Multiple endocrine neoplasia type 1 (MEN1) is caused by germline mutations in the MEN1 gene, including nonsense mutations and missense variants, which result in the formation of truncated inactive menin protein and some of which cause degradation of mutant menin proteins. Here, we describe a c.1462 A > T (p.K488X) mutation in exon 10 of MEN1 as a potential pathogenic mutation in an extended Chinese family with MEN1. We observed that K488X-menin was degraded by ubiquitination modification resulting from the combined actions of carboxy-terminus of Hsc70-interacting protein (CHIP) and Heat Shock Protein Family 70 (Hsp70) in vitro. K488X-menin is a misfolded truncated protein that results in amyloid aggregation in live cells and affected tissues, which is promoted by Hsp70 and/or CHIP. Although Hsp70 can inhibit the aggregation of K488X-menin in vitro, it is not upregulated in the affected tissues in patients with MEN1, and thus cannot completely disaggregate the aggregated K488X-menin. Further, we found that K488X-menin triggers early tumourigenesis in a MEN1 mutant zebrafish model. Moreover, K488X-menin disaggregation was induced by Hsp70 activator and Hsp70 was upregulated in homozygous mutant zebrafish. Our findings provide a novel biophysical mechanism involving Hsp70 underlying MEN1 tumourigenesis in a Chinese family with MEN1.

The role of autophagy in cholangiocarcinogenesis and its development is intricate. Autophagy has a dual role in cholangiocarcinoma, and understanding the function and mechanism of autophagy in cholangiocarcinoma is pivotal in guiding therapeutic approaches to its treatment in clinical settings. Recent studies have revealed that autophagy is involved in the complex biological behavior of cholangiocarcinoma. In this review, we have summarized the genes and drugs that would promote or inhibit autophagy, leading to change in cellular behaviors of cholangiocarcinoma, including apoptosis, proliferation, invasion and migration, and influence its cellular drug resistance. In addition, we concluded the signaling pathways modulating autophagy in cholangiocarcinoma cells, including PI3K/AKT/mTOR,p38MAPK,AMPK/mTOR,LKB1-AMPK, and AKT/WNK1, and ERK signaling pathways, which subsequently impacting apoptosis, death, migration, invasion, and proliferation. In conclusion, we would like that we can provide ideas for future cholangiocarcinoma treatment by comprehensively summarizing the latest studies on the relationship between autophagy and cholangiocarcinoma, including the factors affecting autophagy and related signaling pathways.

Acute myeloid leukemia (AML) is a common hematopoietic disease that results from diverse genetic abnormalities. Dysregulation of important signaling pathways, including the PI3K/AKT/mTOR, Wnt and Hedgehog pathways, plays crucial roles in the development of AML. Hedgehog pathway (Hh) is a conserved signaling pathway that is crucial throughout embryogenesis. Hh plays an important role in the regulation of autophagy, known as the cellular recycling process of organelles and unwanted proteins. Many studies have noted that the modulation of autophagy could act as a survival mechanism in AML. Considering the pivotal role of autophagy and Hh signaling in AML, understanding the relationship between these pathways is important for overcoming leukemia. Therefore, we examined the efficacy of Hh inhibition by GLI-ANTagonist 61 (GANT61) in MOLM-13 and CMK cells via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenil-2H-tetrazolium bromide (MTT) cell viability assays. GANT61 resulted in decreased cell viability in both cell lines. Therefore, we focused on the outcome of autophagy modulation in AML cells. We observed that the autophagy inhibitors ammonium chloride (NH4CI), chloroquine (CQ), and nocodazole led to a significant reduction in the proliferation of both cell lines. Cotreatment with autophagy pathway inhibitors and GANT61 synergistically affected both AML cell lines. Moreover, dual targeting of these pathways resulted in arrest at the G0/G1 phase in MOLM-13 cells but not in CMK cells. Furthermore, the combination of nocodazole and GANT61 increased the expression level of LC3B-II in both cell lines. Compared with that in the untreated control cells, the GLI1 gene expression level in both cell lines was significantly lower after GANT61 and autophagy cotreatment. In conclusion, targeting Hh and autophagy could be a favorable option to combat AML.

Inflammatory bowel disease (IBD) is a serious chronic condition marked by persistent and recurrent intestinal ulcers. Although the exact cause of IBD remains unclear, it is generally accepted that a complex interaction among dietary factors, gut microbiota, and immune responses in genetically predisposed individuals contributes to its development. Pyroptosis, an inflammatory form of programmed cell death activated by inflammasomes, is marked by the rupture of cell membranes and the subsequent release of inflammatory mediators. Emerging evidence indicates that pyroptosis plays a crucial role in the pathogenesis of IBD. Moderate pyroptosis activation can enhance intestinal immune defenses, while excessive inflammasome activation can trigger an inflammatory cascade, resulting in increased damage to intestinal tissues. This article reviews the molecular mechanisms underlying pyroptosis and highlights its role in the onset and progression of IBD. Furthermore, We explore recent advancements in IBD treatment, focusing on small molecule compounds that specifically target and inhibit pyroptosis.

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

To identify key mitochondrial autophagy-related genes (MARGs) in fetal growth restriction (FGR)and evaluate their diagnostic potential through bioinformatics and machine learning approaches.

The GSE24192 dataset were obtained from Gene Expression Omnibus data base (GEO). Differentially expressed genes (DEGs) were identified using differentially expressed analysis. Mitochondrial autophagy-related genes (MARGs) were identified using GeneCards. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed with the clusterProfiler package. Protein-protein interaction (PPI) network was constructed using STRING, and key genes were selected using machine learning. Receiver operating characteristic (ROC) curves assessed diagnostic performance of key genes. Immune infiltration analysis was used to evaluated immune microenvironment. The miRNAs were predicted in TargetScan website.

A total of 42 MARGs were identified in FGR samples, and three key genes (THBS1, RAB15, LMO7) were selected through machine learning methods. These genes showed high diagnostic potential with area under the curve (AUC) values of 0.97, 0.95, and 0.92, respectively. Immune infiltration analysis revealed significant increase of CD8+ T cells, endothelial cells, and macrophages in FGR samples. Correlation analysis indicated THBS1 was positively related to several immune cells, while RAB15 and LMO7 were negatively related to several immune cells. The miRNA-mRNA regulatory network revealed four miRNAs potentially regulating these key genes.

