Cancer is a major public health, societal, and economic challenge worldwide. According to Global Cancer Statistics 2022, it is estimated that by 2050, there will be 35 million new cancer cases globally. Although patient survival rates have improved through various therapeutic approaches, including surgery, chemotherapy, and radiotherapy, treatment efficacy remains limited once tumor metastasis occurs. Among various cancer treatment strategies, radiotherapy plays a crucial role. Along with surgery and chemotherapy, radiotherapy is a cost-effective single-modality treatment, accounting for approximately 5% of total cancer care costs. The use of radiosensitizing agents such as histone deacetylase inhibitors, 2-deoxy-d-glucose, enterolactone, and squalene epoxidase can enhance radiotherapy effectiveness. Recent radiosensitization methods involve physical stimuli and chemical radiosensitizers. However, improving their efficacy, durability, and overcoming radioresistance remain significant challenges. This review first introduces current applications of radiotherapy in cancer treatment, the molecular mechanisms underlying its anticancer effects, and its side effects. Second, it discusses the main types of radiosensitizers, their latest applications, and recent challenges in cancer treatment. Finally, it emphasizes on clinical trials of radiosensitizing agents and explores potential biomarkers for radiotherapy response in cancer. Multifunctional nanoparticles have shown greater clinical applicability than single-functional nanoparticles. Future research will focus on enhancing the drug-carrying capacity of nanomaterials to further improve radiotherapy outcomes.

Autophagy, a conserved cellular mechanism which detoxifies and degrades intracellular structures or biomolecules, has been identified as an important factor in the progression of human breast cancer and the development of treatment resistance. Non-coding RNAs (ncRNAs), a broad family of RNA, have the ability to influence various processes, including autophagy, due to their diverse downstream targets. ncRNAs play an important role in suppressing or activating autophagy by targeting autophagy-triggering components such as the ULK1 complex, Beclin1, and ATGs. Recent research has uncovered the intricate regulatory networks that govern autophagy dynamics, with ncRNAs emerging as key participants in this network. miRNAs, lncRNAs, and circRNAs are the three subfamilies of ncRNAs that have the most well-known interactions with autophagy, particularly macroautophagy. The high prevalence of breast cancer necessitates research into finding new biological processes that can help in early detection as well as enhance the effectiveness of treatment. The positive/negative link between autophagy and ncRNAs can be exploited as a supplementary therapy to improve sensitivity to treatment in breast cancer. This review investigates the regulatory roles of ncRNAs, particularly microRNAs (miRNAs), in modifying autophagy pathways in human breast cancer progression and treatment. However, future studies and clinical practice are needed to determine the most relevant microRNAs as biomarkers and also to better understand their role in breast cancer progression or treatment through modifying autophagy.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and abnormal aggregation of the alpha-synuclein protein. Disruption of the autophagy-lysosomal pathway is closely associated with PD pathogenesis. Here, using western-blot analysis we assessed the level of autophagy-related proteins, including phosphorylated mTOR (p-mTOR), phosphorylated RPS6 (p-RPS6), beclin-1 (BECN1), LC3B, p62, and cathepsin D (CTSD) in macrophages derived from peripheral blood mononuclear cells (PBMC-derived macrophages) of GBA1-PD (p.N370S/N, p.L444P/N), LRRK2-PD (p.G2019S/N), idiopathic PD (iPD) patients, and healthy controls. Our findings revealed mutation-specific disruptions in autophagy pathways among PD patients. In p.N370S-GBA1-PD, PBMC-derived macrophages exhibited elevated levels of p-RPS6, BECN1, LC3B-II and decreased mature form of CTSD levels suggesting more active mTOR-dependent autophagy initiation alongside potential autophagosome accumulation that may lead to downregulation of lysosomal degradation. p.L444P-GBA1-PD PBMC-derived macrophages showed increased levels of p-RPS6 and BECN1, coupled with decreased p62 levels and stable mature form of CTSD and LC3B-II, indicative of enhanced autophagy flux driven by mTOR activity without evident lysosomal dysfunction. In p.G2019S-LRRK2-PD patients, PBMC-derived macrophages demonstrated elevated p-RPS6, LC3B-II, and mature CTSD levels, alongside reduced p62 levels. These changes suggest higher basal autophagosome abundance in steady-state autophagy and turnover, potentially driven by lysosomal alterations rather than direct mTOR dysregulation. These mutation-dependent differences highlight distinct autophagy dynamics in GBA1-PD and LRRK2-PD, underscoring the critical role of genetic mutations in modulating PD pathogenesis. Our results emphasize the necessity for subtype-specific therapeutic strategies targeting autophagy and other mTOR-regulated pathways to address the heterogeneity of PD mechanisms.

The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.

Phosphatidylinositol-3-phosphate (PI(3)P) is important for multiple functions of retinal pigmented epithelial (RPE) cells, but its functions in RPE have not been studied. In RPE from mouse eyes and in cultured human RPE cells, PI(3)P-enriched membranes include endosomes, the trans-Golgi network, phagosomes, and autophagophores. Mouse RPE cells lacking activity of the PI-3 kinase, Vps34, lack detectable PI(3)P and die prematurely. Phagosomes containing rod discs accumulate, as do membrane aggregates positive for autophagosome markers. These autophagy-related membranes recruit LC3/Atg8 without Vps34, but phagosomes do not. Vps34 loss leads to accumulation of lysosomes which do not fuse with phagosomes or membranes with autophagy markers. Thus, Vps34-derived PI(3)P is not needed for initiation of phagocytosis or endocytosis, nor for formation of membranes containing autophagy markers. In contrast, Vps34 and PI(3)P are essential for intermediate and later stages, including membrane fusion with lysosomes.

