NOTEWORTHY There is a strong correlation between the reduced expression of ITGA3 in villous tissues and RSA. ITGA3 facilitates the expression of ULK1, thereby promoting autophagy formation and elevating autophagy levels in trophoblast cells. Consequently, this enhances the invasion and migration abilities of trophoblast cells.

Chronic pancreatitis (CP), a progressive inflammatory disease characterized by pancreatic tissue destruction and fibrosis, is considered a challenging health burden due to insufficiencies of current management procedures. Autophagy impairment has emerged as a major triggering event in pancreatitis, raising interest in exploring the potential of targeting autophagy as a possible interventional strategy. This study aimed to evaluate the possible ameliorative effect of two autophagy modulators, simvastatin and eugenol, on CP-related perturbations in an arginine-induced rat model. Repeated l-arginine administration (5 g/kg divided into 2 doses with a 1 h interval, given intraperitoneally every 3rd day for a total of 10 times) provoked CP features, demonstrated by acinar damage, oxidative stress, inflammation, and fibrosis. Arginine-triggered pancreatitis was accompanied by hampered pancreatic autophagic flux, evidenced by overexpression of pancreatic p62 and LC3-Ⅱ and downregulation of pancreatic AMPK and LAMP-1 mRNA expression. Treatment with simvastatin (20 mg/kg, intraperitoneally 24 h, before each arginine dose) and eugenol (50 mg/kg/day orally for 30 days) achieved significant anti-oxidative, anti-inflammatory, and anti-fibrotic effects, and reversed the arginine-instigated autophagic blockade, with superior ameliorative effects attained by eugenol. Altogether, simvastatin and eugenol provide a promising interventional approach for CP, at least partly, by restoring the impaired autophagic flux associated with CP.

Sirtuins (SIRTs) are multifunctional proteins that exhibit a wide range of substrate preferences and cellular localizations. They are reliant on NAD+ and are essential for the regulation of several cellular functions. The SIRT proteins play important role towards tumor survival and resistance mechanisms in tumor cells. Therefore, molecules targeting SIRT proteins gained significant recognition in cancer research. In this work, we explored the anticancer property, potential and mode of action of 2-(diarylalkyl)aminobenzothiazole derivatives on MCF7 human breast cancer cells. Our studies established that 2-(diarylalkyl)aminobenzothiazole derivatives 1-((6-chlorobenzo[d]thiazol-2-ylamino)(3,4-dichlorophenyl)methyl)naphthalen-2-ol (7ab) and 1-((6-chlorobenzo[d]thiazol-2-ylamino)(4-bromophenyl)methyl)naphthalen-2-ol (7ba) treatment in a dose dependent manner drastically lowered the cell proliferation in MCF7 cells and the IC50 values of 7ab and 7ba was found to be 11.4 µM and 9.6 µM at 24 hr in these cells. Docking and molecular dynamic simulation studies further revealed that 7ab and 7ba show significant binding with SIRT1 protein. Consistently, treatment with 7ab and 7ba reduced the expression levels of SIRT1 protein while increasing acetylation of p53, a known SIRT protein target in MCF-7 cells. We observed that SIRT1inhibition was associated with activation of p53, an essential protein for apoptotic cell death, in MCF-7 cell lines. Furthermore, 7ab and 7ba treatment induced LC3-II expression and vacuole formation in the cytoplasm leading to autophagic cell death. Our findings together reveal the plausible cellular targets and specificity of these new small molecules as SIRT inhibitors, which increase p53 acetylation and suppress the proliferation of MCF-7 human breast cancer cells by triggering autophagic and apoptotic cell death.

Saturated fatty acids (SFAs) are the primary contributors to hepatic lipotoxic injuries accompanied by the accumulation of hepatic insoluble protein inclusions that are composed of ubiquitinated proteins and p62, but the role of these inclusions in the SFA-induced hepatic lipotoxic injuries and their regulatory mechanisms are incompletely understood. In this study, we demonstrated that palmitic acid (PA), a dietary SFA, induced aberrant accumulation of hepatic insoluble protein inclusions, leading to hepatic lipotoxic injuries in zebrafish. Mechanistically, the accumulation of hepatic insoluble protein inclusions and the subsequent lipotoxic injuries induced by PA were attributed to reduced autophagy activity and increased endoplasmic reticulum (ER) stress. In addition, the upregulation of p62 by the ER stress response factor XBP1s and ATF4 further exacerbated PA-induced accumulation of hepatic insoluble protein inclusions and subsequent lipotoxic injuries. Importantly, the ω-6 PUFA linoleic acid (LA) attenuated PA-induced accumulation of hepatic insoluble protein inclusions and subsequent lipotoxic injuries by improving defective autophagy and reducing ER stress induced by PA. Overall, the present study provides new mechanisms by which SFAs and ω-6 PUFA influence hepatic lipotoxic injuries. These findings not only advance the understanding of hepatic lipotoxic injuries induced by SFAs, but also provide new insights for optimizing the rational substitution of fish oil by vegetable oils in aquaculture and the balance of fatty acid intake in human diets.