In conclusion, our study identified THBS1, RAB15, and LMO7 as key mitochondrial autophagy-related genes in FGR, with potential as diagnostic biomarkers.

5-Methylcytosine (m5C) modification is an important type of RNA methylation. Diverse noncoding RNAs can undergo m5C modification and play important roles in tumour development, but circRNA m5C modifications have not been fully revealed in tumours. Here, circFAM190B, which was significantly overexpressed in lung cancer cells and tissues, was identified by constructing a differential expression profile of m5C-modified circRNAs. circFAM190B was found to be associated with lung cancer stage and prognosis. Moreover, we proposed the novel hypothesis that NSUN2 can mediate circFAM190B m5C modification and enhance circFAM190B stability in an m5C-dependent manner. We also clarified the biological function of circFAM190B in significantly promoting the development of lung cancer. Mechanistically, circFAM190B targets SFN and regulates its ubiquitination, thereby inhibiting cellular autophagy through the SFN/mTOR/ULK1 pathway and ultimately promoting lung cancer development. This study reveals the existence of m5C modification of circRNAs, and circRNAs modified by m5C can play important roles in the development of lung cancer, which provides a new theoretical basis for elucidating the molecular mechanism of lung cancer development.

This study clarifies the interaction between autophagy and inflammasome within the cancer framework. The inflammasome generates pro-inflammatory cytokines to direct the immune response to pathogens and cellular stressors. Autophagy maintains cellular homeostasis and can either promote or inhibit cancer. These pathways interact to affect tumorigenesis, immune responses, and therapy. Autophagy controls inflammasome activity by affecting cancer pathogenesis and tumor microenvironment inflammation, highlighting novel cancer therapeutic approaches. Recent studies indicate that modulating autophagy and inflammasome pathways can boost anti-cancer immunity, reduce drug-resistance, and improve therapeutic efficacy. Recent studies indicate modulating inflammasome and autophagy pathways can augment anti-cancer immunity, mitigate therapy resistance, and improve treatment efficacy. Cancer research relies on understanding the inflammasome-autophagy relationship to develop targeted therapies that enhance anti-tumor efficacy and reduce inflammatory symptoms. Customized therapies may improve outcomes based on autophagy gene variations and inflammasome polymorphisms. This study investigates autophagy pathways and the inflammasome in tumor immunopathogenesis, cytokine function, and cancer therapeutic strategies, highlighting their significance in cancer biology and treatment.

Obstructive sleep apnea syndrome is closely associated with tumor growth. Chronic intermittent hypoxia promotes autophagy and is related to malignant tumor development. However, the role of autophagy in obstructive sleep apnea syndrome progression remains unclear.

obstructive sleep apnea syndrome datasets (GSE135917 and GSE38792) from Gene Expression Omnibus were analyzed to identify differentially expressed genes and autophagy-related differentially expressed genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis were conducted, and a protein-protein interaction network identified hub genes. Colorectal cancer datasets from The Cancer Genome Atlas were used for differential expression and survival analyses, along with gene set enrichment analysis and immune infiltration analysis. Chronic intermittent hypoxia-induced autophagy and oxidative stress were investigated in Sprague-Dawley rats using reactive oxygen species assays. Hub genes were validated in rats and obstructive sleep apnea syndrome patient samples.

Gene set enrichment analysis revealed significant differences in autophagy-related gene expression among obstructive sleep apnea syndrome patients. Hub genes ATG5, CASP1, MAPK8, EIF4G1, and TANK-binding kinase 1 were identified, with ATG5 and TANK-binding kinase 1 validated. Autophagy-related differentially expressed genes were predominantly upregulated in colorectal cancer tissues. TANK-binding kinase 1 expression in colorectal cancer patients was associated with enhanced sensitivity to immunotherapy and CD8 + T cell, macrophage, and regulatory T cell infiltration, potentially influencing the immune microenvironment. The animal experiments showed that chronic intermittent hypoxia increased reactive oxygen species levels, suggesting that chronic intermittent hypoxia plays a role in autophagy. TANK-binding kinase 1 expression was significantly higher in obstructive sleep apnea syndrome patients than in controls, and continuous positive airway pressure did not alter TANK-binding kinase 1 levels.

This study is the first to describe the potential contribution of TANK-binding kinase 1 to the development of obstructive sleep apnea syndrome and its potential as a novel biomarker and potential therapeutic target for obstructive sleep apnea syndrome.

Malignant gliomas are the most common primary brain tumors in adults. These tumors have a diverse molecular origin and a very poor prognosis. There is a lack of effective treatment at WHO grade IV glioma, and all glioblastomas progress or recur. Current treatments including surgical intervention, radiation therapy, and chemotherapy are insufficient and can cause damage to healthy brain tissue and neurological deficits. The preservation of healthy brain tissue during therapeutic intervention is made extremely difficult by the ability of malignant gliomas to diffusely infiltrate the surrounding brain parenchyma. Photodynamic therapy (PDT) is a treatment modality for glioma that can possibly overcome the inherent shortcommings of traditional therapies. Photodynamic therapy involves the use of a photosensitizer (PS) which, upon absorption of light by photosensitized tissue, triggers photochemical reactions generating reactive oxygen species (ROS) leading to the killing of tumor cells. Research focusing on the effective use of PDT in the treatment of glioma is already underway with promising results. Clinical studies on PDT for the treatment of gliomas have shown it to be a safe therapeutic modality with acceptable levels of side effects. However, some adverse sequelae have been observed during PDT of these tumours, such as increased photosensitivity, increased intracranial pressure or transient aphasia and worsening of pre-existing neurological deficits. Although the clinical sequelae of PDT are well described, the molecular mechanisms of PDT's effects on the healthy brain have not yet been thoroughly characterized. In our work, we attempt to summarize the molecular mechanisms of the effects of photosensitization on neural tissue, brain vasculature and the blood-brain barrier (BBB). We also point to findings presenting molecular approaches to protect the healthy brain from the adverse effects of photodynamic damage.