The problem of microplastics (MPs) pollution has caused many health risks to residents of Chinese cities. In this study, nine kinds of MPs or microrubbers (MRs) from dust fall (DF) in Xi'an, a megacity in northwestern China, were measured by pyrolysis-gas chromatography-mass spectroscopy, namely, polyethylene, polypropylene, nylon 88, polybutylene, polytetrafluorethylene, polyisoprene, polyvinyl chloride, natural rubber, and synthesis rubber. Here, 51.20% of MPs were extracted from the original DF (samples denoted DF-O). After the subtracting procedure, MPs and their residual (DF-S samples) were divided into two parts. Our results indicated that the DF-O and MPs samples exhibited higher cytotoxicity, inflammatory, and oxidative stress levels than the DF-S samples did. The DF-O and MPs samples suppressed autophagy by decreasing expression levels of microtubule-associated protein light chain 3 (LC3B), p-phosphatidylinositol 3-kinase (p-PI3K), phosphorylated AKT protein (p-Akt), and p-mammalian target of rapamycin (p-mTOR) while increasing the level of p62. Meanwhile, DF-O and MPs samples induced apoptosis through increasing levels of Bax/Bcl-2 and Cleaved Caspase-3/Caspase-3 in Raw264.7 cells. These trends could be reversed through removing half of the MPs in DF-O. Therefore, dust fall microplastics inhibited autophagy and induced apoptosis via activating the PI3K/Akt/mTOR pathway, increasing the Bax/Bcl-2 and Cleaved Caspase-3/Caspase-3 ratios. Here we provide a comprehensive perspective into the studies of atmospheric MPs pollution status and mechanisms of inhalation toxicity for health risk assessment of MPs in DF.

Autophagy is a degradative process that makes rapid turnover of old and impaired proteins and organelles possible. It is highly instigated by stress signals, like starvation, and contributes to the cell's homeostasis. Autophagy performs a crucial function in keeping cell genomic integrity stable. Impaired autophagic flux is implicated in neurodegenerative diseases, abnormal ageing, and cancerous diseases. In diseases like cancer, autophagy performs a dualistic function; it can have both a tumor-suppressive and supportive role. Autophagy in the initial phases of tumorigenesis maintains the integrity of the genome and, if it fails, leads to cell death, thus having a tumor-suppressive role. Meanwhile, autophagy also imparts the function of the pro-survival mechanism in the latter stages of tumorigenesis and supports the cancerous cells in surviving conditions like hypoxia and increased oxidative stress. Autophagy also helps cancerous cells develop drug resistance in some cases. Thus, modulation of the autophagic mechanism is a possible therapeutic strategy in cancer therapy as its inhibition can sensitise cancer cells to anti-cancerous drugs. The promotion of autophagy, in some cases, can also safeguard cells from toxic protein aggregation and enhanced oxidative stress. Excessive autophagy can result in autophagic cell death. Autophagy also regulates several cellular processes and cell death pathways, like apoptosis. Therefore, an in-depth knowledge of the autophagy process and its regulating molecules is critically important. Pharmaceutical small molecules or cellular target modulation can help modulate the cellular autophagy process in the context of specific disease conditions.

Lysosomes, as crucial organelles within cells, carry out diverse biological functions such as waste degradation, regulation of the cellular environment, and precise control of cell signaling. This paper reviews the core functions and structural characteristics of lysosomes, and delves into the current research status of lysosomes damage repair mechanisms. Subsequently, we explore in depth the close association between lysosomes and various diseases, including but not limited to age-related chronic diseases, neuro-degenerative diseases, tumors, inflammation, and immune imbalance. Additionally, we also provide a detailed discussion of the application of lysosome-targeted substances in the field of regenerative medicine, especially the enormous potential demonstrated in key areas such as stem cell regulation and therapy, and myocardial cell repair. Though the integration of multidisciplinary research efforts, we believe that lysosomes damage repair mechanisms will demonstrate even greater application value in disease treatment and regenerative medicine.

Several studies have investigated the efficacy of estrogen in age-related diseases, showing promising results in several models of neurodegeneration, such as Alzheimer's disease. Animal and cellular models indicate that estrogen and related compounds can reduce the accumulation of amyloid plaques and tau protein, which are associated with Alzheimer's disease. Therefore, it is crucial to develop appropriate models to study the neuroprotective effects of estrogen, and three-dimensional (3D) models have recently emerged as a viable alternative to animal testing. This study aimed to investigate the potential of 3D tauopathy models for drug testing, focusing on estrogen-related signaling. The results demonstrate that a scaffold-free neurospheroid with inducible tau protein expression allows for the observation of tau protein distribution throughout the spheroid. Moreover, the study found that the G-protein-coupled estrogen receptor antagonist, G15, reduced tau protein concentration in both 2D and 3D models. Thus, this study highlights the importance of estrogen-related compounds in 3D cultures, which could facilitate investigations into the mechanisms of action and the neuroprotective role of estrogen in neurodegenerative diseases.

Hypoxia-induced pulmonary hypertension (HPH), a consequence of lung pathologies, is linked to changes in immune responses and inflammation. SIRT5 is recognized as the only enzyme capable of removing succinyl groups. The focus of this research was to explore the involvement of SIRT5 in HPH and to elucidate the associated mechanisms. Models simulating HPH were created in both living organisms and controlled laboratory settings under conditions of low oxygen. To investigate autophagy, transmission electron microscopy (TEM) was employed for ultrastructural analysis, while reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to measure the expression of autophagy-related genes. Cell viability was determined using the cell counting kit-8 (CCK-8) assay. The concentrations of inflammatory cytokines were quantified using ELISA, and flow cytometry was applied to evaluate reactive oxygen species (ROS) levels. To explore the interaction between PDK1 and SIRT5, co-immunoprecipitation (Co-IP) followed by Western blot analysis was conducted. Findings revealed that low oxygen conditions prompted mitophagy and elevated levels of both mRNA and proteins associated with this process in experiments conducted in organisms as well as in cellular models. Under conditions of low oxygen, the expression of SIRT5 was found to be reduced. Hypoxia enhanced cell viability, ROS level, angiogenesis-related protein levels, and inflammatory cytokine levels in pulmonary microvascular endothelial cells (PMVECs), effects that were reversed upon SIRT5 overexpression. Mechanistically, SIRT5 interacted with PDK1, desuccinylating PDK1 and thereby inhibiting mitophagy and inflammation associated with HPH. In conclusion, SIRT5 inhibited mitophagy and inflammation in HPH by regulating the desuccinylation of PDK1, potentially offering effective therapeutic strategies for treating HPH.

Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues. Both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1596 heterogeneous stock (HS) rats. Rats underwent a Pavlovian conditioned approach task that characterized the responses to food-associated stimuli ("cues"). Responses ranged from cue-directed "sign-tracking" behavior to food-cup directed "goal-tracking" behavior (12 measures, SNP heritability: 0.051-0.215). Next, rats performed novel operant responses for unrewarded presentations of the cue using the conditioned reinforcement procedure. GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits across both tasks. Interval sizes of these QTLs varied widely. Seven traits shared a QTL on chromosome 1 that contained a few genes (e.g., Tenm4, Mir708) that have been associated with substance use disorders and other psychiatric disorders in humans. Other candidate genes (e.g., Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on addiction-related behaviors in HS rats and found that the QTL on chromosome 1 was also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive motivational processes and provide further support for a relationship between the attribution of incentive salience and drug abuse-related traits.

Fine particulate matter (PM2.5) exposure is significantly linked to lung epithelial cell senescence, and autophagy dysfunction being a key contributor to the aging process. Although the anti-aging properties of ellagic acid (EA) are well-documented, its specific protective effect on PM2.5-induced lung epithelial cell senescence still needs to be studied in depth. To investigate the impacts of PM2.5 on autophagy and senescence in lung epithelial cells, 16HBE and A549 cells were exposed to PM2.5 suspension. Additionally, to explore the potential intervention effect of EA, cells were pretreated with EA before exposure to PM2.5 suspension. Cell morphology, proliferation, senescence-related markers, senescence-associated secretory phenotype (SASP), and autophagy-related markers were then assessed. Our results showed that the proliferation of 16HBE and A549 cells were inhibited and autophagy dysfunction and senescence were induced under PM2.5 exposure. However, pretreatment with EA can significantly improve the obstruction of autophagy flux caused by PM2.5, thereby effectively alleviating cell senescence. This study reveals the mechanism by which PM2.5 induces senescence in lung epithelial cells and confirms the protective role of ellagic acid in this process.

Lipid accumulation and foam cell formation are significant features that expedite the progression of atherosclerosis (AS). Abnormal autophagy is a key factor in the development of AS. The importance of berberine (BBR) in AS has been well established. However, its exact role in regulating autophagy and alleviating atherosclerotic inflammation remains unclear.

This study was aimed at exploring the role and mechanism of BBR in alleviating AS by activating autophagy and alleviating inflammation.

Network pharmacology predicts the potential mechanism of BBR in regulating AS and verifies this mechanism through in vivo and in vitro experiments, thereby providing new thinking for clinical treatment.

The potential mechanism through which BBR regulates AS was predicted by network pharmacology. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) were measured by administering BBR (100 mg/kg) via the stomach. Hematoxylin and eosin (HE) and oil red O staining were used for histological analysis. Expression levels of the RAGE and p-NF-κB pathways and autophagy-associated proteins were evaluated by immunofluorescence. The ApoE-/- mouse model was established with a high-fat diet (HFD) to verify the effect and mechanism of BBR in vivo.

Functional and pathway enrichment analysis demonstrated that BBR significantly modulated the inflammation-related signaling pathways of AS. Additionally, in vivo experiments indicated that BBR reduced aortic lipid deposition and reduced the atherosclerotic plaque area. BBR decreased the expression levels of RAGE, p-NF-κB, TNF-α, and P62 in the aorta, and upregulated the expression levels of IL-10, CD31, VEGF, LC3B, and Beclin1. Similar results were obtained in vitro experiments, further supporting the in vivo findings. Notably, NF-κΒ activator 1 attenuated the effect of BBR.

In summary, BBR alleviated the disease progression of AS by regulating the expression of RAGE and p-NF-κB and activating autophagy.

Parkinson's disease (PD) is a common neurodegenerative disorder in the elderly, characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies. Hufeng Jiu from Vespa magnifica Smith, a traditional remedy used by the Chinese Jingpo minority, is documented in the Pharmacopoeia of China (2020) for treating rheumatic arthritis. Notably, recent research suggests that components of wasp venom (WV) from Vespa magnifica Smith, particularly polypeptides such as Mastoparan-M (Mast-M) and Vespakinin-M, may have potential therapeutic effects for neurological disorders. However, the specific polypeptide components of WV and their therapeutic effects on PD models remain insufficiently understood.

This study aims to characterize the neuroactive polypeptides in Vespa magnifica Smith venom and investigate the therapeutic potential of Mast-M for PD.

Neuroactive polypeptides in WV were identified using LC/MS, and Mast-M derived from venom of Vespa magnifica Smith was verified with HPLC. The neuroprotective effects of WV and its peptides were assessed using the CCK-8 assay in 1-methyl-4- phenylpyridinium (MPP+)-induced SH-SY5Y human neuroblastoma cells. Mast-M was identified as a potent antagonist against MPP+-induced neurotoxicity. The toxicity, hemolytic activity, and blood-brain-barrier (BBB) permeability of Mast-M were evaluated in mice, and its therapeutic effects were assessed in an MPTP-induced PD mouse model, focusing on motor function and tyrosine hydroxylase (TH) levels. Additionally, Mast-M's impact on mitochondrial membrane potential (MMP), autophagy, and the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signling pathway was investigated.