Proteostasis (protein homeostasis) refers to the general biological process that maintains the proper balance between the synthesis of proteins, their folding, trafficking, and degradation. It ensures proteins are functional, locally distributed, and appropriately folded inside cells. Genetic information enclosed in mRNA is translated into proteins. To ensure newly synthesized proteins take on the exact three-dimensional conformation, molecular chaperones assist in proper folding. Misfolded proteins can be refolded or targeted for elimination to stop aggregation. Cells utilize different degradation pathways, for instance, the ubiquitin-proteasome system, the autophagy-lysosome pathway, and the unfolded protein response, to degrade unwanted or damaged proteins. Quality control systems of the cell monitor the folding of proteins. These checkpoint mechanisms are aimed at degrading or refolding misfolded or damaged proteins. Under stress response pathways, such as heat shock response and unfolded protein response, which are triggered under conditions that perturb proteostasis, the capacity for folding is increased, and degradation pathways are activated to help cells handle stressful conditions. The deregulation of proteostasis is implicated in a variety of illnesses, comprising cancer, metabolic diseases, cardiovascular diseases, and neurological disorders. Therapeutic strategies with a deeper insight into the mechanism of proteostasis are crucial for the treatment of illnesses linked with proteostasis and to support cellular health. Thus, proteostasis is required not only for the maintenance of cellular homeostasis and function but also for proper protein function and prevention of injurious protein aggregation. In this review, we have covered the concept of proteostasis, its mechanism, and how disruptions to it can result in a number of disorders.

Pancreatic cancer is a highly aggressive malignant tumor, often diagnosed late, leading to a poor prognosis and extremely high mortality rates. In recent years, the role of cellular autophagy in tumors has become increasingly prominent, gradually becoming an important target for malignant tumors. HIF-3α is a member of HIF family with potential oncogenic function. However, the role of HIF-3α in pancreatic cancer is not clear. The present study revealed its role in pancreatic cancer by exploring the regulatory mechanism of HIF-3α on autophagy. HIF-3α was found markedly upregulated in pancreatic cancer cell lines. In HIF-3α silenced MiaPaCa-2 cells, largely declined migration distance, reduced number of invaded cells and colonies, increased number of autophagosome, downregulated p62, and upregulated Beclin1, LC3II/I, and ATG7 were observed, accompanied by elevated TP53INP2 expressions. on the contrary, in HIF-3α overexpressed PANC-1 cells, notably increased migration distance, and elevated number of invaded cells and colonies were observed, along with decreased autophagosome, upregulated p62, and downregulated Beclin1, LC3II/I, ATG7, and TP53INP2. Subsequently, HIF-3α overexpressed PANC-1 cells were transfected with TP53INP2 overexpressing vector. The influence of HIF-3α overexpression on the proliferation, migration, invasion, and autophagy was abolished by TP53INP2 overexpressing. Furthermore, HIF-3α overexpression facilitated the in vivo growth of PANC-1 cells, accompanied by the autophagy inhibition in tumor tissues, which were remarkably abolished by TP53INP2 overexpressing. Collectively, HIF-3α facilitated the proliferation and migration in pancreatic cancer by inhibiting autophagy through downregulating TP53INP2.

Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.

Parkinson's disease (PD), a progressive neurodegenerative disorder, is characterized by the loss of dopaminergic neurons and pathological aggregation of α-synuclein (α-Syn). Emerging evidence highlights the interplay between genetic susceptibility, neuroinflammation, and transcriptional dysregulation in driving PD pathogenesis. This review brings together the latest information on three important players: α-Syn, the transcription factor Orphan nuclear receptor (NURR1), and the NOD-like receptor 3 (NLRP3) inflammasome. Pathogenic α-syn aggregates cause damage to neurons by disrupting mitochondria and lysosomes and spreading in a way similar to prion proteins. They also turn on the NLRP3 inflammasome, which is a key player in neuroinflammation. NLRP3-driven release of pro-inflammatory cytokines exacerbates neurodegeneration and creates a self-sustaining inflammatory milieu. Meanwhile, reduced NURR1 activity, a pivotal modulator of dopaminergic neuron survival and development, exposes neurons to oxidative stress, neuroinflammation, and α-Syn toxicity, hence exacerbating disease progression. So, targeting this trio exhibits transformative potential against PD pathogenesis.