Lactobacillus reuteri (L. reuteri) therapies represent a potentially effective approach to eradicating Helicobacter pylori (H. pylori). However, the difficulty in bacterial viability preservation and harsh gastric environment compromises the survival and on-target delivery of L. reuteri. This study presents a novel bacterium-mediated bacterial elimination strategy using an edible L. reuteri@HTP probiotic powder for targeted bacterial elimination. The probiotic powder is obtained by grinding a lyophilized hydrogel composed of L. reuteri, hyaluronic acid (HA), tannic acid (TA), and polyvinyl alcohol (PVA). Upon contact with water, the powder quickly transforms into a hydrogel, enhancing L. reuteri's survival in the harsh gastric environment and ensuring selective release at H. pylori-infected inflammatory sites. L. reuteri targets and reduces H. pylori colonization while secreting reuterin to eliminate the bacteria. Additionally, TA's antioxidant properties help alleviate inflammation, and HA supports gastric mucosal repair. L. reuteri@HTP powder preserves the integrity of the gut microbiota, facilitating the restoration of a healthy microbiome. In particular, the probiotic powder remains stable at room temperature for at least six months, providing a promising alternative to traditional antibiotics for H. pylori treatment. This strategy combines targeted eradication, mucosal healing, and microbiome restoration, offering a new approach to treating gastric infections.

Autophagy plays a crucial role in maintaining neuronal homeostasis and function, and its disruption is linked to various brain diseases. Melatonin, an endogenous hormone that primarily acts through MT1 and MT2 receptors, regulates autophagy via multiple pathways. Growing evidence indicates that melatonin's ability to modulate autophagy provides therapeutic and preventive benefits in brain disorders, including neurodegenerative and affective diseases. In this review, we summarize the key mechanisms by which melatonin affects autophagy and explore its therapeutic potential in the treatment of brain disorders.

Mitophagy is an essential cellular process that is conserved and crucial for maintaining cellular balance by selectively eliminating malfunctioning mitochondria. However, there is still limited knowledge regarding the influence of mitophagy-related genes (MRGs) on the prognosis and response to treatment of triple-negative breast cancer (TNBC). In here, the TCGA and GEO databases were used to acquire the transcriptomic and clinical information of patients with TNBC, correspondingly. Using LASSO and multivariable Cox regression analyses, a risk signature related to mitophagy was established based on the prognostic MRGs. The prognostic signature associated with mitophagy consisted of five genes (BSG, JMJD6, DNAJA3, DISC1, and SQSTM1) and independently predicted the prognosis of patients with TNBC, regardless of clinical factors (p < 0.05). Patients classified within the high-risk group demonstrated significantly lower overall survival rates when contrasted with those in the low-risk group. The model exhibited excellent performance in predicting survival and risk stratification, as evidenced by the receiver operating characteristic and C-index. The findings stayed unchanged following external validation. Moreover, we observed a notable variation in the tumor immune microenvironment among the different risk categories. Patients with a low risk of TNBC demonstrated a more favorable response to immunotherapy compared to patients with a high risk. In conclusion, our study uncovered the possible impacts of MRGs on the tumor microenvironment, clinical and pathological characteristics, and outlook of TNBC. The CRG-related signature was strongly linked to the immune response against TNBC and has the potential to serve as a valuable tool in predicting the prognosis and immunotherapy response of patients.

Nod-like receptor protein 3 (NLRP3) is a member of the leucine-rich repeat-containing protein (NLR) canonical inflammasome family. It regulates the pathophysiology of cancer by facilitating immune responses and apoptotic proteins. Furthermore, it has been observed that chemotherapy activates NLRP3 in human malignancies. The secretion of IL-1β and IL-22 to promote cancer spread may be triggered by NLRP3 activation. Furthermore, earlier studies have exhibited that NLRP3 may cause medication resistance when used in cancer treatments given that cell viability may be regulated by NLRP3 depletion. Additionally, clinical studies have demonstrated correlation between NLRP3 expression, lymphogenesis, and cancer metastasis. Various NLRP3 agonists may cause the EMT process, stimulate IL-1β and Wnt/β-catenin signaling, and alter miRNA function in drug-resistant cells. This review seeks to clarify the possibility involvement of NLRP3-related pathways in the control of cancer cells' resistance to widely used treatment approaches, such as chemotherapy. In the end, an improved perception of the corresponding mechanisms behind NLRP3's tumor-supporting activities will help NLRP3-based treatments advance in the future.

Intervertebral disc degeneration disease (IVDD) is a major cause of disability and reduced work productivity worldwide. Annulus fibrosus degeneration is a key contributor to IVDD, yet its mechanisms remain poorly understood. Autophagy, a vital process for cellular homeostasis, involves the lysosomal degradation of cytoplasmic proteins and organelles. This study aimed to investigate the role of autophagy in IVDD using a hydrogen peroxide (H2O2)-induced model of rat annulus fibrosus cells (AFCs).

AFCs were exposed to H2O2 to model oxidative stress-induced degeneration. Protein expression levels of collagen I, collagen II, MMP3, and MMP13 were quantified. GEO database analysis identified alterations in miR-2355-5p expression, and its regulatory role on the mTOR pathway and autophagy was assessed. Statistical tests were used to evaluate changes in protein expression and pathway activation.

H2O2 exposure reduced collagen I and collagen II expression to approximately 50% of baseline levels, while MMP3 and MMP13 expression increased twofold. Activation of autophagy restored collagen I and II expression and decreased MMP3 and MMP13 levels. GEO analysis revealed significant alterations in miR-2355-5p expression, confirming its role in regulating the mTOR pathway and autophagy.

Autophagy, mediated by the miR-2355-5p/mTOR pathway, plays a protective role in AFCs degeneration. These findings suggest a potential therapeutic target for mitigating IVDD progression.

