It is widely recognized that there is currently no established treatment for individuals with Non-alcoholic Fatty Liver Disease (NAFLD). In recent years, there has been a surge of interest in natural products derived from plants, driven by their minimal toxicity and notable efficacy. It was reported that natural products could ameliorate NAFLD via various mechanisms. On the other hand, autophagy has been suggested to be involved in the pathogenesis of NAFLD. The aim of this review is to understand whether the beneficial effects of natural products on NAFLD are mediated by affecting autophagy pathways. In this review, we have compiled data elucidating how these natural products exhibit the potential to improve NAFLD by modulating core autophagic pathways. Specifically, we demonstrate that these natural products, including resveratrol, berberine, curcumin, quercetin, punicalagin, epigallocatechin-3-gallate, apigenin, and many others, regulate autophagy through key signaling pathways, such as AMPK/SIRT1/mTOR. Interestingly, these compounds might activate or inhibit autophagy, depending on the context. We explore how autophagy activation promotes the degradation of lipid droplets and alleviates liver injury, while autophagy inhibition contributes to reducing inflammation, apoptosis, and pyroptosis, and also resulting in improved NAFLD outcomes. Taken together, these findings suggest that targeting autophagy with natural products presents a promising mechanism for preventing and treating NAFLD.

Understanding   the mechanism behind Alzheimer's disease is imperative due to the critical role of the autophagy pathway in protein homeostasis and neuronal survival. Autophagy pathway irregularities in neurons may increase exosome-mediated toxic protein transport, which can spread neurodegenerative diseases. Compelling evidence hints that acacetin (ACA) is a naturally occurring biocomponent exhibiting neuroprotective pharmacological properties. However, further molecular investigations are pressing to uncover the therapeutic potential of ACA. The present investigation endeavors to scrutinize the impact of ACA on the autophagy pathway and exosome release in an amyloid beta (Aβ) peptide-induced toxicity model. Herein, first, molecular modeling was performed between ACA and autophagy-related proteins. Afterward, the Aβ peptide-induced toxicity model cells were treated with ACA, and total and exosomal protein isolation was carried out and analyzed. Considering the findings, our molecular dynamics simulation of the ACA-protein complexes, spanning 100 ns, conclusively demonstrated stable protein-ligand interactions. Additionally, ACA was determined to regulate LC3II, Beclin-1, p62, and Lamp2a protein levels and reduce amyloid-β and Alix protein levels. In conclusion, our study highlights the significant in vitro neuroprotective effect of ACA against Aβ toxicity through autophagy. Moving forward, future studies may seek to elucidate the specific neuroprotective, therapeutic effects and mechanisms of ACA via autophagy in in vivo models. Addressing the identified limitations and capitalizing on the outlined future prospects are essential steps towards harnessing the therapeutic potential of ACA in combating neurodegenerative diseases, offering renewed hope for patients and caregivers alike.

Autophagy is a fundamental cellular process that maintains homeostasis by degrading damaged components and regulating stress responses. It plays a crucial role in cancer biology, including tumor progression, metastasis, and therapeutic resistance. Oxidative stress, similarly, is key to maintaining cellular balance by regulating oxidants and antioxidants, with its disruption leading to molecular damage. The interplay between autophagy and oxidative stress is particularly significant, as reactive oxygen species (ROS) act as both inducers and by-products of autophagy. While autophagy can function as a tumor suppressor in early cancer stages, it often shifts to a pro-tumorigenic role in advanced disease, aiding cancer cell survival under adverse conditions such as hypoxia and nutrient deprivation. This dual role is mediated by several signaling pathways, including PI3K/AKT/mTOR, AMPK, and HIF-1α, which coordinate the balance between autophagic activity and ROS production. In this review, we explore the mechanisms by which autophagy and oxidative stress interact across different hematological malignancies. We discuss how oxidative stress triggers autophagy, creating a feedback loop that promotes tumor survival, and how autophagic dysregulation leads to increased ROS accumulation, exacerbating tumorigenesis. We also examine the therapeutic implications of targeting the autophagy-oxidative stress axis in cancer. Current strategies involve modulating autophagy through specific inhibitors, enhancing ROS levels with pro-oxidant compounds, and combining these approaches with conventional therapies to overcome drug resistance. Understanding the complex relationship between autophagy and oxidative stress provides critical insights into novel therapeutic strategies aimed at improving cancer treatment outcomes.

Global disparities in cancer prevention, detection, and treatment demand a unified international effort to reduce the disease's burden and improve outcomes. Despite advances in chemotherapy and radiotherapy, many tumors remain resistant to these treatments. Gold nanoparticles (AuNPs) have shown promise as radiosensitizers, enhancing the effectiveness of low-energy X-rays by emitting Auger electrons that cause localized cellular damage. In this study, spherical AuNPs of 5 nm and 10 nm were characterized and tested on various cell lines, including malignant breast cells (MCF-7), non-malignant cells (CHO-K1 and MCF-10A), and human lymphocytes. Cells were treated with AuNPs and irradiated with attenuated 6 megavoltage (MV) X-rays or p(66)/Be neutron radiation to assess DNA double-strand break (DSB) damage, cell viability, and cell cycle progression. The combination of AuNPs and neutron radiation induced higher levels of γ-H2AX foci and micronucleus formation compared to treatments with AuNPs or X-ray radiation alone. AuNPs alone reduced cellular kinetics and increased the accumulation of cells in the G2/M phase, suggesting a block of cell cycle progression. For cell proliferation, significant effects were only observed at the concentration of 50 μg/mL of AuNPs, while lower concentrations had no inhibitory effect. Further research is needed to quantify internalized AuNPs and correlate their concentration with the observed cellular effects to unravel the biological mechanisms of their radioenhancement.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown a dismal survival prognosis, resulting in less than a year of life in the metastatic setting. Methods: The pressing need to find better therapeutic methods brought about the discovery of new targeted therapies against the infamous KRAS mutations, the major oncological drivers of PDAC. Results: The most common KRAS mutation is KRASG12D, which causes a conformational change in the protein that constitutively activates downstream signaling pathways driving cancer hallmarks. Novel anti-KRASG12D therapies have been developed for solid-organ tumors, including small compounds, pan-RAS inhibitors, protease inhibitors, chimeric T cell receptors, and therapeutic vaccines. Conclusions: This comprehensive review summarizes current knowledge on the biology of KRAS-driven PDAC, the latest therapeutic options that have been experimentally validated, and developments in ongoing clinical trials.