Nucleosome assembly protein 1-like 1 (NAP1L1) has been implicated in promoting tumor cell proliferation. However, its role in regulating autophagy in tumors, including nasopharyngeal carcinoma (NPC), remains unclear. In this study, we observed that autophagy-inducing agents reduced NAP1L1 protein levels without affecting its mRNA expression. Reduced NAP1L1 enhanced autophagosome formation and maturation, thereby promoting cisplatin (DDP) chemosensitivity in both in vitro and in vivo NPC models. Mechanistically, reduced NAP1L1 impaired the recruitment of ubiquitin-specific protease 14 (USP14), limiting the deubiquitination of heparin-binding growth factor (HDGF) and decreasing HDGF protein levels. In turn, reduced HDGF suppressed USP14-mediated p62 deubiquitination, leading to further declines in p62 protein levels. Notably, the F-box and WD repeat domain-containing protein 7 (FBXW7), an inhibitory E3 ubiquitin ligase, directly interacted with and ubiquitinated NAP1L1, promoting its degradation. This degradation triggered NPC autophagy and enhanced DDP chemosensitivity by disrupting NAP1L1-induced HDGF/p62 signaling. Clinically, NAP1L1 protein expression was inversely correlated with FBXW7 levels in NPC tissue samples. Patients exhibiting high NAP1L1 and low FBXW7 levels had the poorest DDP chemosensitivity and survival outcomes. Our findings demonstrate that FBXW7-mediated NAP1L1 degradation suppresses HDGF-p62 signaling, thereby inducing autophagy and enhancing DDP chemosensitivity. These results underscore the potential of NAP1L1 and FBXW7 as therapeutic targets for NPC treatment.

DDX11 is a DNA helicase involved in critical cellular functions, including DNA replication/repair/recombination as well as sister chromatid cohesion establishment. Bi-allelic mutations of DDX11 lead to Warsaw breakage syndrome (WABS), a rare genome instability disorder marked by significant prenatal and postnatal growth restriction, microcephaly, intellectual disability, and sensorineural hearing loss. The molecular mechanisms underlying WABS remain largely unclear. In this study, we uncover a novel role of DDX11 in regulating the macroautophagic/autophagic pathway. Specifically, we demonstrate that knockout of DDX11 in RPE-1 cells hinders the progression of autophagy. DDX11 depletion significantly reduces the conversion of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3), suggesting a defect in autophagosome biogenesis. This is supported by imaging analysis with a LC3 reporter fused in tandem with the red and green fluorescent proteins (mRFP-GFP-LC3), which reveals fewer autophagosomes and autolysosomes in DDX11-knockout cells. Moreover, the defect in autophagosome biogenesis, observed in DDX11-depleted cells, is linked to an upstream impairment of the ATG16L1-precursor trafficking and maturation, a step critical to achieve the LC3 lipidation. Consistent with this, DDX11-lacking cells exhibit a diminished capacity to clear aggregates of a mutant HTT (huntingtin) N-terminal fragment fused to the green fluorescent protein (HTTQ74-GFP), an autophagy substrate. Finally, we demonstrate the occurrence of a functional interplay between DDX11 and SQSTM1, an autophagy cargo receptor protein, in supporting LC3 modification during autophagosome biogenesis. Our findings highlight a novel unprecedented function of DDX11 in the autophagy process with important implications for our understanding of WABS etiology.

Cardiac fibrosis is a critical factor in cardiac structural remodeling and dysfunction, closely associated with the progression of various cardiovascular diseases (CVDs), including heart failure and myocardial infarction (MI). It is characterized by excessive extracellular matrix (ECM) deposition, which disrupts normal cardiac architecture and impairs cardiac function. Autophagy, a cellular degradation and recycling mechanism, is essential for maintaining cardiac homeostasis, mitigating stress responses, and preventing cellular damage. Recent studies have revealed a significant link between autophagy and cardiac fibrosis, suggesting that autophagic dysregulation can exacerbate fibrosis by promoting fibroblast activation and ECM accumulation. Conversely, proper autophagic activity may attenuate cardiac fibrosis by removing damaged cellular components and regulating fibrotic signaling pathways. This review examines the role of autophagy in cardiac fibrosis. It also emphasizes potential pharmacological strategies that can be used to modulate autophagic processes. These strategies may serve as therapeutic approaches for treating cardiac fibrosis, with the ultimate goal of preventing excessive fibrosis and enhancing cardiac function.