Itraconazole, a widely used antifungal medication, has shown potential in inhibiting tumor growth and reducing angiogenesis. However, its role in melanoma tumor growth remains insufficiently explored. This study investigates the inductive effect of itraconazole on autophagy-mediated apoptosis in melanoma cells.

Potential drug targets were identified using the PMF machine learning algorithm. Apoptosis and cell cycle in melanoma cell lines A375 and A2058 were assessed via flow cytometry. Western blot analysis was performed to examine autophagy and associated signaling proteins, while autophagy flux and autophagosome formation were visualized using fluorescence microscopy. A melanoma cell xenograft mouse model was established to evaluate the inhibitory mechanisms of itraconazole on tumor cell proliferation.

Using the PMF machine learning algorithm, SQSTM1 was identified as the primary target of itraconazole. Itraconazole inhibited melanoma cell proliferation by inducing G1 phase arrest and autophagy-mediated apoptosis in A375 and A2058 cells. Furthermore, itraconazole suppressed Hedgehog signaling and counteracted the activation of the Hedgehog agonist recombinant human Sonic Hedgehog (rhShh). In vivo, itraconazole significantly reduced tumor growth in A375 and A2058 xenograft models.

Itraconazole induces autophagy-mediated apoptosis in melanoma cells by inhibiting Hedgehog signaling, underscoring its potential as a therapeutic option for melanoma treatment.

Current knowledge about Alzheimer's disease highlights the accumulation of β-amyloid plaques (Aβ1-42) and neurofibrillary tangles composed of hyperphosphorylated Tau, which lead to the loss of neuronal connections. Microglial activation and the release of inflammatory mediators play a significant role in the progression of Alzheimer's pathology. Recent advances have identified the involvement of inflammasomes, particularly NOD-like receptor NLR family pyrin domain containing 3 (NLRP3), whose activation promotes the release of proinflammatory cytokines and triggers pyroptosis, exacerbating neuroinflammation. Aggregates of Aβ1-42 and hyperphosphorylated Tau have been shown to activate these inflammasomes, while the apoptosis-associated speck-like protein (ASC) components form aggregates that further accelerate Aβ aggregation. Defects in the autophagic clearance of inflammasomes have also been implicated in Alzheimer's disease, contributing to sustained inflammation. This review explores strategies to counteract inflammation in Alzheimer's, emphasizing the degradation of ASC specks and the inhibition of NLRP3 inflammasome activation. Notably, the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor emerges as a promising therapeutic target due to its dual role in mitigating oxidative stress and directly inhibiting NLRP3 inflammasome formation. By reducing inflammasome-driven inflammation, Nrf2 offers significant potential for addressing the neuroinflammatory aspects of Alzheimer's disease.

Autophagy dysfunction is associated with changes in autophagy-related genes. Various factors are connected to autophagy, and the mechanism regulating autophagy is highly complicated. Epigenetic changes, such as aberrant expression of histone demethylase, are actively associated not only with oncogenesis but also with inflammatory responses. Among post-translational modifications, histone lysine methylation holds significant importance. There are over 30 members of histone lysine demethylases (KDMs), which act as epigenetic regulators in physiological processes and diseases. Importantly, KDMs are abnormally expressed in the regulation of cellular autophagy and inflammation, representing a crucial mechanism affecting inflammation-related diseases. This article reviewed the function of KDMs proteins in autophagy and inflammation. Specifically, It focused on the specific regulatory mechanisms underlying the activation or inhibition of autophagy, as well as their abnormal expression in inflammatory responses. By analyzing each KDM in epigenetic modification, this review provides a reliable theoretical basis for clinical decision marking regarding autophagy abnormalities and inflammatory diseases.

Inflammation has a pivotal role in the initiation and progression of various cancers, contributing to crucial processes such as metastasis, angiogenesis, cell proliferation and invasion. Moreover, the release of cytokines mediated by inflammation within the tumour microenvironment (TME) has a crucial role in orchestrating these events. The activation of inflammatory caspases, facilitated by the recruitment of caspase-1, is initiated by the activation of pattern recognition receptors on the immune cell membrane. This activation results in the production of proinflammatory cytokines, including IL-1β and IL-18, and participates in diverse biological processes with significant implications. The NOD-Like Receptor Protein 3 (NLRP3) inflammasome holds a central role in innate immunity and regulates inflammation through releasing IL-1β and IL-18. Moreover, it interacts with various cellular compartments. Recently, the mechanisms underlying NLRP3 inflammasome activation have garnered considerable attention. Disruption in NLRP3 inflammasome activation has been associated with a spectrum of inflammatory diseases, encompassing diabetes, enteritis, neurodegenerative diseases, obesity and tumours. The NLRP3 impact on tumorigenesis varies across different cancer types, with contrasting roles observed. For example, colorectal cancer associated with colitis can be suppressed by NLRP3, whereas gastric and skin cancers may be promoted by its activity. This review provides comprehensive insights into the structure, biological characteristics and mechanisms of the NLRP3 inflammasome, with a specific focus on the relationship between NLRP3 and tumour-related immune responses, and TME. Furthermore, the review explores potential strategies for targeting cancers via NLRP3 inflammasome modulation. This encompasses innovative approaches, including NLRP3-based nanoparticles, gene-targeted therapy and immune checkpoint inhibitors.

Calreticulin (CALR) is a multifunctional calcium-binding protein. Recent studies have revealed that CALR contributes to tumor development and promotes cancer cell proliferation. However, how CALR affects the development of laryngeal squamous cell carcinoma (LSCC) remains mysterious. Thus, this study aimed to explore the effect of CALR on LSCC development and uncover its underlying mechanisms.

CALR expression in LSCC cell lines and tissues was examined by qRT-PCR and western blot analysis and its functional role was detected via in vivo and in vitro assays. Cell proliferation was discriminated with CCK-8 and colony formation assays, while apoptosis was analyzed using flow cytometry. Autophagy levels were measured via LC3 immunofluorescence, and western blot assay was conducted to assess apoptosis- and autophagy-related proteins. Additionally, a mouse xenograft model was employed to determine the impact of CALR knockdown on tumor growth.