A total of 1007 peptides were identified in the WV, including 187 UniProtKB unreviewed, with 185 predicted to be BBB-permeability. Our results show that Mast-M exhibits a time-dependent distribution in mice, initially localizing in the peritoneal region and subsequently accumulating in the brain, liver, and kidney. Cellular uptake studies reveal that Mast-M penetrates cell membranes and accumulates intracellularly over time. In the MPP+-induced neurotoxicity model using SH-SY5Y cells, Mast-M significantly enhances cell viability and MMP. In vivo safety assessments indicate that Mast-M is well-tolerated at doses up to 100 μg/kg, with no significant toxicological effects observed. However, higher doses induce hepatic distress, necessitating dose optimization. Hemolysis was absent at concentrations ≤37 μg/mL, with an EC50 for hemolytic activity of 197 μg/mL. In MPTP-induced PD models, Mast-M partially ameliorates motor deficits and preserves TH expression in dopaminergic neurons, supporting its neuroprotective role. Mechanistically, Mast-M activates autophagic pathways, as evidenced by the upregulation of autophagy-related protein LC3 in MPP+-challenged SH-SY5Y cells. Furthermore, Mast-M promotes mitophagy and mitochondrial biogenesis, modulating the AMPK/mTOR signaling axis to facilitate mitochondrial turnover.

Mast-M emerges as a promising therapeutic candidate for PD, capable of crossing the BBB, enhancing autophagy, and providing neuroprotection in PD models. Further studies are warranted to optimize dosing and elucidate its full therapeutic potential.

Breast cancer is the most prevalent cancer and the second leading cause of cancer-related mortality among women globally, resulting in considerable psychological and physical distress for patients. Our previous study synthesized a novel derivative, 2-Deoxy-Rh2, which exhibited anticancer properties by influencing glycolysis and mitochondrial respiration. The objective of the current study was to investigate the anti-proliferative effects and underlying mechanisms of 2-Deoxy-Rh2 on human breast cancer cell lines MCF-7 and MDA-MB-231. In our experiments, we observed that 2-Deoxy-Rh2 reduced cell viability and induced cell cycle arrest, reactive oxygen species accumulation, and mitochondrial dysfunction. Furthermore, treatment with 2-Deoxy-Rh2 affected autophagic flux and induction, leading to increased expression of microtubule-associated protein light chain 3B (LC3B) and decreased expression of sequestosome 1 (P62) expression in both two breast cancer cell lines, which could be reversed by 3-Methyladenine (3-MA). Additionally, the AMPK signaling pathway plays a crucial role in 2-Deoxy-Rh2-induced autophagy. 2-Deoxy-Rh2 modulated the expression levels of mTOR and AMPK in MCF-7 and MDA-MB-231 cells, resulting in the cellular homeostasis disruption, autophagy and apoptosis, which was further corroborated by compound C (CC). Finally, the study validated the antitumor activity and mechanism of 2-Deoxy-Rh2 in vivo using Balb/c mice bearing 4T1 tumor cells. Overall, the results suggest that 2-Deoxy-Rh2 can induce apoptosis and autophagic cell death through the AMPK/mTOR signaling pathway, positioning it as a promising candidate for an antitumor agent against breast cancer.

The identification of new biomarkers that improve existing cardiovascular risk prediction models for acute coronary syndrome is essential for accurately identifying high-risk patients and refining treatment strategies. Autophagy, a vital cellular degradation mechanism, is important for maintaining cardiac health. Dysregulation of autophagy has been described in cardiovascular conditions such as myocardial ischemia-reperfusion injury, a key factor in myocardial infarction (MI). Recently, Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein), a key negative regulator of autophagy, has been identified in the modulation of cardiac stress response.

This study aimed to explore the relationship between circulating Rubicon levels and MI, and to evaluate the incremental predictive value of Rubicon when integrated into a clinical risk prediction model for MI.

We analyzed plasma Rubicon concentrations in 177 participants, comprising type I MI patients and high-risk control subjects. Our results revealed significantly elevated plasma Rubicon levels in MI patients compared to the control group (126.5 pg/mL vs. 53 pg/mL, p < 0.001). Furthermore, Rubicon levels showed a positive correlation with cardiovascular risk factors such as total cholesterol and LDL cholesterol. Multivariate analysis confirmed that Rubicon levels were independently associated with an increased risk of MI. The inclusion of Rubicon in traditional cardiovascular risk models notably enhanced predictive accuracy for MI, with the area under the curve (AUC) rising from 0.868 to 0.905 (p < 0.001).

These findings suggest that Rubicon is a valuable biomarker associated with MI risk, providing additional predictive value beyond standard cardiovascular risk factors. This highlights the importance of Rubicon's critical role in the pathophysiology of CVD.

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.

The rising aging population and changing lifestyles have led to a global increase in diabetes and its complications, making it one of the most prevalent diseases worldwide. Chronic inflammation is a key pathogenic feature of diabetes and its complications, yet the precise mechanisms remain unclear, impeding the development of targeted therapies. Recent studies have highlighted the β cell-macrophage crosstalk pathway as a crucial factor in chronic low-grade inflammation and glucose homeostasis imbalance in both type 1 and type 2 diabetes. Furthermore, impaired macrophage phagocytic functions, including pathogen phagocytosis, efferocytosis, and autophagy, play a significant role in diabetes complications. Given their high plasticity, macrophages represent a promising research target. This review summarizes recent findings on macrophage phagocytic dysfunction in diabetes and its complications, and explores emerging therapies targeting macrophage phagocytic function. We also discuss the current challenges in translating basic research to clinical practice, aiming to guide researchers in developing targeted treatments to regulate macrophage status and phagocytic function, thus preventing and treating metabolic inflammatory diseases.

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has continued to increase annually. Recent studies have indicated that inhibition of metabotropic glutamate receptor 5 (mGluR5) may alleviate hepatic steatosis. However, the precise mechanism warrants further exploration.