The human endogenous retrovirus type W envelope glycoprotein (ERVWE1), located at chromosome 7q21-22, has been implicated in the pathophysiology of schizophrenia. Our previous studies have shown elevated ERVWE1 expression in schizophrenia patients. Growing evidence suggests that autophagy dysfunction contributes to schizophrenia, yet the relationship between ERVWE1 and autophagy remains unclear. In this study, bioinformatics analysis of the human prefrontal cortex RNA microarray dataset (GSE53987) revealed that differentially expressed genes were predominantly enriched in autophagy-related pathways. Clinical data further demonstrated that serum levels of microtubule-associated protein 1 light chain 3β (LC3B), a key marker of macroautophagy, were significantly elevated in schizophrenia patients compared to controls, and positively correlated with ERVWE1 expression. Cellular and molecular experiments suggested that ERVWE1 promoted macroautophagy by increasing the LC3B II/I ratio, enhancing autophagosome formation, and reducing sequestosome 1 (SQSTM1) expression via upregulation of NADPH oxidase activator 1 (NOXA1). Concurrently, NOXA1 downregulated the expression of key micromitophagy-related genes, including PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin-protein ligase (Parkin), and the pyruvate dehydrogenase E1 subunit α 1 (PDHA1). As a result, ERVWE1, via NOXA1, inhibited micromitophagy by suppressing the expression of PINK1, Parkin, and PDHA1, thereby leading to impaired production of mitochondrial-derived vesicles (MDVs). Mechanistically, ERVWE1 enhanced NOXA1 transcription by upregulating upstream transcription factor 2 (USF2). In conclusion, ERVWE1 promotes macroautophagy and inhibits micromitophagy through USF2-NOXA1 axis, providing novel mechanistic insight into the role autophagy dysregulation in schizophrenia. These findings suggest that targeting autophagy pathways may offer novel therapeutic strategies for schizophrenia treatment.

PROM1 gene mutations are increasingly recognized as significant contributors to inherited retinal diseases, demonstrating considerable heterogeneity in mutation loci and types. In our investigation of a Chinese pedigree presenting with autosomal recessive cone-rod dystrophy, we identified two compound heterozygous frame-shift variants of the PROM1 gene: c.1645-1648del (p.K549Qfs∗3) and c.2321delC (p.A774Vfs∗2). We focused on elucidating the pathogenicity and underlying mechanisms of the novel c.2321delC variant. Following the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, this novel variant was assessed as likely pathogenic. Cellular assays demonstrated that the mutated protein exhibited aberrant subcellular localization and decreased stability compared to wild-type counterparts. Notably, cellular models revealed significant autophagic activation evidenced by elevated LC3II/I ratios, while apoptosis markers remained unaffected. Despite preserved apoptotic pathways, the variant induced marked cellular viability impairment.

Excessive fluorine accumulation poses a significant threat to soil ecology and even human health, yet its impact on soil fauna, especially earthworms, remains poorly understood. This study employed multi-omics and biomarkers to investigate high fluorine-induced biochemical changes that cause tissue damages in Eisenia fetida. The results demonstrated that earthworms exhibited obvious damage with fluorine addition exceeding 200 mg kg-1, with stress levels escalating as fluorine contents increased. Further analysis of the underlying mechanisms revealed that fluorine could upregulate genes encoding mitochondrial respiratory chain complexes I-III and downregulate those for IV-V, leading to reactive oxygen species (ROS) accumulation despite antioxidant system activation. The resulting ROS interfered with deoxyribonucleoside triphosphate synthesis, prompting homologous recombination as the main DNA repair mechanism. Additionally, fluorine-induced ROS also attacked and disrupted protein and lipid related metabolisms ultimately causing oxidative damages. These cumulative oxidative damages from high fluorine contents subsequently triggered autophagy or apoptosis, resulting in tissue ulceration and epithelial exfoliation. Therefore, high fluorine could threaten earthworms by inducing ROS accumulation and subsequent biomolecule damages.