We found that CALR knockdown reduced LSCC cell viability and proliferation while enhancing apoptosis, whereas CALR overexpression showed opposite effects. In vivo experiments verified that CALR knockdown suppressed tumor growth. In addition, elevated CALR expression induced autophagy in LSCC cells, while autophagy inhibitor 3-MA (2.5 mM) reversed the anti-apoptosis effects of CALR overexpression.

Our study identifies CALR as an oncogene in LSCC, where it promotes tumor progression by inducing autophagy and inhibiting apoptosis. Targeting CALR or modulating autophagy may represent novel therapeutic strategies for LSCC.

The N6-methyladenine (m6A) modification is the most common modification of messenger RNAs in eukaryotes and has crucial roles in multiple cancers, including bladder cancer (BLCA). This paper aimed to probe the molecular mechanism of zinc-finger CCCH-type containing 13 (ZC3H13)-mediated N6-methyladenine (m6A) modification in BLCA progression via autophagy. Differential expression of ZC3H13 in BLCA was analyzed by the bioinformatics database. ZC3H13 expression in BLCA tissues and cell lines was determined, and malignant behaviors of BLCA cells were examined in vitro and in vivo. ZC3H13 was decreased in BLCA tissues and cell lines relative to adjacent tissues and normal uroepithelial cells. ZC3H13 overexpression restricted BLCA cell growth in vitro and curbed BLCA development in vivo. ZC3H13 promoted the mRNA stability of paraja ring finger 2 (PJA2) through m6A modification, leading to the ubiquitination degradation of the kinase suppressor of Ras 1 (KSR1). Knockdown of PJA2 and overexpression of KSR1 reversed the inhibitory effect of ZC3H13 on BLCA progression. ZC3H13 degraded KSR1 through m6A modification of PJA2, promoted cell autophagy, and repressed BLCA progression. Overall, ZC3H13 promotes the mRNA stability of PJA2 through m6A modification to degrade KSR1, thereby promoting autophagy in BLCA.

Fluoride (F) and cadmium (Cd) as well known environmental pollutants can cause nephrotoxicity to damage human health, while the joint toxicity of F and Cd to the renal tubular epithelial cells remains still elusive. The interactive influence between F and Cd in oxidative stress, apoptosis, and mitochondrial autophagy of renal tubular epithelial cells was explored. Cells were submitted to varying concentrations with of NaF (1, 5, 10, and 15 μg/mL) combined with CdCl2·2.5H2O (1 μg/mL) for 12 h. Following this, the combined cytotoxicity was assessed. Our results show that different doses of F had varying effects on Cd-mediated nephrotoxicity, with a synergistic effect observed in the high F (15 μg/mL) co-treated with Cd. In response to the Cd induction, the high F treatment resulted in the formation of multiple autophagosomes and notably increased the levels of LDH, ROS, and MMP. It also elevated the MDA contents while decreasing the activities of SOD, GSH-Px, and CAT. Additionally, it yielded a higher Bax/Bcl-2 ratio, which further promotes the apoptotic process. The treatment also disturbed energy metabolism, resulting in a reduction of both ATP and ADP. Furthermore, autophagy-related genes and proteins, including PINK1, Parkin, LC3A, LC3B, and SQSTM1, were significantly improved. In brief, high F of 15 μg/mL aggravated Cd-mediated nephrotoxicity of renal tubular epithelial cells via the ROS-PINK1/Parkin pathway.

Hepatitis B virus (HBV) is an enveloped DNA virus that causes chronic hepatitis B (CHB) infection. Annexin, a Ca2+-activated protein, is widely expressed in various organs and tissues and has potential utility in disease diagnosis and treatment. However, the relationship between the annexin family and CHB remains unclear.

Clinical samples from hepatitis patients and donors or healthy individuals were collected. Transcriptome sequencing in CHB liver tissues and HBV-infected cells were performed. HepG2.2.15 cells with the full-length HBV genome and HBV-infected HepG2-NTCP cell models were established. HBV-infected mouse model was constructed and adeno-associated virus was utilized.

ANXA4 expression was elevated during CHB infection. ANXA4 knockdown promoted HBV replication and aggravated liver injury, while ANXA4 overexpression alleviated that. Mechanistically, autophagy pathway was activated by ANXA4 deficiency, promoting autophagic degradation of minichromosome maintenance complex component 2 (MCM2). MCM2 inhibition activated HBV replication, while MCM2 overexpression attenuated ANXA4 deficiency-induced HBV replication and liver injury. Clinically, the expression of hepatitis B viral protein was negatively correlated with the ANXA4 levels, and CHB patients with high ANXA4 levels (> 8 ng/ml) showed higher sensitivity to interferon therapy.

ANXA4 functions as a protective factor during HBV infection. ANXA4 expression is elevated under HBV attack to restrict HBV replication by inhibiting autophagic degradation of MCM2, thereby alleviating liver injury and suppressing the CHB infection process. ANXA4 also enhances the sensitivity of CHB patients to interferon therapy. Therefore, ANXA4 is expected to be a new target for CHB treatment and prognostic evaluation.

Osteolysis resulting from wear particles and subsequent aseptic loosening is a leading cause of revision surgery of artificial joints. The underlying pathogenesis of particle-induced osteolysis (PPO) has remained largely uncertain. Addressing how to mitigate osteolysis caused by wear particles presents a significant challenge for orthopedic surgeons. This study aimed to explore the molecular mechanism by which Angiopoietin (Ang-1) inhibits osteoclast activation to alleviate osteolysis. RAW264.7 mouse macrophages were stimulated with LPS or RANKL to induce osteoclast formation. Additionally, titanium (Ti) particles (50 mg) were subperiosteally implanted around the cranial suture of mice to establish a calvarial osteolysis model. Ang-1, a member of the pro-angiogenic factor protein family and an important inflammatory regulator molecule, was utilized in this model. TRAP staining was utilized to detect osteoclast activation, while a western blot was conducted to identify key proteins associated with mitophagy and pyroptosis. Scanning electron microscopy was employed to observe the morphology and dimensions of Ti particles. Additionally, a combination of micro-CT, H&E, Masson's trichrome, and immunohistochemical staining techniques were applied to analyze the calvarial samples. Results indicated that Ang-1 could inhibit LPS- or RANKL-induced osteoclastogenesis and alleviate Ti particle-induced calvarial osteolysis in mice. TBK-1, a key signaling molecule involved in initiating mitophagy, was found to be mechanistically enhanced by Ang-1 through promoting TBK-1 phosphorylation in macrophages. This process inhibited AIM2 inflammasome-mediated pyroptosis and impeded osteoclastogenesis. Overall, this research uncovers a novel mechanism by which Ang-1 can attenuate inflammatory osteolysis, potentially offering a new therapeutic approach for PPO.