Autophagy is a critical cellular process that maintains homeostasis by recycling damaged or aberrant components. This process is orchestrated by a network of proteins that form autophagosomes, which engulf and degrade intracellular material. In cancer, autophagy plays a dual role: it suppresses tumor initiation in the early stages but supports tumor growth and survival in advanced stages. Chronic myeloid leukemia (CML), a hematological malignancy, is characterized by the Philadelphia chromosome, a chromosomal abnormality resulting from a translocation between chromosomes 9 and 22. Autophagy has emerged as a key factor in CML pathogenesis, promoting cancer cell survival and contributing to resistance against tyrosine kinase inhibitors (TKIs), the primary treatment for CML. Targeting autophagic pathways is being actively explored as a therapeutic approach to overcome drug resistance and enhance cancer cell death. Recent research highlights the intricate interplay between autophagy and CML progression, underscoring its role in disease biology and treatment outcomes. This review aims to provide a comprehensive analysis of the molecular and cellular mechanisms underlying CML, with a focus on the therapeutic potential of targeting autophagy.

Myocardial ischemia/reperfusion (IR) injury is a common adverse event in the clinical treatment of myocardial ischemic disease. Autosis is a form of cell death that occurs when autophagy is excessive in cells, and it has been associated with cardiac IR damage. This study aimed to investigate the regulatory mechanism of circRNA CDR1AS on autosis in cardiomyocytes under IR. The expression of CDR1AS increases after myocardial IR, and overexpression of CDR1AS detrimentally affects cardiac function, increases infarct area, promotes excessive autophagy, and blocks the flow of autophagy to induce autosis after IR. Conversely, knockdown of CDR1AS reversed the autophagy-related markers caused by IR, increasing cardiomyocyte activity, improving cardiac dysfunction and infarct area, and restoring the flow of autophagy. Further analysis of RNA sequencing and validation experiments revealed that CDR1AS aggravated autophagic damage, increased autophagosome accumulation, and promoted autosis by inhibiting the levels of LAMP2 and mTORC1 proteins. Additionally, RIP and pull-down assays showed that CDR1AS interacts with LAMP2 or mTORC1. First-time evidence reveals that circRNA CDR1AS regulates lysosomal membrane proteins by regulating the mTORC1/ULK1 pathway during myocardial IR-induced autosis. This suggests that maintaining moderate autophagy is a crucial part of the fight against myocardial IR damage. KEY MESSAGES: CDR1AS expression was significantly increased in myocardium following IR. CDR1AS can increase the occurrence of autosis after IR. CDR1AS reduces the phosphorylation of ULK1, promoting the formation of autophagosomes. CDR1AS binds to LAMP2 and blocks the autophagosome clearance pathway. The specific mechanism of CDR1AS regulating IR is achieved by regulating autosis.

Autophagy, the lysosome-driven breakdown of intracellular components, is pivotal in regulating eukaryotic cellular processes and maintaining homeostasis, making it physiologically important even under normal conditions. Cellular mechanisms involving autophagy include the response to nutrient deprivation, intracellular quality control, early development, and cell differentiation. Despite its established health significance, the role of autophagy in cancer and other diseases remains complex and not fully understood. A comprehensive understanding of autophagy is crucial to facilitate the development of novel therapies and drugs that can protect and improve human health. High-throughput technologies, such as single-cell RNA sequencing (scRNA-seq), have enabled researchers to study transcriptional landscapes at single-cell resolution, significantly advancing our knowledge of autophagy pathways across diverse physiological and pathological contexts. This review discusses the latest advances in scRNA-seq for autophagy research and highlights its potential in the molecular characterization of various diseases.

1. This study determined the effective indicators and proteins involved in long-duration fertility (DF) in chickens.2. Three lines of Chinese Xinhua chickens (900) were compared using seven phenotypic trait indicators, and the best was determined based on repeatability value. Subsequently, differential expression analysis, functional annotation and protein-protein interaction (PPI) network analyses were performed to investigate the pathways and hub proteins. Finally, qPCR analysis was conducted to validate the expression of identified hub proteins, and functional annotation with previously published genes was performed to explain how hub proteins work to maintain the trait.3. The study found that the number of fertilised eggs (FN) and maximum fertilised eggs (MCF) were the most repeatable among the seven indicators. It identified 231 differentially expressed proteins, with 144 being down-regulated and 87 being up-regulated. The differentially expressed proteins exhibited high clustering within various cellular compartments, including the cytosol and cytoplasm and GTP binding. Multiple pathways were identified, including tight and adherens junctions, TGF-beta signalling, autophagy-animal, regulation of actin cytoskeleton and the ribosome that may regulate the trait. Three hub proteins, KRAS, RPL5 (p < 0.001), and HSPA4 (p < 0.01), were significantly differentially expressed between high and low DF groups.4. This study identified FN and MCF as effective indicators for addressing DF. As it is a quantitative trait, KRAS, HSPA4, and RPL5 are potential hub proteins that work with other genes to maintain the trait.