Porcine epidemic diarrhea (PED) is a highly pathogenic and infectious intestinal disease caused by the PED virus (PEDV) and has inflicted substantial economic losses on the global swine industry. Therefore, it is imperative to explore appropriate targets to restrain PEDV infection. PEDV spike (S) protein is crucial for viral infection and is regarded as an ideal target for the development of vaccines and antiviral therapeutics. Palmitoylation is a significant post-translational modification implicated in multiple viral replication cycles. Despite the fact that palmitoylation of certain coronavirus S proteins has been reported, the specific biological significance and underlying molecular mechanisms of PEDV S protein palmitoylation have not been fully defined. In the present study, we uncover that palmitoylation enhances the stability of PEDV S protein to promote viral proliferation. Mechanistically, we identify that a cysteine-rich region within the cytoplasmic tail of PEDV S protein is palmitoylated by the zinc finger Asp-His-His-Cys domain palmitoyltransferase 5 (ZDHHC5). We further illustrate that palmitoylation prevents the recognition of Lys-Phe-Glu-Arg-Gln (KFERQ)-like motif in PEDV S protein by heat shock cognate protein of 70 kDa (HSC70), thereby antagonizing its degradation via chaperone-mediated autophagy (CMA). Collectively, our findings underscore the importance of palmitoylation for PEDV pathogenesis and provide prospective targets for the development of antiviral interventions.IMPORTANCEPEDV poses a serious threat to pig farming worldwide. As a consequence, a comprehensive investigation of PEDV pathogenesis is of great significance for the prevention and control of the virus. Here, we verify that ZDHHC5-mediated palmitoylation of PEDV S protein enhances its stability through impeding recognition by HSC70 and antagonizing degradation via CMA to facilitate viral propagation. Our findings highlight the important role of palmitoylation in PEDV proliferation and support palmitoylation as a promising target for the development of antiviral strategies.

Increased autophagy in fibroblasts drives their differentiation into myofibroblasts, a key process in dermal fibrosis during hypertrophic scar (HS) progression. While N6-methyladenosine (m6A) modification is implicated in fibrosis and autophagy, its mechanistic role in HS remains unclear. In this study, we investigated the involvement of fibroblast autophagy in HS progression and the regulatory mechanisms underlying this process. Our findings demonstrated that HS development is associated with significant autophagy in both human patients and rabbit models, as evidenced by the activation of fibroblast-associated alpha-smooth muscle actin (α-SMA) and type I collagen. Pharmacological inhibition of autophagy using 3-methyladenine effectively suppressed fibroblast-to-myofibroblast differentiation. We further discovered that excessive m6A modifications enhanced autophagy in fibroblasts derived from HS tissues. Mechanistically, we elucidated that methyltransferase-like 3 (METTL3)-mediated m6A modification upregulated unc-51-like kinase 2 (ULK2), a key regulator of autophagy initiation, through techniques such as m6A RNA immunoprecipitation sequencing (MeRIP-seq), qRT-PCR, and Western blotting. Silencing METTL3 impaired autophagic flux, as confirmed by transmission electron microscopy and LC3-II/I ratio analysis, thereby inhibiting fibroblast-to-myofibroblast differentiation. Notably, subcutaneous injection of METTL3 small interfering RNA (siRNA) attenuated cellular autophagy in HS tissues and mitigated HS formation in rabbit ears. These results clarify the causal relationship between METTL3-mediated m6A modification, autophagy, and fibroblast-to-myofibroblast differentiation, providing a mechanistic basis for the therapeutic potential of targeting METTL3 in HS treatment.

Grass carp reovirus (GCRV) is the most virulent pathogen within the genus Aquareovirus, belonging to the family Spinareoviridae. GCRV is categorized into three genotypes, with type II (GCRV-II) being the predominant strain circulating in China. Reoviruses are known to replicate and assemble in cytoplasmic inclusion bodies termed viroplasms; however, information regarding the formation of GCRV-II viroplasms and their specific roles in virus infection remains largely unknown. In this study, we investigated the formation and characteristics of viroplasms during GCRV-II infection. Immunofluorescence and confocal microscopy indicate that GCRV-II infection induces the formation of viroplasms, with the nonstructural protein NS79 being the key protein responsible for this process. Live-cell imaging and fluorescence recovery after photobleaching assays reveal that GCRV-II viroplasms lack liquid-like properties. Transmission electron microscopy confirms that GCRV-II viroplasms are membranous structures. Notably, we demonstrate that GCRV-II infection induces autophagy and the formation of autophagosomes and that GCRV-II utilizes these autophagosomes for viroplasm formation and virion assembly. Furthermore, we found that GCRV-II uses autophagosomes to evade the host immune system, establishing subclinical persistent infection. GCRV-II also employs autophagosomes for nonlytic release and viral spread. Collectively, these findings highlight distinctive characteristics of GCRV-II viroplasms compared to those of other animal reoviruses, offering valuable insights for the prevention and control of this virus.IMPORTANCEGrass carp reovirus (GCRV) is categorized into three genotypes, with GCRV-II being the most prevalent in China. Despite reoviruses being known for their replication and assembly in viroplasms, the specifics of GCRV-II viroplasm formation and its role in infection were unclear. Our study demonstrates that GCRV-II infection triggers the formation of viroplasms, primarily mediated by the nonstructural protein NS79. GCRV-II viroplasms are membranous structures that lack liquid-like properties, which are significantly different from the viroplasms of other reoviruses. Notably, our research unveils that GCRV-II infection induces autophagy and utilizes autophagosomes for viroplasm formation and virion assembly. Furthermore, we also confirm that GCRV-II utilizes autophagosomes for subclinical persistent infection, nonlytic release, and viral spread. Our results indicate that GCRV-II hijacks autophagosomes to form viroplasms and complete its life cycle. The characteristics of GCRV-II are significantly different from those of other animal reoviruses, providing important information for prevention and control of this virus.