The NLRP1 inflammasome is a crucial muti-protein complex in the host anti-pathogen immune response. The previous studies have revealed that the anti-apoptotic protein BCL-xL played a non-apoptotic role by impeding the activation of NLRP1 inflammasome in mammals. However, the potential role of BCL-xL in regulating the inflammasome in fish remains unclear. In the present study, the BCL-xL (CcBCL-xL) was cloned from the head kidney of common carp (Cyprinus carpio L.), and its regulatory effect on the NLRP1 inflammasome was explored. It was found that CcBCL-xL predominantly localized in the brain, spleen and head kidney of common carp, and upon stimulation with Aeromonas hydrophila (A. hydrophila), Edwardsiella tarda (E. tarda), or spring viremia of carp virus (SVCV), the expression of CcBCL-xL significantly increased in multiple immune organs. The interaction between CcBCL-xL and CcNLRP1 was confirmed by co-immunoprecipitation and immunofluorescence. Meanwhile, we also found that CcBCL-xL significantly inhibited the assembly of the CcNLRP1 inflammasome, through ASC oligomerization, ASC specks formation and cytotoxicity experiments. Furthermore, our results revealed that CcBCL-xL interacted with the NACHT, LRR, FIIND, and CARD domains of CcNLRP1. Taken together, the results provide a theoretical foundation for further exploring the regulatory mechanism of NLRP1, and for the prevention and treatment of infectious diseases in fish.

Disulfidptosis is a novel form of cell death that is distinguishable from established programmed cell death pathways such as apoptosis, pyroptosis, autophagy, ferroptosis, and oxeiptosis. This process is characterized by the rapid depletion of nicotinamide adenine dinucleotide phosphate (NADPH) in cells and high expression of solute carrier family 7 member 11 (SLC7A11) during glucose starvation, resulting in abnormal cystine accumulation, which subsequently induces andabnormal disulfide bond formation in actin cytoskeleton proteins, culminating in actin network collapse and disulfidptosis. This review aimed to summarize the underlying mechanisms, influencing factors, comparisons with traditional cell death pathways, associations with related diseases, application prospects, and future research directions related to disulfidptosis.

BmNPV is a pathogen that infects silkworms exclusively. Although the interaction between BmNPV and the silkworm has been widely noticed and studied, its specific mechanism has still not been elucidated. In this study, we investigated whether BmNPV infection induces the onset of host cell autophagy to enhance viral replication. We observed a significant increase in double- or single-membrane vesicles and an accumulation of enhanced green fluorescent protein eGFP-ATG8 spots in virus-infected cells 72 h after BmNPV infection, accompanied by a conversion of ATG8 to ATG8-PE. In addition, we observed changes in the mitochondrial morphology of BmN cells after BmNPV infection by transmission electron microscopy. By detecting the mitochondrial membrane potential, we found that BmNPV infection resulted in the decrease of mitochondrial membrane potential, and that eGFP-ATG8 was able to co-localise with mitochondria after virus infection of the cells. Moreover, the use of drugs to regulate the occurrence of autophagy affects the replication of cellular BmNPV. Our data demonstrates that BmNPV infection induces host cell autophagy and leads to cellular mitochondrial damage, which in turn may lead to mitochondrial autophagy, and that BmNPV-induced host autophagy promotes its replication in cells. These findings will provide clues for further understanding of host-virus interactions.

Patients with colorectal cancer (CRC) frequently present with anemia and signs of infection. However, the relationships between these factors remain unclear. This study investigated the potential association between anemia, inflammatory indices, and CRC.

We analyzed data from the 2011-2018 National Health and Nutrition Examination Survey to investigate links between anemia, inflammation, and CRC. Inflammatory indices, including the neutrophil-percentage-to-albumin ratio, neutrophil-to-lymphocyte ratio, and eosinophil-to-lymphocyte ratio, were analyzed. Following rigorous inclusion criteria, 14,114 participants were included. Statistical methods such as logistic regression and subgroup analyses were employed. Moreover, survival analysis was performed.

Among the 14,114 participants, 0.6% had CRC and 11.0% were diagnosed with anemia. Anemia and inflammatory indices were associated with CRC, suggesting an increased risk (OR range: 2.03-2.50, P<0.05). Patients with CRC had lower red blood cell counts, reduced hemoglobin levels, and higher inflammatory indices. This is accompanied by an increase in the inflammatory indices, which is also a risk factor for CRC (OR range: 1.12-7.00, P<0.05). Survival analyses indicated that anemia was associated with lower survival rates, impacting all-cause, cancer, and CRC mortality.

Our results indicate that anemia and inflammatory indices are correlated with CRC. Patients with CRC tend to exhibit increased inflammatory indices and decreased red blood cell count and albumin levels, potentially impacting survival.