Regulated cell death is a fate of cells in (patho)physiological conditions during which extrinsic or intrinsic signals or redox equilibrium pathways following infection, cellular stress or injury are coupled to cell death modalities like apoptosis, necroptosis, pyroptosis or ferroptosis. An immediate survival response to cellular stress is often induction of autophagy, a process that deals with removal of aggregated proteins and damaged organelles by a lysosomal recycling process. These cellular processes and their regulation are crucial in several human diseases. Exploiting high-throughput assays which discriminate distinct cell death modalities and autophagy are critical to identify potential therapeutic agents that modulate these cellular responses. In the past few years, luciferase-based assays have been widely developed for assessing regulated cell death and autophagy pathways due to their simplicity, sensitivity, known chemistry, different spectral properties and high-throughput potential. Here, we review basic principles of bioluminescent reactions from a mechanistic perspective, along with their implication in vitro and in vivo for probing cell death and autophagy pathways. These include applying luciferase-, luciferin-, and ATP-based biosensors for investigating regulated cell death modalities. We discuss multiplex bioluminescence platforms which simultaneously distinguish between the various cell death phenomena and cellular stress recovery processes such as autophagy. We also highlight the recent technological achievements of bioluminescent tools for the prediction of drug effectiveness in pathways associated with regulated cell death.

Fibroblast growth factor 9 (FGF9) is a member of the human FGF family known for its pivotal roles in various biological processes, such as cell proliferation, tissue repair, and male sex determination including testis formation. Cordycepin, a bioactive compound found in Cordyceps sinensis, exhibits potent antitumor effects by triggering apoptosis and/or autophagy pathways. Our research has unveiled that FGF9 promotes proliferation and tumorigenesis in MA-10 mouse Leydig tumor cells, as the phenomena are effectively countered by cordycepin through apoptosis induction. Moreover, we have observed FGF9-mediated stimulation of proliferation and tumorigenesis in TM3 mouse Leydig progenitor cells, prompting an investigation into the potential inhibitory effect of cordycepin on TM3 cell proliferation under FGF9 treatment. Hence, we hypothesized that cordycepin induces cell death via apoptosis and/or autophagy in FGF9-treated TM3 cells.

TM3 cells were treated with cordycepin and/or FGF9, and the flow cytometry, immunofluorescent plus western blotting assays were used to determine how cordycepin regulated Leydig cell death under FGF9 treatment.

Our findings reveal that cordycepin restricts cell viability and colony formation while inducing morphological alterations associated with cell death in FGF9-treated TM3 cells. Surprisingly, cordycepin fails to elicit the expression of key apoptotic markers, suggesting an alternate mechanism of action. Although the expression of certain autophagy-related proteins remains unaltered, a significant up-regulation of LC3-II, indicative of autophagy, is observed in cordycepin-treated TM3 cells under FGF9 influence. Moreover, the inhibition of autophagy by chloroquine reverses cordycepin-induced TM3 cell death, highlighting the crucial role of autophagy in this process.

Our study demonstrates that cordycepin activates autophagy to induce cell death in TM3 cells under FGF9 treatment conditions.

Diabetes leads to a significantly accelerated incidence of various related macrovascular complications, including peripheral vascular disease and cardiovascular disease (the most common cause of mortality in diabetes), as well as microvascular complications such as kidney disease and retinopathy. Endothelial dysfunction is the main pathogenic event of diabetes-related vascular disease at the earliest stage of vascular injury. Understanding the molecular processes involved in the development of diabetes and its debilitating vascular complications might bring up more effective and specific clinical therapies. Long-acting glucagon-like peptide (GLP)-1 analogs are currently available in treating diabetes with widely established safety and extensively evaluated efficacy. In recent years, autophagy, as a critical lysosome-dependent self-degradative process to maintain homeostasis, has been shown to be involved in the vascular endothelium damage in diabetes. In this review, the GLP-1/GLP-1R system implicated in diabetic endothelial dysfunction and related autophagy mechanism underlying the pathogenesis of diabetic vascular complications are briefly presented. This review also highlights a possible crosstalk between autophagy and the GLP-1/GLP-1R axis in the treatment of diabetic angiopathy.

Autophagy is a critical conserved cellular process in maintaining cellular homeostasis by clearing and recycling damaged organelles and intracellular components in lysosomes and vacuoles. Autophagy plays a vital role in cell survival, bioenergetic homeostasis, organism development, and cell death regulation. Malfunctions in autophagy are associated with various human diseases and health disorders, such as cancers and neurodegenerative diseases. Significant effort has been devoted to autophagy-related research in the context of genes, proteins, diagnosis, etc. In recent years, there has been a surge of studies utilizing state of the art machine learning (ML) tools to analyze and understand the roles of autophagy in various biological processes. We taxonomize ML techniques that are applicable in an autophagy context, comprehensively review existing efforts being taken in this direction, and outline principles to consider in a biomedical context. In recognition of recent groundbreaking advances in the deep-learning community, we discuss new opportunities in interdisciplinary collaborations and seek to engage autophagy and computer science researchers to promote autophagy research with joint efforts.