Targeting metabolic disorders has emerged as a promising therapeutic strategy in the treatment of chronic kidney disease (CKD). 18β-glycyrrhetinic acid (18β-GA) is known for its metabolic regulatory and antioxidant effects in various diseases. However, the precise effects and underlying mechanisms of 18β-GA on CKD remain unclear.

This study aims to evaluate the therapeutic efficacy of 18β-GA on CKD and to identify the molecular targets of 18β-GA with a particular emphasis on its role in metabolic regulation.

A high-fat diet-induced CKD model was established to investigate the influence of 18β-GA on lipid metabolic disorders, cellular senescence and fibrosis in the kidneys. Co-immunoprecipitation was performed to investigate the impact of 18β-GA on the interaction between transcription factor EB (TFEB) and sirtuin 1 (SIRT1). Additionally, network pharmacology and molecular docking analyses were conducted to identify the specific target proteins of 18β-GA.

18β-GA alleviated renal lipid accumulation, tubular cell senescence and renal interstitial fibrosis in CKD mice. Treatment with 18β-GA largely restored mitochondrial function and attenuated intracellular lipotoxicity and associated cellular senescence by promoting lipophagy in renal tubular cells. Mechanistically, 18β-GA acting as a partial antagonist of peroxisome proliferator-activated receptor gamma (PPARγ) enhanced lipophagy through SIRT1-mediated nuclear translocation of TFEB which induced the expression of microtubule-associated protein light chain 3 (LC3).

Our findings demonstrate that 18β-GA, functioning as a partial antagonist of PPARγ, counteracts CKD progression by activating the SIRT1-TFEB-LC3 signaling axis-mediated lipophagy and thus uncover a novel mechanism by which 18β-GA improves renal lipid metabolism disorders and exerts renoprotective effects. These results highlight the potential of 18β-GA as a promising therapeutic agent for the treatment and prevention of CKD.

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly, and the role of chaperonin containing TCP1 subunit 2 (CCT2) remains unclear. This study aims to elucidate the mechanistic link between CCT2 and AMD, contributing to improved understanding and potential therapeutic strategies. Retinal and RPE-Choroid transcriptome array data from 130 AMD patients and 121 normal donors (GSE29801 dataset) were reanalyzed to assess CCT2 expression across different AMD subtypes, age groups, and genders. Single-sample gene set enrichment analysis was performed to explore correlations with autophagy-related genes and other established AMD causes. Additionally, CCT2 expression was validated in sodium iodate (NaIO₃)-induced 661 W cells (photoreceptor-like cells) using quantitative real-time PCR (qRT-PCR). CCT2 was significantly enriched in advanced AMD retinas compared to intermediate stages in retina (both macular and extramacular) and early stages in extramacular retina (p < 0.05). NaIO3-treated 661 W cells exhibited a similar expression trend, confirming transcriptomic findings. CCT2 is significantly upregulated in advanced AMD and may contribute to drusen degradation. It shows potential as both a biomarker and an independent diagnostic indicator, particularly for advanced-stage AMD.