Breast cancer (BC) is a prevalent cancer of the female reproductive system and a major contributor to cancer-related mortality. The activation of NLRP3, a key inflammasome, has been extensively associated with tumor-related molecular and cellular processes; however, the regulatory mechanisms and specific role of NLRP3 in breast cancer remain incompletely elucidated. This study aimed to evaluate the molecular mechanisms of NLRP3-related genes in BC. Utilizing bioinformatics methods, the present research analyzed the TCGA-BRCA dataset, which included four groups of transcriptome sequencing data as follows, normal (WT), NLRP3 knockout (KO), non-knockout-BRCA (BC-WT), and NLRP3-knockout-BRCA (BC-KO). Results indicated that NLRP3 was significantly down-regulated in TCGA-BRCA. Key module genes were mainly enriched in leukocyte cell-cell adhesion and cytokine-cytokine receptor interaction. Moreover, correlation analysis showed that NLRP3 was positively associated with cancer-associated fibroblasts and negatively associated with CD4+ Th1 T-cells. In addition, the DEGs1 and DEGs2 overlapping indicated 505 feature genes, with Chac1 (negative) and Ugt8a (positive) had the strongest correlation with differential immune cells (class-switched memory B cells). Pathway intersection revealed 13 co-KEGG pathways. The BC-KO group indicated markedly reduced levels of four genes (Ccl19, Ccl20, Ccl21a, and H2-Oa) and increased levels of two genes (Il2ra and H2-Ob). This study delved into the role of NLRP3 in BC, exploring its regulatory mechanisms and the impact gene knockout. Bioinformatics approaches identified NLRP3-associated genes, their enriched pathways, and interactions within the tumor microenvironment (TME), providing novel insights into NLRP3 function, TME dynamics, and potential targets for BC prevention and treatment.

Breast cancer (BC) is a prevalent malignancy globally. Autophagy plays a pivotal role in all stages of this disease, including development, metastasis, and onset. Therefore, it is envisaged that targeting cell autophagy through appropriate tactics would evolve into a novel breast cancer prevention and therapy strategy. A multitude of chemotherapeutic medications can stimulate autophagy in tumor cells. It has led to divergent opinions on the function of autophagy in cancer treatment, as both stimulating and blocking autophagy can improve the effectiveness of anticancer medications. Consequently, the decision of whether to stimulate or inhibit autophagy during breast cancer treatment has become crucial. Understanding the distinctive mechanisms of autophagy in BC and its significance in medication therapy might facilitate the creation of targeted treatment plans based on the roles particular to autophagy. This review summarizes recent studies on the autophagy mechanism in breast cancer and provides insights into autophagy-based BC therapeutic techniques, giving fresh avenues for future BC treatment.

Carbon dioxide (CO2), traditionally viewed as a mere byproduct of cellular respiration, plays a multifaceted role in human physiology beyond simple elimination through respiration. CO2 may regulate the tumor microenvironment by significantly affecting the release of oxygen (O2) to tissues through the Bohr effect and by modulating blood pH and vasodilation. Previous studies suggest hypercapnia (elevated CO2 levels) might trigger optimized cellular mechanisms with potential therapeutic benefits. The role of CO2 in cellular stress conditions within tumor environments and its impact on O2 utilization offers a new investigative area in oncology.

This study aims to explore CO2's role in the tumor environment, particularly how its physiological properties and adaptive responses can influence therapeutic strategies.

By applying a structured translational approach using the Work Breakdown Structure method, the study divided the analysis into six interconnected work packages to comprehensively analyze the interactions between carbon dioxide and the tumor microenvironment. Methods included systematic literature reviews, data analyses, data integration for identifying critical success factors and exploring extracellular environment modulation. The research used SMART criteria for assessing innovation and the applicability of results.

The research revealed that the human body's adaptability to hypercapnic conditions could potentially inform innovative strategies for manipulating the tumor microenvironment. This could enhance O2 utilization efficiency and manage adaptive responses to cellular stress. The study proposed that carbon dioxide's hormetic potential could induce beneficial responses in the tumor microenvironment, prompting clinical protocols for experimental validation. The research underscored the importance of pH regulation, emphasizing CO2 and carbonic acid's role in modulating metabolic and signaling pathways related to cancer.

The study underscores CO2 as vital to our physiology and suggests potential therapeutic uses within the tumor microenvironment. pH modulation and cellular oxygenation optimization via CO2 manipulation could offer innovative strategies to enhance existing cancer therapies. These findings encourage further exploration of CO2's therapeutic potential. Future research should focus on experimental validation and exploration of clinical applications, emphasizing the need for interdisciplinary and collaborative approaches to tackle current challenges in cancer treatment.

3-Monochloropropane-1,2-diol (3-MCPD) is a chloropropyl alcohol contaminant mainly from the thermal processing of food and could affect kidneys. Pyroptosis is programmed cell death mediated by inflammasomes and gasdermins, and excessive cellular pyroptosis and inflammation can lead to tissue injury. In the present study, we found that 3-MCPD increased lactate dehydrogenase (LDH) levels in vitro and in vivo, increased the protein expression of NOD-like receptor family pyrin domain containing 3 (NLRP3), N-terminal domain of GSDMD (GSDMD-N), and cleaved caspase-1 and promoted the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), which induced renal cell pyroptosis and inflammation. Mechanistic studies indicated that the addition of N-acetylcysteine (NAC), a ROS scavenger, inhibited NLRP3 activation and attenuated pyroptosis. Furthermore, we revealed that 3-MCPD induced ROS accumulation by inhibiting ESCRT-III-mediated mitophagy. These results were further validated by the overexpression of charged multivesicular body protein 4B (CHMP4B), a key subunit of ESCRT-III, and the addition of the mitophagy activator carbonyl cyanide m-chlorophenylhydrazone (CCCP) and rapamycin (Rapa). Thus, our results showed that 3-MCPD could induce mitochondrial damage and produce ROS. 3-MCPD suppressed mitophagy, leading to the accumulation of damaged mitochondria and ROS, thereby activating NLRP3 and pyroptosis. Meanwhile, 3-MCPD-mediated suppression of ESCRT-III hindered the repair of GSDMD-induced cell membrane rupture, which further caused the occurrence of pyroptosis. Our findings provide new perspectives for studying the mechanisms underlying 3-MCPD-induced renal injury.