Vacuole membrane protein 1 (VMP1) is an integral membrane protein that plays a pivotal role in cellular processes, particularly in the regulation of autophagy. Autophagy, a self-degradative mechanism, is essential for maintaining cellular homeostasis by degradation and recycling damaged organelles and proteins. VMP1 involved in the autophagic processes include the formation of autophagosomes and the subsequent fusion with lysosomes. Moreover, VMP1 modulates endoplasmic reticulum (ER) calcium levels, which is significant for various cellular functions, including protein folding and cellular signaling. Recent studies have also linked VMP1 to the cellular response against viral infections and lipid droplet (LD). Dysregulation of VMP1 has been observed in several pathological conditions, including neurodegenerative diseases such as Parkinson's disease (PD), pancreatitis, hepatitis, and tumorogenesis, underscoring its potential as a therapeutic target. This review aims to provide an overview of VMP1's multifaceted roles and its implications in disease pathology.

Autophagy is a process that occurs in almost all eukaryotic cells and this process is controlled by several molecular processes. Its biological roles include the provision of energy, the maintenance of cell homeostasis, and the promotion of aberrant cell death. The importance of autophagy in pregnancy is gradually becoming recognized. In literature, it has been indicated that autophagy has three different effects on the onset and maintenance of pregnancy: embryo (embryonic development), feto-maternal immune crosstalk, and maternal (decidualization). In humans, proper decidualization is a major predictor of pregnancy accomplishment and it can be influenced by different factors. This review highlights the genes, pathways, regulation, and function of autophagy in endometrial decidualization and other involved factors in this process.

Hepatocellular carcinoma (HCC) stands as a formidable global health challenge due to its prevalence, marked by high mortality and morbidity rates. This cancer type exhibits a multifaceted etiology, prominently linked to viral infections, non-alcoholic fatty liver disease, and genomic mutations. The inherent heterogeneity of HCC, coupled with its proclivity for developing drug resistance, presents formidable obstacles to effective therapeutic interventions. Autophagy, a fundamental catabolic process, plays a pivotal role in maintaining cellular homeostasis, responding to stressors such as nutrient deprivation. In the context of HCC, tumor cells exploit autophagy, either augmenting or impeding its activity, thereby influencing tumorigenesis. This comprehensive review underscores the dualistic role of autophagy in HCC, acting as both a pro-survival and pro-death mechanism, impacting the trajectory of tumorigenesis. The anti-carcinogenic potential of autophagy is evident in its ability to enhance apoptosis and ferroptosis in HCC cells. Pertinently, dysregulated autophagy fosters drug resistance in the carcinogenic context. Both genomic and epigenetic factors can regulate autophagy in HCC progression. Recognizing the paramount importance of autophagy in HCC progression, this review introduces pharmacological compounds capable of modulating autophagy-either inducing or inhibiting it, as promising avenues in HCC therapy.

Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and graft-versus-host disease (GVHD). We demonstrate in vitro that both tumor necrosis factor and IL-1β, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy-deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In a major histocompatibility complex-mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T-cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus, autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic stem cell transplant and may represent a therapeutic target to prevent graft failure during GVHD.

Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults, and effective clinical treatment strategies are still lacking. Autophagy is a lysosome-dependent degradation system that can encapsulate abnormal proteins, damaged organelles. However, dysfunctional autophagy has multiple types and plays a complex role in tumorigenicity depending on many factors, such as tumor stage, microenvironment, signaling pathway activation, and application of autophagic drugs.

A systematic review of the literature was conducted to analyze the role of autophagy in UM, as well as describing the development of autophagic drugs and the link between autophagy and the tumor microenvironment.

In this review, we summarize current research advances regarding the types of autophagy, the mechanisms of autophagy, the application of autophagy inhibitors or agonists, autophagy and the tumor microenvironment. Finally, we also discuss the relationship between autophagy and UM.

Understanding the molecular mechanisms of how autophagy differentially affects tumor progression may help to design better therapeutic regimens to prevent and treat UM.

Psoriasis is a recurrent and protracted disease that severely impacts the patient's physical and mental health. Thus, there is an urgent need to explore its pathogenesis to identify therapeutic targets. The expression level of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) was analyzed by immunohistochemistry techniques in psoriatic tissues and imiquimod-induced psoriatic mouse models. PTPN2 and signal transducer and activator of transcription 3 (STAT3) were overexpressed or silenced in human keratinocytes or an interleukin (IL)-6-induced psoriasis HaCaT cell model using overexpression plasmid transfection or small interfering RNA technology in vitro, and the effects of PTPN2 on STAT3, HaCaT cell function, and autophagy levels were investigated using reverse transcription-quantitative polymerase chain reaction, Western blot, Cell Counting Kit 8, 5-ethynyl-20-deoxyuridine, flow cytometry, and transmission electron microscopy. PTPN2 expression was found to be significantly downregulated in psoriatic tissues. Then, the in vitro antipsoriatic properties of PTPN2 were investigated in an IL-6-induced psoriasis-like cell model, and the results demonstrated that inhibition of keratinocyte proliferation by PTPN2 may be associated with elevated STAT3 dephosphorylation and autophagy levels. These findings provide novel insights into the mechanisms of autophagy in psoriatic keratinocytes and may be essential for developing new therapeutic strategies to improve inflammatory homeostasis in psoriatic patients.