The persistent organic pollutant perfluorooctane sulfonate (PFOS) is demonstrated to induce hepatotoxicity through disrupting iron homeostasis and subsequent ferroptosis in hepatocytes. However, it is still elusive in the mechanisms underneath the dysfunctional iron metabolism caused by PFOS. In this study, we observed that PFOS activated the nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in mice liver and human hepatocytes. PFOS reduced the ubiquitination of NCOA4, subsequently causing an increase in the expression of NCOA4. PFOS induced the ubiquitination of HECT and RLD domain-containing E3 ubiquitin protein ligase 2 (HERC2), an upstream negative regulator of NCOA4, leading to the degradation of HERC2. PFOS upregulated the level of detyrosinated α-tubulin (detyr-α-tubulin) in hepatocytes. Under PFOS exposure, detyr-α-tubulin interacted with tripartite motif containing 21 (TRIM21), another E3 ubiquitin ligase responsible for HERC2 degradation. Despite the reduction in the protein level of HERC2, the increases in detyr-α-tubulin and the interaction between detyr-α-tubulin and TRIM21 caused by PFOS facilitated the interaction between TRIM21 and HERC2. Furthermore, inhibiting α-tubulin detyrosination by parthenolide reversed the ferritinophagy and the following ferroptosis caused by PFOS. Collectively, this study points out the existence of ferritinophagy and enriches the understanding of the alteration in iron metabolism under PFOS exposure, providing novel mechanistic insights into the hepatic toxicity of PFOS.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron degeneration and α-synuclein (aSyn) accumulation. Environmental factors play a significant role in PD progression, highlighting the potential of non-pharmacological interventions. This study investigates the therapeutic effects of intermittent fasting (IF) in an rAAV-aSyn mouse model of PD. IF, initiated four weeks post-induction of aSyn pathology, improved motor function and reduced dopaminergic neuron and axon terminal degeneration. Additionally, IF preserved dopamine levels and synaptic integrity in the striatum. Mechanistically, IF enhanced autophagic activity, promoting phosphorylated-aSyn clearance and reducing its accumulation in insoluble brain fractions. Transcriptome analysis revealed IF-induced modulation of inflammation-related genes and microglial activation. Validation in primary cultures confirmed that autophagy activation and inflammatory modulators (CCL17, IL-36RN) mitigate aSyn pathology. These findings suggest that IF exerts neuroprotective effects, supporting further exploration of IF and IF-mimicking therapies as potential PD treatments.

As obligate parasites, viruses strictly rely on the host translation machinery for progeny production. To compete for host translation resources, the porcine reproductive and respiratory syndrome virus (PRRSV) employs multiple strategies to suppress host protein synthesis. Mechanistically, the mRNA nuclear export and canonical translation initiation are suppressed in cells with PRRSV infection. Nsp2 was identified to induce host translation shutoff targeting the mTOR signaling pathway. Nsp2TF shares its N-terminal domains with nsp2, while nsp2N is a C-terminal truncation of nsp2. In this study, we investigated the role of nsp2-related proteins in suppressing host protein synthesis, defining their mechanistic impact on translational regulation. In a puromycin incorporation assay, the inactivation of nsp2TF and nsp2N translation attenuated the inhibitory effect of PRRSV infection on nascent peptide synthesis. PRRSV utilizes a multi-faceted approach to suppress host translation, primarily through modulation of eIF2α phosphorylation before 12 hpi and inhibition of the mTOR signaling pathway at 24 hpi. The nsp2-related proteins (nsp2, nsp2TF, and nsp2N) contribute to the modulation of the mTOR signaling pathway via divergent mechanisms. While nsp2 broadly suppresses mTOR effector proteins (4E-BP1, S6K, and rpS6), nsp2TF and nsp2N mainly downregulate the 4E-BP1 phosphorylation. The activity of mTORC1 may be regulated by additional PRRSV-encoded proteins, suggesting a coordinated viral strategy to hijack host translational machinery. This study provides novel insights into the molecular mechanisms by which nsp2-related proteins subvert host protein synthesis to facilitate viral replication.

The cGAS-STING pathway, well-known to elicit interferon (IFN) responses, is also a key inducer of autophagy upon virus infection or other stimuli. Whereas the mediators for cGAS-induced IFN responses are well characterized, much less is known about how cGAS elicits autophagy. Here, we report that TRIM23, a unique TRIM protein harboring both ubiquitin E3 ligase and GTPase activity, is crucial for cGAS-STING-dependent antiviral autophagy. Genetic ablation of TRIM23 impairs autophagic control of HSV-1 infection. HSV-1 infection or cGAS-STING stimulation induces TBK1-mediated TRIM23 phosphorylation at S39, which triggers TRIM23 autoubiquitination and GTPase activity and ultimately elicits autophagy. Fibroblasts from a patient with herpes simplex encephalitis heterozygous for a dominant-negative, kinase-inactivating TBK1 mutation fail to activate autophagy by TRIM23 and cGAS-STING. Our results thus identify the cGAS-STING-TBK1-TRIM23 axis as a key autophagy defense pathway and may stimulate new therapeutic interventions for viral or inflammatory diseases.