To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.

Free fatty acids (FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG. Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content. Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II, as well as the expression of the key signaling molecules AMPK and ULK1, in the treated cells. To further elucidate the contributions of autophagy and AMPK, we used chloroquine (CQ) to inhibit autophagy and compound C (CC) to inhibit AMPK activity. In parallel, wild-type mice and mGluR5 knockout (KO) mice fed a normal chow diet or a high-fat diet (HFD) were used to evaluate the effect of mGluR5 inhibition in vivo.

mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression. The autophagy inhibitor CQ reversed the effects of MPEP. In addition, MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs. MPEP treatment led to the nuclear translocation of transcription factor EB, which is known to promote p62 expression. This effect was negated by the AMPK inhibitor CC. mGluR5 KO mice presented reduced body weight, improved glucose tolerance and reduced hyperlipidemia when fed a HFD. Additionally, the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.

Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway. These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.

Autophagy, a cellular process essential for maintaining homeostasis, plays a fundamental role in recycling damaged components and in adapting to stress. The dysregulation of autophagy is implicated in numerous human diseases, including cancer, where it exhibits a dual role as both a suppressor and a promoter, depending on the context and the stage of tumor development. The significant sex differences observed in autophagic processes are determined by biological factors, such as genetic makeup and sex hormones. Estrogens, through their interaction with specific receptors, modulate autophagy and influence tumor progression, therapy resistance, and the immune response to tumors. In females, the escape from X inactivation and estrogen signaling may be responsible for the advantages, in terms of lower incidence and longer survival, observed in oncology. Women often show better responses to traditional chemotherapy, while men respond better to immunotherapy. The action of sex hormones on the immune system could contribute to these differences. However, women experience more severe adverse reactions to anticancer drugs. The estrogen/autophagy crosstalk-involved in multiple aspects of the tumor, i.e., development, progression and the response to therapy-deserves an in-depth study, as it could highlight sex-specific mechanisms useful for designing innovative and gender-tailored treatments from the perspective of precision medicine.

Platycodin D2 (PD2) is a triterpenoid saponin extracted from the root of Platycodon grandiflorum , a common source of medicine and food. Platycodon grandiflorum saponins have anti-inflammatory, antioxidative, antitumor, and immunity-promoting effects. However, the effect of PD2 on breast cancer cells has not been reported. The purpose of this study is to explore the molecular mechanism underlying the effect of PD2 on breast cancer cells. We analyzed the inhibitory effects and pathways of PD2 on breast cancer by CCK-8 assay, WB assay, and immunofluorescence assay. Subsequently, autophagy and ferroptosis were analyzed using different inhibitors. It was found that PD2 caused mitochondrial damage and promoted mitochondrial reactive oxygen species (mtROS) production, leading to autophagy flux inhibition and ferroptosis. Blockage of autophagy flux and ferroptosis promoted each other, resulting in the inhibition of breast cancer cell proliferation. Similar results were obtained in the tumor-bearing model in vivo. PD2 promoted autophagy flux blockage and ferroptosis in breast cancer cells, which induced each other under the action of mtROS, thus inhibiting the proliferation of breast cancer cells. PD2 is a potential new strategy for the treatment of breast cancer.

Microglia activation and autophagy changes are associated with the regulation of pain, but no study to date has been designed to address whether these features apply to trigeminal neuropathic pain. This study aimed to investigate how alterations in autophagy affect nociceptive behaviors may be associated with microglia activation in the caudal part of the spinal trigeminal nucleus (SpVC) in a rat model of trigeminal neuropathic pain. This model was established by chronic constriction injury of the infraorbital nerve. Autophagy inhibitors and agonists were injected into the lateral ventricle to regulate autophagy. The autophagy markers microtubule-associated protein light chain 3 I (LC3-I), LC3-II, sequestosome1 (p62), and LC-3 were examined by western blotting and/or immunofluorescence. The microglia marker ionized calcium binding adapter molecule 1 (Iba-1) was examined by immunohistochemistry. Nociceptive behavior changes were detected by measuring the mechanical thresholds and face-grooming duration. The results showed that microglia in SpVC were activated, and autophagy flux was blocked in the trigeminal neuropathic pain model. Autophagy agonists inhibited microglia activation and alleviated nociceptive behaviors. In contrast, autophagy inhibitors further activated microglia and exacerbated nociceptive behaviors. In a rat model of trigeminal neuropathic pain, autophagy blockage leads to microglia activation, which significantly influences nociceptive processes.

Panax ginseng (P. ginseng) C. A. Meyer. has been used extensively globally as a medicine. It has a therapeutic effect on sleep and is an attractive alternative for patients with insomnia. The United States Patent of Invention has approved the use of P. ginseng alcohol extract (GAE) in nutraceuticals or food to improve sleep. It has shown promise as an effective therapeutic agent for improving sleep and cognition. However, its mechanism of action is not yet fully understood.

To investigate the therapeutic benefits of GAE on sleep and cognition and its underlying mechanism in aged sleep-deprived rats, with a focus on orexin-mediated autophagy function.

We conducted in vivo tests in an aged sleep-deprivation rat model produced using p-chlorophenylalanine (PCPA) coupled with modified multi-platform method to examine the therapeutic effects and mechanisms of GAE. A pentobarbital sodium-induced sleep test and water maze were used to assess sleep and cognitive performance, respectively. An enzyme-linked immunosorbent assay was used to determine orexin levels and aging and sleep markers in serum and hypothalamic tissues. Hematoxylin-eosin staining and Nissl staining were used to assess histopathological changes, and autophagy levels were assessed using transmission electron microscopy, immunofluorescence. Western blot and immunohistochemical staining were performed to detect the levels of orexin, orexin-receptor proteins, and autophagy-associated proteins to study the effects of GAE on hippocampal neurons, and the underlying mechanisms.