Autophagy in eukaryotes functions to maintain homeostasis by degradation and recycling of long-lived and unwanted cellular materials. Autophagy plays important roles in pathogenicity of various fungal pathogens, suggesting that autophagy is a novel target for development of antifungal compounds. Here, we describe bioluminescence resonance energy transfer (BRET)-based high-throughput screening (HTS) strategy to identify compounds that inhibit fungal ATG4 cysteine protease-mediated cleavage of ATG8 that is critical for autophagosome formation. We identified ebselen (EB) and its analogs ebselen oxide (EO) and 2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PT) as inhibitors of fungal pathogens Botrytis cinerea and Magnaporthe oryzae ATG4-mediated ATG8 processing. The EB and its analogs inhibit spore germination, hyphal development, and appressorium formation in Ascomycota pathogens, B. cinerea, M. oryzae, Sclerotinia sclerotiorum and Monilinia fructicola. Treatment with EB and its analogs significantly reduced fungal pathogenicity. Our findings provide molecular insights to develop the next generation of antifungal compounds by targeting autophagy in important fungal pathogens.

Cell death plays an essential function in organismal development, wellbeing, and ageing. Many types of cell deaths have been described in the past 30 years. Among these, apoptosis remains the most conserved type of cell death in metazoans and the most common mechanism for deleting unwanted cells. Other types of cell deaths that often play roles in specific contexts or upon pathological insults can be classed under variant forms of cell death and programmed necrosis. Studies in Drosophila have contributed significantly to the understanding and regulation of apoptosis pathways. In addition to this, Drosophila has also served as an essential model to study the genetic basis of autophagy-dependent cell death (ADCD) and other relatively rare types of context-dependent cell deaths. Here, we summarise what is known about apoptosis, ADCD, and other context-specific variant cell death pathways in Drosophila, with a focus on developmental cell death.

Mitophagy, a form of selective autophagy, plays an essential role to maintain a population of healthy and functional mitochondria for normal cellular metabolism. Acting mainly as one of the B-cell lymphoma 2 (Bcl-2) family pro-apoptotic members, Bim (also known as BCL2L11) was identified to be a co-chaperone of Hsp70 to promote mitophagy in mammalian cells. Herein, with the help of a specific Hsp70/Bim disruptor and Om45-GFP processing assay, we illustrated that ectopic BimEL is able to promote mitophagy through Hsp70/Bim interaction in yeast, where Bax/Bak is absent. The Hsp70/Bim-mediated mitophagy is conserved in eukaryotes, from yeast to humans.

Cholangiocarcinoma (CCA) is a malignant tumor that originates from the biliary epithelial cells. It is characterized by a difficult diagnosis and limited treatment options. Autophagy is a cellular survival mechanism that maintains nutrient and energy homeostasis and eliminates intracellular pathogens. It is involved in various physiological and pathological processes, including the development of cancer. However, the role, mechanism, and potential therapeutic targets of autophagy in CCA have not been thoroughly studied. In this review, we introduce the classification, characteristics, process, and related regulatory genes of autophagy. We summarize the regulation of autophagy on the progression of CCA and collect the latest research progress on some autophagy modulators with clinical potential in CCA. In conclusion, combining autophagy modulators with immunotherapy, chemotherapy, and targeted therapy has great potential in the treatment of CCA. This combination may be a potential therapeutic target for CCA in the future.

Fibroblast growth factor 9 (FGF9) is a member of FGF family, and abnormal expression of FGF9 can promote tumorigenesis. Cordycepin, a major bioactive component in fungus Cordyceps sinensis, could suppress various tumors. We have shown that cordycepin could inhibit FGF9-induced testicular tumor growth in vitro and in vivo with MA-10 mouse Leydig tumor cells. In the present study, the mechanisms related to apoptosis and autophagy were determined. Results show that cordycepin significantly suppressed cell viability and colony formation with correlatedly morphological change related to cell death in FGF9-treated MA-10 cells. Flow cytometry and western blotting results further demonstrate that cordycepin induced apoptosis through the cleavage of caspase-8, -9, -3 and PARP in FGF9-treated MA-10 cells. However, the expressions of LC3-II, beclin-1 and p62 were not stimulated by cordycepin with the presence of FGF9, suggesting cordycepin would activate apoptosis, but not autophagy, in FGF9-treated MA-10 cells. Moreover, inhibition of ERK signal pathway and autophagy would enhance cordycepin-induced cell death effects in FGF9-treated MA-10 cells, referring that ERK signaling was regulated under cordycepin and FGF9 treatments. In NOD-SCID mouse allograft model inoculated with MA-10 cells, cordycepin significantly suppressed tumor growth with the presence of FGF9, and the cleavage of caspase-3 could be observed in tumor tissue, implying cordycepin induced caspase cascade to suppress tumor growth. Moreover, cordycepin plus U0126, ERK inhibitor, further significantly suppressed tumor growth with the presence of FGF9 as compared to the FGF9 only group, confirming the involvement of ERK signaling in this event. In conclusion, cordycepin induced caspase and ERK pathways to promote MA-10 cell apoptosis, but not autophagy, with the presence of FGF9.

Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.

Autophagy plays a complex impact role in tumor initiation and development. It serves as a double-edged sword by supporting cell survival in certain situations while also triggering autophagic cell death in specific cellular contexts. Understanding the intricate functions and mechanisms of autophagy in tumors is crucial for guiding clinical approaches to cancer treatment. Recent studies highlight its significance in various aspects of cancer biology. Autophagy enables cancer cells to adapt to and survive unfavorable conditions by recycling cellular components. However, excessive or prolonged autophagy can lead to the self-destruction of cancer cells via a process known as autophagic cell death. Unraveling the molecular mechanisms underlying autophagy regulation in cancer is crucial for the development of targeted therapeutic interventions. In this review, we seek to present a comprehensive summary of current knowledge regarding autophagy, its impact on cancer cell survival and death, and the molecular mechanisms involved in the modulation of autophagy for cancer therapy.