Autophagy plays a crucial role in tumor drug resistance by enabling cancer cells to survive under stress conditions, including chemotherapy. It helps tumor cells maintain homeostasis, resist cell death, and contribute to therapy failure. This study analyzed the literature related to autophagy and tumor drug resistance based on the Web of Science Core Collection (WoSCC) database. The results revealed that there are 9284 relevant articles published to date, covering 103 countries and regions, with contributions from 5964 institutions and 37,240 researchers. The annual number of publications has steadily increased since 2004, especially after 2019, indicating the growing importance of autophagy in tumor drug resistance research. China leads globally in terms of publication output, accounting for nearly 50% of the total publications. Additionally, international collaboration and cross-country research have become increasingly prominent, particularly collaborations between China and countries like South Korea and Japan. Journal analysis showed that the International Journal of Molecular Sciences and Oncotarget are the most productive journals, while Autophagy stands out with a higher impact factor. Author, citation, and keyword analyses revealed research hotspots and future trends in the field of autophagy and tumor drug resistance, including chemotherapy resistance, cell death mechanisms, and immunotherapy. This study provides a systematic academic perspective for future research in the field of autophagy and tumor drug resistance and emphasizes the importance of strengthening international cooperation.

Glaesserella parasuis (Gps) is an important pathogen that causes polyserositis, peritonitis and meningitis in pigs, causing considerable economic losses to the pig industry worldwide. In recent years, due to the abuse of antibiotic drugs, Gps drug resistance and multi-drug resistance have become increasingly serious, especially for macrolides. Thus, by inducing Tydigrosin resistant bacteria, we found that PgtP is a Gps-produced virulence gene that plays a crucial role in the disease, but its interaction in host cells remains unclear. To characterize the function of the PgtP gene in Gps, we constructed ΔPgtP mutants. Notably, deletion of the PgtP gene resulted in increased adhesion to mouse macrophages, suggesting that PgtP is essential for adhesion of Gps. In addition, as a member of the cell membrane transporter family, PgtP links activated inflammation with autophagy and oxidative stress metabolism. To further investigate the role of PgtP, we infected mouse macrophages with ΔPgtP mutants and wild strains respectively. We found that ΔPgtP mutations can reduce the level of intracellular reactive oxygen species (ROS), up-regulate the number of intracellular autophagosomes, and down-regulate the expression of cytokines IL-6 and TNF-a. Further mechanistic studies showed that PGTP-associated p38 mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways were involved in autophagy and oxidative stress and demonstrated that the related signaling pathways were also activated in mice. These results highlight the potential of PgtP as a target for therapeutic intervention and provide important new insights into how it contributes to the aggressiveness and persistence of Gps.

Copper, an essential micronutrient, plays significant roles in numerous biological functions. Recent studies have identified imbalances in copper homeostasis across various cancers, along with the emergence of cuproptosis, a novel copper-dependent form of cell death that is crucial for tumor suppression and therapeutic resistance. As a result, manipulating copper levels has garnered increasing interest as an innovative approach to cancer therapy. In this review, we first delineate copper homeostasis at both cellular and systemic levels, clarifying copper's protumorigenic and antitumorigenic functions in cancer. We then outline the key milestones and molecular mechanisms of cuproptosis, including both mitochondria-dependent and independent pathways. Next, we explore the roles of cuproptosis in cancer biology, as well as the interactions mediated by cuproptosis between cancer cells and the immune system. We also summarize emerging therapeutic opportunities targeting copper and discuss the clinical associations of cuproptosis-related genes. Finally, we examine potential biomarkers for cuproptosis and put forward the existing challenges and future prospects for leveraging cuproptosis in cancer therapy. Overall, this review enhances our understanding of the molecular mechanisms and therapeutic landscape of copper and cuproptosis in cancer, highlighting the potential of copper- or cuproptosis-based therapies for cancer treatment.

Senecavirus A (SVA) can infect pigs of all ages and poses a significant risk to the swine industry. RNA interference (RNAi) is a conserved antiviral immune defense pathway in eukaryotes, and many viruses have been proven to encode viral proteins as viral RNAi suppressors (VSRs) to evade RNAi-mediated antiviral response. However, it is unclear whether SVA regulates RNAi for its infection and replication. In this study, it is found that SVA nonstructural protein 3 A has a VSR function. Mechanistically, 3 A effectively inhibited double-stranded RNA and small interfering RNA-induced RNAi, degrading Argonaute2 (Ago2) through autophagy. This paper demonstrated that SVA encoded 3 A as VSR to resist RNAi pathway, escaping host immunity and promoting viral replication, which expands the understanding of the interaction between SVA and its host.