In aged sleep-deprived rats, GAE treatment prolonged sleep duration, improved cognitive function, prevented hippocampal neuronal damage, increased the number of Nissl bodies, improved aging and sleep markers, and enhanced the LC3A/B expression in autophagosomes and neurons. The amount of orexin in serum and hypothalamic tissue and OX1R, OX2R, and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) proteins also reduced, which resulted in the inhibition of the PI3K/Akt/mTOR pathway and activation of the autophagy process.

GAE may reduce hypothalamic orexin secretion and interact with orexin receptors to inhibit the PI3K/Akt/mTOR signalling network and activate autophagy. This may be a potential mechanism of action of GAE in regulating sleep-related cognitive function.

Hepatocellular carcinoma (HCC) poses a significant health burden due to its high incidence, and current treatment effectiveness is hindered by drug resistance. Thus, investigation of novel therapeutic approaches derived from natural sources is crucial for improving patient outcomes.

This study aimed to explore the potential of Tetramethylpyrazine (TMP), bioactive alkaloid (ligustrazine) isolated from Chuanxiong (Ligusticum Wallichii), in targeting HCC by inducing apoptosis and enhancing autophagy. The study focused on elucidating the molecular mechanisms underlying anti-cancer effects of TMP.

To determine the influence of TMP on apoptosis and autophagy, Western blot analysis, annexin V assay, cell cycle analysis, acridine orange staining, and immunocytochemistry were performed. Next, the activation of the STAT3 signaling pathway and the anti-cancer effects of TMP in vivo were examined in an orthotopic HCCLM3-Lu mouse model.

TMP treatment induced apoptosis in HCCLM3 and Hep3B cells by activating key apoptotic factors while inhibiting proteins associated with cell survival and angiogenesis. Additionally, TMP enhanced autophagy by promoting the formation of autophagosomes and stimulating autophagy-related proteins. Furthermore, TMP suppressed the activation of the STAT3 signaling pathway by upregulating SHP-1, thereby inhibiting tumorigenesis and activating cell death pathways. Additionally, our in vivo research demonstrated that TMP significantly inhibited tumor growth and triggered the activation of both apoptosis and autophagy in tumor tissues.

Our findings of this study demonstrate that TMP exerts a dual-action mechanism by modulating both apoptosis and autophagy, thus offering a promising strategy to overcome drug resistance in HCC.

Macroautophagy, a universal cellular process, sends cellular material to lysosomes for breakdown and is often activated by stressors like hypoxia or drug exposure. It is vital for protein balance, neurotransmitter release, synaptic function, and neuron survival. The role of macroautophagy in substance use disorders is dual. On one hand, substances like cocaine, methamphetamine, opiates, and alcohol can activate macroautophagy pathways to degrade various neuroinflammatory factors in neuronal cells, providing a protective function. On the other hand, long-term and excessive use of addictive substances can inhibit macroautophagy pathways, obstructing the fusion of autophagosomes with lysosomes and losing the original protective function. This review first summarizes the key proteins and signaling pathways involved in macroautophagy, including mTORC1, AMPK, and endoplasmic reticulum stress, and suggests that the regulation of macroautophagy plays a central role in drug-rewarding behavior and addiction. Second, we focus on the interactions between macroautophagy and neuroinflammation induced by drugs, evaluating the potential of macroautophagy modulators as therapeutic strategies for substance use disorder (SUD), and identifying autophagy-related biomarkers that can be used for early diagnosis and monitoring of treatment response. Our review summarizes the important scientific basis involved in macroautophagy pathways for the development of new therapies for SUD.

As BAG family members, Bcl-2 associated athanogene family protein 1 (BAG1) and 2 (BAG2) are implicated in multiple cellular processes, including apoptosis, autophagy, protein folding and homeostasis. Although structurally similar, they considerably differ in many ways. Unlike BAG2, BAG1 has four isoforms (BAG1L, BAG1M, BAG1S and BAG1 p29) displaying different expression features and functional patterns. BAG1 and BAG2 play different cellular functions by interacting with different molecules to participate in the regulation of various diseases, including cancer/tumor and neurodegenerative diseases. Commonly, BAG1 acts as a protective factor to predict a good prognosis of patients with some types of cancer or a risk factor in some other cancers, while BAG2 is regarded as a risk factor to promote cancer/tumor progression. In neurodegenerative diseases, BAG2 commonly acts as a neuroprotective factor. In this review, we summarized the differences in molacular structure and biological function between BAG1 and BAG2, as well as the influences of them on pathogenesis of diseases, and explore the prospects for their clinical therapy application by specifying the activators and inhibitors of BAG1 and BAG2, which might provide a better understanding of the underlying pathogenesis and developing the targeted therapy strategies for diseases.

CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, plays an important role not only in the immune system but also in tumor progression. CD40 ligation reportedly promotes autophagy in immune cells. However, the effects of CD40 ligation on autophagy and its mechanism in solid tumor cells are still unclear. In this study, we find that CD40 ligation promotes autophagosome formation and consequently promotes autophagic flux in cervical cancer cells. Mechanistically, this effect relies on ERK contributing to CD40 ligation-induced ATG13 upregulation by p53. Furthermore, we demonstrate that CD40 ligation-induced autophagy increases the radiosensitivity of cervical cancer cells. Taken together, our results provide new evidence for the involvement of the CD40 pathway in autophagy and radiotherapy in cervical cancer cells.