In recent decades, the incidence of thyroid cancer keeps growing at a shocking rate, which has aroused increasing concerns worldwide. Autophagy is a fundamental and ubiquitous biological event conserved in mammals including humans. Basically, autophagy is a catabolic process that cellular components including small molecules and damaged organelles are degraded for recycle to meet the energy needs, especially under the extreme conditions. The dysregulated autophagy has indicated to be involved in thyroid cancer progression. The enhancement of autophagy can lead to autophagic cell death during the degradation while the produced energies can be utilized by the rest of the cancerous tissue, thus this influence could be bidirectional, which plays either a tumor-suppressive or oncogenic role. Accordingly, autophagy can be suppressed by therapeutic agents and is thus regarded as a drug target for thyroid cancer treatments. In the present review, a brief description of autophagy and roles of autophagy in tumor context are given. We have addressed summary of the mechanisms and functions of autophagy in thyroid cancer. Some potential autophagy-targeted treatments are also summarized. The aim of the review is linking autophagy to thyroid cancer, so as to develop novel approaches to better control cancer progression.

Although CircHULC was overexpressed in several cancers, the role of CircHULC in malignancies has yet to be elucidated.

Gene infection, tumorigenesis test in vitro and in vivo and the signaling pathway analysis were performed.

our results indicate that CircHULC promotes growth of human liver cancer stem cells and the malignant differentiation of hepatocyte-like cells. Mechanistically, CircHULC enhances the methylation modification of PKM2 via CARM1 and the deacetylase Sirt1. Moreover, CircHULC enhances the binding ability of TP53INP2/DOR with LC3 and LC3 with ATG4, ATG3, ATG5, ATG12. Therefore, CircHULC promotes the formation of autophagosomes. In particular, the binding ability of phosphorylated Beclin1 (Ser14) to Vps15, Vps34, ATG14L were significantly increased after CircHULC was overexpressed. Strikingly, CircHULC affects the expression of chromatin reprogramming factors and oncogenes through autophagy. Thereafter, Oct4, Sox2, KLF4, Nanog, and GADD45 were significantly decreased and C-myc was increased after CircHULC was overexpressed. Thus, CircHULC promotes the expression of H-Ras, SGK, P70S6K, 4E-BP1, Jun, and AKT. Interestingly, both CARM1 and Sirt1 determine the cancerous function of CircHULC dependent on autophagy.

we shed light on the fact that the targeted attenuation of deregulated functioning of CircHULC could be a viable approach for cancer treatment, and CircHULC may acts as the potential biomarker and therapeutic target for liver cancer.

Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are associated with the development of acute systemic hyperinflammation. Additionally, critical atherosclerotic ischemia of the lower extremities induces paracoagulation and the development of chronic systemic inflammation. Conversely, sepsis, other critical conditions, and severe systemic chronic diseases contribute to atherogenesis. In summary, atherosclerosis can be characterized as an independent form of inflammation, sharing similarities but also having fundamental differences from low-grade inflammation and various variants of canonical inflammation (classic vasculitis).

Autophagy is an important process that maintains the quality of intracellular proteins and organelles. There is extensive evidence that autophagy has an important role in the lens. Human lens epithelial cells (HLECs) play a key role in the internal homeostasis of the lens. HLEC subtypes have been identified, but autophagy-prominent cell clusters among HLECs have not been characterized.

To explore the existence of autophagy-prominent cell clusters in HLECs.

Three donated lenses (HLECs from two whole lenses and HLECs from one lens without the anterior central 6-mm zone) were used for single-cell RNA sequencing (scRNA-seq). AUCell and AddModuleScore analysis were used to identify potential autophagy-prominent cell clusters. Transmission electron microscopy (TEM) was used to confirm the results.

High-quality transcripts from 18,120 cells were acquired by scRNA-seq of the two intact lenses. Unsupervised clustering classified the cells into four clusters. AUCell and AddModuleScore analysis revealed cluster 1 is autophagy-prominent. scRNA-seq analysis of HLECs from the lens capsule lacking the central zone confirmed the cluster 1 HLECs was located in the central capsule zone. The TEM result showed that greater autophagy activity was observed in the HLECs in central capsule zone, which further supported the above conclusions based on scRNA-seq analysis that autophagy was prominent in the central zone where the cluster 1 HLECs located.

We identified an autophagy-prominent cell cluster among HLECs and revealed that it was localized in the central zone of the lens capsule. Our findings will aid investigations of autophagy in HLECs and provide insights to guide related research.

Cells activate protective mechanisms to overcome stressful conditions that threaten cellular homeostasis, including imbalances in calcium, redox, and nutrient levels. Endoplasmic reticulum (ER) stress activates an intracellular signaling pathway, known as the unfolded protein response (UPR), to mitigate such circumstances and protect cells. Although ER stress is sometimes a negative regulator of autophagy, UPR induced by ER stress typically activates autophagy, a self-degradative pathway that further supports its cytoprotective role. Sustained activation of ER stress and autophagy is known to trigger cell death and is considered a therapeutic target for certain diseases. However, ER stress-induced autophagy can also lead to treatment resistance in cancer and exacerbation of certain diseases. Since the ER stress response and autophagy affect each other, and the degree of their activation is closely related to various diseases, understanding their relationship is very important. In this review, we summarize the current understanding of two fundamental cellular stress responses, the ER stress response and autophagy, and their crosstalk under pathological conditions to help develop therapies for inflammatory diseases, neurodegenerative disorders, and cancer.

Oxidative stress is defined as an injury resulting from a disturbance in the dynamic equilibrium of the redox environment due to the overproduction of active/radical oxygen exceeding the antioxidative ability of the body. This is a key step in the development of various diseases. Oxidative stress is modulated by different factors and events, including the modification of histones, which are the cores of nucleosomes. Histone modification includes acetylation and deacetylation of certain amino acid residues; this process is catalyzed by different enzymes. Histone deacetylase 6 (HDAC6) is a unique deacetylating protease that also catalyzes the deacetylation of different nonhistone substrates to regulate various physiologic processes. The intimate relationship between HDAC6 and oxidative stress has been demonstrated by different studies. The present paper aims to summarize the data obtained from a mechanistic study of HDAC6 and oxidative stress to guide further investigations on mechanistic characterization and drug development.

Post-traumatic epilepsy (PTE) caused by mild TBI (mild traumatic brain injury, mTBI) has a high incidence and poor prognosis, but its mechanisms are unclear. Herein, we investigated the role of reduced levels of neuronal autophagy during the latency period in the increased susceptibility to PTE. In the study, a gentle whole-body mechanical trauma rat model was prepared using Noble-Collip drums, and the extent of injury was observed by cranial CT and HE staining of hippocampal tissue. The incidence of epilepsy and its seizure form were observed 7-90 days after mTBI, and electroencephalography (EEG) was recorded during seizures in rats. Subcortical injection of non-epileptogenic dose of ferrous chloride (FeCl₂) was used to observe the changes of PTE incidence after mTBI. Western blot and Real-time PCR were used to detect the level of autophagy in hippocampal cells at different time points during the latency period of PTE, and its incidence was observed after up-regulation of autophagy after administration of autophagy agonist-rapamycin. The results showed that mTBI was prepared by Noble-Collip drum, which could better simulate the clinical mTBI process. There was no intracerebral hemorrhage and necrosis in rats, no early-onset seizures, and the incidence of PTE after mTBI was 26.7%. The incidence of PTE was 56.7% in rats injected cortically with FeCl₂ at a dose lower than the epileptogenic dose 48 h after mTBI, and the difference was significant compared with no FeCl₂ injection, suggesting an increased susceptibility to PTE after mTBI. Further study of neuronal autophagy during PTE latency revealed that autophagy levels were reduced, and the incidence of PTE was significantly reduced after administration of rapamycin to upregulate autophagy. Taken together, the decreased level of neuronal autophagy during the latency period may be a possible mechanism for the increased susceptibility to PTE after mTBI.

All cells and intracellular components are remodeled and recycled in order to replace the old and damaged cells. Autophagy is a process by which damaged, and unwanted cells are degraded in the lysosomes. There are three different types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Autophagy has an effect on adaptive and innate immunity, suppression of any tumour, and the elimination of various microbial pathogens. The process of autophagy has both positive and negative effects, and this pertains to any specific disease or its stage of progression. Autophagy involves various processes which are controlled by various signaling pathways, such as Jun N-terminal kinase, GSK3, ERK1, Leucine-rich repeat kinase 2, and PTEN-induced putative kinase 1 and parkin RBR E3. Protein kinases are also important for the regulation of autophagy as they regulate the process of autophagy either by activation or inhibition. The present review discusses the kinase catalyzed phosphorylated reactions, the kinase inhibitors, types of protein kinase inhibitors and their binding properties to protein kinase domains, the structures of active and inactive kinases, and the hydrophobic spine structures in active and inactive protein kinase domains. The intervention of autophagy by targeting specific kinases may form the mainstay of treatment of many diseases and lead the road to future drug discovery.

Recent evidence has shown that G protein-coupled receptors (GPCRs) are direct sensors of the autophagic machinery and opioid receptors regulate neuronal plasticity and neurotransmission with an as yet unclarified mechanism. Using in vitro and in vivo experimental approaches, this study aims to clarify the potential role of autophagy and κ-opioid receptor (κ-OR) signaling in synaptic alterations. We hereby demonstrate that the selective κ-OR agonist U50,488H, induces autophagy in a time-and dose-dependent manner in Neuro-2A cells stably expressing the human κ-OR by upregulating microtubule-associated protein Light Chain 3-II (LC3-II), Beclin 1 and Autophagy Related Gene 5 (ATG5). Pretreatment of neuronal cells with pertussis toxin blocked the above κ-OR-mediated cellular responses. Our molecular analysis also revealed a κ-OR-driven upregulation of becn1 gene through ERK1,2-dependent activation of the transcription factor CREB in Neuro-2A cells. Moreover, our studies demonstrated that sub-chronic U50,488H administration in mice causes profound increases of specific autophagic markers in the hippocampus with a concomitant decrease of several pre-and post-synaptic proteins, such as spinophilin, postsynaptic density protein 95 (PSD-95) and synaptosomal associated protein 25 (SNAP25). Finally, using acute stress, a stimulus known to increase the levels of the endogenous κ-OR ligand dynorphin, we are demonstrating that administration of the κ-ΟR selective antagonist, nor-binaltorphimine (norBNI), blocks the induction of autophagy and the stress-evoked reduction of synaptic proteins in the hippocampus. These findings provide novel insights about the essential role of autophagic machinery into the mechanisms through which κ-OR signaling regulates brain plasticity.