Acute myeloid leukemia (AML) with FLT3-ITD mutation represents a quarter of AML patients and is associated with high relapse rate and dismal prognosis. FLT3 tyrosine kinase inhibitors (TKIs) were developed in order to target this genetic alteration and among these TKIs, AC220 (quizartinib) combined with chemotherapy has already shown an increased overall survival for patients with AML with FLT3-ITD mutation. Even though this increase in overall survival was significant, it remains discrete, and relapse rate is still high, so there is an unmet medical need. All-trans retinoic acid (ATRA) is well known for its effectiveness in acute promyelocytic leukemia (APL) treatment and has already been shown to have synergistic effects combined with another TKI, sorafenib. In this study, quizartinib, a more potent FLT3-TKI, was tested in combination with ATRA in the AML FLT3-ITD positive cell lines MOLM-13 and MV4-11. ATRA has effectively improved AC220 induced cell death via caspase activation. In addition, ATRA in combination with AC220 treatment notably enhanced BECN1 cleavage compared to AC220 treatment alone. Finally, in a xenotransplantation model ATRA plus AC220 was more efficient to reduce the leukemic burden than monotherapy with ATRA or AC220. Taken together, our results are a proof of the concept that ATRA and AC220 have synergistic anti-leukemic effects.

Cardiovascular disease is the most common cause of mortality globally, accounting for approximately one out of three deaths. The main underlying pathology is atherosclerosis, a dyslipidemia-driven, chronic inflammatory disease. The interplay between immune cells and non-immune cells is of great importance in the complex process of atherogenesis. During atheroprogression, intracellular metabolic pathways, such as amino acid metabolism, are master switches of immune cell function. Autophagy, an important stress survival mechanism involved in maintaining (immune) cell homeostasis, is crucial during the development of atherosclerosis and is strongly regulated by the availability of amino acids. In this review, we focus on the interplay between amino acids, especially L-leucine, L-arginine, and L-glutamine, and autophagy during atherosclerosis development and progression, highlighting potential therapeutic perspectives.

Melanin's pivotal role in skin protection and its overproduction leading to hyperpigmentation disorders highlight the necessity of regulating melanogenesis, with autophagy identified as a key degradation pathway. Imperatorin, a compound from Angelica dahurica, has been revealed to reduce melanin in epidermal keratinocytes, with the specific effects and mechanisms unknown. The purpose of this study was to investigate the mechanism by which imperatorin, reduces melanin production in HaCaT cells, with a focus on its potential role in promoting autophagy and regulating the PI3K/Akt signaling pathway.

The study used HaCaT cells to investigate the effects of imperatorin on melanin production, autophagy, and PI3K/Akt signaling. Melanin content was measured using a spectrophotometric method. Protein levels of PMEL, ATG1, ATG5, and LC3B II were assessed by Western blotting. Autophagy was further visualized by GFP-LC3B puncta formation. The autophagy inhibitor 3-MA, the PI3K/Akt inhibitor LY294002 and PI3K/Akt activator 740 Y-P were used to assess the role of autophagy and PI3K/Akt signaling in imperatorin's effects. Cell viability was monitored to ensure that imperatorin's effects were not due to cytotoxicity.

Imperatorin reduced melanin content in HaCaT cells in a dose-dependent manner without compromising cell viability. This reduction in melanin was accompanied by decreased levels of PMEL protein, a key player in melanosome formation. Additionally, imperatorin promoted autophagy in HaCaT cells, as evidenced by increased levels of autophagy-associated markers ATG1, ATG5, and LC3B II, as well as an increase in GFP-LC3B puncta. The autophagy inhibitor 3-MA partially reversed the effects of imperatorin on both autophagy markers and PMEL levels, indicating that autophagy plays a crucial role in imperatorin's depigmentation action. Furthermore, imperatorin inhibited Akt and mTOR phosphorylation, which are downstream targets of PI3K/Akt signaling, enhancing autophagy and further reducing melanin levels. The PI3K/Akt inhibitor LY294002 amplified imperatorin's effects on PI3K and Akt phosphorylation, autophagy, and melanin levels. While, PI3K/Akt activator 740 Y-P reversed imperatorin's effects on these factors.

Imperatorin reduces melanin in HaCaT cells via promoting autophagy and melanin degradation, possibly via the PI3K/Akt signaling. Taken together, imperatorin has the therapeutic potential for the treatment of hyperpigmentation disorders.

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.

Programmed cell death represents a precisely regulated and active cellular demise, governed by a complex network of specific genes and proteins. The identification of multiple forms of programmed cell death has significantly advanced the understanding of its intricate mechanisms, as demonstrated in recent studies. A thorough grasp of these processes is essential across various biological disciplines and in the study of diseases. Nonetheless, despite notable progress, the exploration of the relationship between programmed cell death and disease, as well as its clinical application, are still in a nascent stage. Therefore, further exploration of programmed cell death and the development of corresponding therapeutic methods and strategies holds substantial potential. Our review provides a detailed examination of the primary mechanisms behind apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Following this, the discussion delves into biological functions and diseases associated dysregulated programmed cell death. Finally, we highlight existing and potential therapeutic targets and strategies focused on cancers and neurodegenerative diseases. This review aims to summarize the latest insights on programmed cell death from mechanisms to diseases and provides a more reliable approach for clinical transformation.

Autophagy captures damaged or dysfunctional proteins and organelles through the lysosomal pathway to achieve proper cellular homeostasis. Autophagy possesses distinct characteristics and is given recognized functions in numerous physiological and pathological conditions, such as cancer. Early stage cancer development can be stopped by autophagy. After tumor cells have successfully undergone transformation and progressed to a late stage, the autophagy-mediated system of dynamic degradation and recycling will support cancer cell growth and adaptation to various cellular stress responses while preserving energy homeostasis. In the present study, the dual function that autophagy plays in various oral cancer development contexts and stages, the existing arguments for and against autophagy, and the ways in which autophagy contributes to oral cancer modifications, such as carcinogenesis, drug resistance, invasion, metastasis and self-proliferation, are reviewed. Special attention is paid to the mechanisms and functions of autophagy in oral cancer processes, and the most recent findings on the application of certain conventional drugs or natural compounds as novel agents that modulate autophagy in oral cancer are discussed. Overall, further research is needed to determine the validity and reliability of autophagy promotion and inhibition while maximizing the difficult challenge of increasing cancer suppression to improve clinical outcomes.