The central nervous system (CNS) is a constitutive structure of various cell types conserved by anatomical barriers. Many of the major CNS cell-type populations distributed across the different brain regions are targets for several neurotropic viruses. Numerous studies have demonstrated that viral susceptibility within the CNS is not absolute and initiates a cell-type specific antiviral defence response. Neurons, astrocytes, and microglial cells are among the major resident cell populations within the CNS and are all equipped to sense viral infection and induce a relative antiviral response mostly through type I IFN production, however, not all these cell types adopt a similar antiviral strategy. Rising evidence has suggested a diversity regarding IFN production and responsiveness based on the cell type/sub type, regional distinction and cell`s developmental state which could shape distinct antiviral signatures. Among CNS resident cell types, neurons are of the highest priority to defend against the invading virus due to their poor renewable nature. Therefore, infected and uninfected glial cells tend to play more dominant antiviral roles during a viral infection and have been found to be the major CNS IFN producers. Alternatively, neuronal cells do play an active part during antiviral responses but may adopt differential strategies in addition to induction of a typical type I IFN response, to minimize the chance of cellular damage. Heterogeneity observed in neuronal IFN responsiveness may be partially explained by their altered ISGs and/or lower STATS expression levels, however, further in vivo studies are required to fully elucidate the specificity of the acquired antiviral responses by distinct CNS cell types.

Autophagy is an evolutionarily conserved eukaryotic cellular mechanism through which cytosolic fragments, misfolded/aggregated proteins and organelles are degraded and recycled. Priming of mitochondria through ubiquitylation is required for the clearance the organelle by autophagy (mitophagy). Familial Parkinson's Disease-related proteins, including the E3-ligase PARK2 (PARKIN) and the serine/threonine kinase PARK6 (PINK1) control these ubiquitylation reactions and contribute to the regulation of mitophagy. Here we describe, novel protein complexes containing autophagy protein ATG5 and ubiquitin-proteasome system (UPS) components. We discovered that ATG5 interacts with PSMA7 and PARK2 upon mitochondrial stress. Results suggest that all three proteins translocate mitochondria and involve in protein complexes containing autophagy, UPS and mitophagy proteins. Interestingly, PARK2 and ATG5 recruitment onto mitochondria requires proteasome components PSMA7 and PSMB5. Strikingly, we discovered that subunit of 20 S proteasome, PSMA7, is required for the progression of PARK2-PARK6-mediated mitophagy and the proteasome activity following mitochondrial stress. Our results demonstrate direct, dynamic and functional interactions between autophagy and UPS components that contribute to the regulation of mitophagy.

Autophagy plays a critical role in balancing sources of energy in response to harsh conditions and nutrient deprivation. Autophagy allows cells to survive in harsh condition and also serve as a death mechanism. Any dysregulation in autophagy signaling may lead to several disorders. Autophagy has been proposed to explain chemotherapy resistance in acute myeloid leukemia (AML). This signaling pathway can either act as a tumor suppressive function or chemo-resistance mechanism. Conventional chemotherapy drugs enhance apoptosis and indicate clinical benefit, but in some cases, relapse and chemotherapy resistance are observed. In leukemia, autophagy may promote cell survival in response to chemotherapy drugs. Therefore, new strategies by inhibiting or activating autophagy may find a broad application for treating leukemia and may significantly enhance clinical outcomes. In this review, we discussed the dimensional role of autophagy in leukemia.

Several processes including oxidative stress, apoptosis, inflammation and autophagy are related to testicular function. Recent studies indicate that a crosstalk between apoptosis and autophagy is essential in regulating testicular function. Autophagy and apoptosis communicate with each other in a complex way, allowing them to work for or against each other in testicular cell survival and death. Several xenobiotics especially endocrine-disrupting chemicals (EDCs) have caused reproductive toxicity because of their potential to modify the rate of autophagy and trigger apoptosis. Therefore, the purpose of the present review was to shed light on how autophagy and apoptosis interact together in the testis.

Arrayed libraries of defined mutants have been used to elucidate gene function in the post-genomic era. Yeast haploid gene deletion libraries have pioneered this effort, but are costly to construct, do not reveal phenotypes that may occur with partial gene function and lack essential genes required for growth. We therefore devised an efficient method to construct a library of barcoded insertion mutants with a wider range of phenotypes that can be generalized to other organisms or collections of DNA samples. We developed a novel but simple three-dimensional pooling and multiplexed sequencing approach that leveraged sequence information to reduce the number of required sequencing reactions by orders of magnitude, and were able to identify the barcode sequences and DNA insertion sites of 4391 Schizosaccharomyces pombe insertion mutations with only 40 sequencing preparations. The insertion mutations are in the genes and untranslated regions of nonessential, essential and noncoding RNA genes, and produced a wider range of phenotypes compared to the cognate deletion mutants, including novel phenotypes. This mutant library represents both a proof of principle for an efficient method to produce novel mutant libraries and a valuable resource for the S. pombe research community.

Disulfiram (DSF), which is an inhibitor of aldehyde dehydrogenase (ALDH) and approved by the FDA for the treatment of alcoholism previously, has been repurposed for use as a cancer treatment because of its potent effect in preclinical studies. In this study, we found that disulfiram forms potent complexes with copper (DSF/Cu) inhibited cell proliferation, induced apoptosis in human pancreatic cancer cells, which was detected by flow cytometry and western blotting. Meanwhile, autophagy and autophagic flux also clearly observed by transmission electron microscopy, confocal microscopy and flow cytometry. Our results also showed that DSF/Cu induced transcription factor p8 upregulation and PI3K/mTOR signaling pathway activation detected by real-time PCR and western blotting. Additionally, suppression of p8 inactivated the mTOR signaling pathway and autophagic flux maintained. Furthermore, mechanism study indicated that autophagy induced by DSF/Cu was regulated by p8 and was related to PI3K/mTOR/p70S6K signaling pathway in pancreatic cancer cells. Our findings provide insights into the role of p8 in regulating autophagy induced by DSF/Cu effects in pancreatic cancer cells.