Autophagy is frequently observed in tissues during the aging process, yet the tissues most strongly correlated with autophagy during aging and the underlying regulatory mechanisms remain inadequately understood. The purpose of this study is to identify the tissues with the highest correlation between autophagy and aging, and to explore the functions and mechanisms of autophagy in the aging tissue microenvironment.

Integrated bulk RNA-seq from over 7000 normal tissue samples, single-cell sequencing data from blood samples of different ages, more than 2000 acute myeloid leukemia (AML) bulk RNA-seq, and multiple sets of AML single-cell data. The datasets were analysed using various bioinformatic approaches.

Blood tissue exhibited the highest positive correlation between autophagy and aging among healthy tissues. Single-cell resolution analysis revealed that in aged blood, classical monocytes (C. monocytes) are most closely associated with elevated autophagy levels. Increased autophagy in these monocytes correlated with a higher proportion of C. monocytes, with hypoxia identified as a crucial contributing factor. In AML, a representative myeloid blood disease, enhanced autophagy was accompanied by an increased proportionof C. monocytes. High autophagy levels in monocytes are associated with pro-inflammatory gene upregulation and Reactive Oxygen Species (ROS) accumulation, contributing to tissue aging.

This study revealed that autophagy is most strongly correlated with aging in blood tissue. Enhanced autophagy levels in C. monocytes demonstrate a positive correlation with increased secretion of pro-inflammatory factors and elevated production of ROS, which may contribute to a more rapid aging process. This discovery underscores the critical role of autophagy in blood aging and suggests potential therapeutic targets to mitigate aging-related health issues.

Autophagy is a conserved cellular process crucial for recycling cytoplasmic components and maintaining cellular homeostasis in eukaryotes. During autophagy, the formation of a protein complex involving AUTOPHAGY-RELATED PROTEIN 6 (ATG6) and phosphatidylinositol 3-kinase is pivotal for recruiting proteins involved in phagophore expansion. However, the intricate molecular mechanism regulating this protein complex in plants remains elusive.

Here, we aimed to unravel the molecular regulation of autophagy dynamics in Arabidopsis thaliana by investigating the involvement of the scaffold proteins 14-3-3λ and 14-3-3κ in regulating the proteolysis of ATG6. Phenotypic analyses revealed that 14-3-3λ and 14-3-3κ overexpression lines exhibited increased sensitivity to nutrient starvation, premature leaf senescence, and a decrease in starvation-induced autophagic vesicles, resembling the phenotypes of autophagy-defective mutants, suggesting the potential roles of 14-3-3 proteins in regulating autophagy in plants. Furthermore, our investigation unveiled the involvement of 14-3-3λ and 14-3-3κ in the RING finger E3 ligase SINAT1-mediated ubiquitination and destabilization of ATG6 in vivo. We also observed repressed turnover of ATG6 and translocation of GFP-ATG6 to mCherry-ATG8a-labelled punctate structures in the autophagy-defective mutant, which suggesting that ATG6 is probably a target of autophagy. Additionally, 14-3-3λ and 14-3-3κ interacted with Tumor necrosis factor Receptor Associated Factor 1a (TRAF1a) to promote the stability of TRAF1a in vivo under nutrient-rich conditions, suggesting a feedback regulation of autophagy. These findings demonstrate that 14-3-3λ and 14-3-3κ serve as scaffold proteins to regulate autophagy by facilitating the SINAT1-mediated proteolysis of ATG6, involving both direct and indirect mechanisms, in plants.

14-3-3 proteins regulate autophagy by directly or indirectly binding to ATG6 and SINAT1 to promote ubiquitination and degradation of ATG6. 14-3-3 proteins are involved in modulating autophagy dynamics by facilitating SINAT1-mediated ubiquitination and degradation of ATG6.

Autophagy is an important catabolic process to maintain cellular homeostasis and antagonize cellular stresses. The initiation and activation are two of the most important aspects of the autophagic process. This review focuses on mechanisms underlying autophagy initiation and activation and signaling pathways regulating the activation of autophagy found in recent years. These findings include autophagy initiation by liquid-liquid phase separation (LLPS), autophagy initiation in the endoplasmic reticulum (ER) and Golgi apparatus, and the signaling pathways mediated by the ULK1 complex, the mTOR complex, the AMPK complex, and the PI3KC3 complex. Through the review, we attempt to present current research progress in autophagy regulation and forward our understanding of the regulatory mechanisms and signaling pathways of autophagy initiation and activation.

Ischemia-reperfusion is a complex brain disease involving multiple biological processes, including autophagy, oxidative stress, and mitochondria-associated apoptosis. Chaperone-mediated autophagy (CMA), a selective autophagy, is involved in the development of various neurodegenerative diseases and acute nerve injury, but its role in ischemia-reperfusion is unclear. Here, we used middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models to simulate cerebral ischemic stroke in vivo and in vitro, respectively. LAMP2A (lysosome-associated membrane protein 2A), a key molecule of CMA, was dramatically downregulated in ischemia-reperfusion. Enhancement of CMA activity by LAMP2A overexpression reduced the neurological deficit, brain infarct volume, pathological features, and neuronal apoptosis of the cortex in vivo. Concomitantly, enhanced CMA activity alleviated OGD/R-induced apoptosis and mitochondrial membrane potential decline in vitro. In addition, we found that CMA inhibited the P53(Tumor protein p53) signaling pathway and reduced P53 translocation to mitochondria. The P53 activator, Nutlin-3, not only reversed the inhibitory effect of CMA on apoptosis, but also significantly weakened the protective effect of CMA on OGD/R and MCAO/R. Taken together, these results indicate that inhibition of P53-mediated mitochondria-associated apoptosis is essential for the neuroprotective effect of CMA against ischemia-reperfusion.