Inflammasomes contribute to colorectal cancer signaling by primarily inducing inflammation in the surrounding tumor microenvironment. Its role in inflammation is receiving increasing attention, as inflammation has a protumor effect in addition to inducing tissue damage. The inflammasome's function is complex and controlled by several layers of regulation. Epigenetic processes impact the functioning or manifestation of genes that are involved in the control of inflammasomes or the subsequent signaling cascades. Researchers have intensively studied the significance of epigenetic mechanisms in regulation, as they encompass several potential therapeutic targets. The regulatory interactions between the inflammasome and autophagy are intricate, exhibiting both advantageous and harmful consequences. The regulatory aspects between the two entities also encompass several therapeutic targets. The relationship between the activation of the inflammasome, autophagy, and epigenetic alterations in CRC is complex and involves several interrelated pathways. This article provides a brief summary of the newest studies on how epigenetics and autophagy control the inflammasome, with a special focus on their role in colorectal cancer. Based on the latest findings, we also provide an overview of the latest therapeutic ideas for this complex network.

Pyroptosis has attracted widespread concerns in cancer therapy, while the therapeutic efficiency could be significantly restricted by using the crucial pyroptosis checkpoint of autophagy and tumor hypoxia. Herein, a DNA nanocomplex (DNFs@ZnMn), containing cascade DNAzymes, promoter-like ZnO2-Mn nanozymes and photosensitizers, was constructed in one pot through rolling circle amplification reactions to induce pyroptosis through disrupting autophagy. After targeting cancer cells with a high expression of H+ and glutathione, DNFs@ZnMn decomposed to expose DNAzymes and promoter-like ZnO2-Mn nanozymes. Then, sufficient metal ions and O2 were released to promote cascade DNA/RNA cleavage and relieving of tumor hypoxia. The released DNAzyme-1 self-cleaved long DNA strands with Zn2+ as the cofactor and simultaneously exposed DNAzyme-2 to cleave ATG-5 mRNA (with Mn2+ as the cofactor). This cascade DNAzyme-mediated gene regulation process induced downregulation of ATG-5 proteins to disrupt autophagy. Simultaneously, the released ZnO2 donated sufficient H2O2 to generate adequate O2 to relieve tumor hypoxia, obtaining highly cytotoxic 1O2 to trigger pyroptosis. By using dynamic cascade gene silencing to disrupt the pyroptosis checkpoint and synergistic relieving of hypoxia, this DNA nanocomplex significantly weakened cellular resistance to achieve efficient pyroptosis therapy both in vitro and in vivo.

Autophagy is a cellular self-degradation process that plays a crucial role in maintaining metabolic functions in cells and organisms. Dysfunctional autophagy has been linked to various diseases, including cancer. In cancer, dysregulated autophagy is closely associated with the development of cancer and drug resistance, and it can have both oncogenic and oncostatic effects. Research evidence supports the connection between m6A modification and human diseases, particularly cancer. Abnormalities in m6A modification are involved in the initiation and progression of cancer by regulating the expression of oncogenes and oncostatic genes. There is an interaction between m6A modification and autophagy, both of which play significant roles in cancer. However, the molecular mechanisms underlying this relationship are still unclear. m6A modification can either directly inhibit autophagy or promote its initiation, but the complex relationship between m6A modification, autophagy, and cancer remains poorly understood. Therefore, this paper aims to review the dual role of m6A and autophagy in cancer, explore the impact of m6A modification on autophagy regulation, and discuss the crucial role of the m6A modification-autophagy axis in cancer progression and treatment resistance.

Tumour immune microenvironment (TIME) plays an indispensable role in tumour progression, and tumour-associated macrophages (TAMs) are the most abundant immune cells in TIME. Non-apoptotic regulated cell death (RCD) can avoid the influence of tumour apoptosis resistance on anti-tumour immune response. Specifically, autophagy, ferroptosis, pyroptosis and necroptosis mediate the crosstalk between TAMs and tumour cells in TIME, thus reprogram TIME and affect the progress of tumour. In addition, although some achievements have been made in immune checkpoint inhibitors (ICIs), there is still defect that ICIs are only effective for some people because non-apoptotic RCD can bypass the apoptosis resistance of tumour. As a result, ICIs combined with targeting non-apoptotic RCD may be a promising solution. In this paper, the basic molecular mechanism of non-apoptotic RCD, the way in which non-apoptotic RCD mediates crosstalk between TAMs and tumour cells to reprogram TIME, and the latest research progress in targeting non-apoptotic RCD and ICIs are reviewed.

Autophagy refers to the conserved cellular catabolic process relevant to lysosome activity and plays a vital role in maintaining the dynamic equilibrium of intracellular matter by degrading harmful and abnormally accumulated cellular components. Accumulating evidence has recently revealed that dysregulation of autophagy by genetic and exogenous interventions may disrupt cellular homeostasis in human diseases. In silico approaches as powerful aids to experiments have also been extensively reported to play their critical roles in the storage, prediction, and analysis of massive amounts of experimental data. Thus, modulating autophagy to treat diseases by in silico methods would be anticipated.

Here, we focus on summarizing the updated in silico approaches including databases, systems biology network approaches, omics-based analyses, mathematical models, and artificial intelligence (AI) methods that sought to modulate autophagy for potential therapeutic purposes, which will provide a new insight into more promising therapeutic strategies.

Autophagy-related databases are the data basis of the in silico method, storing a large amount of information about DNA, RNA, proteins, small molecules and diseases. The systems biology approach is a method to systematically study the interrelationships among biological processes including autophagy from a macroscopic perspective. Omics-based analyses are based on high-throughput data to analyze gene expression at different levels of biological processes involving autophagy. mathematical models are visualization methods to describe the dynamic process of autophagy, and its accuracy is related to the selection of parameters. AI methods use big data related to autophagy to predict autophagy targets, design targeted small molecules, and classify diverse human diseases for potential therapeutic applications.

Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 1 (NLRP1) participates in neuroinflammation. This study aimed to identify serum NLRP as a potential prognostic biomarker of acute intracerebral hemorrhage (ICH).

This prospective cohort study enrolled 145 patients with supratentorial ICH and 51 healthy controls. Serum NLRP1 levels were quantified on admission of all 145 patients, on days 1, 3, 5, 7, and 10 after stroke in 51 of 145 patients and at entry into the study of controls. Poststroke 6-month modified Rankin Scale (mRS) scores of 3-6 signified a poor prognosis.

Compared to controls, patients had prominently increased serum NLRP1 levels until day 10 after ICH, with the highest levels at days 1 and 3. Serum NLRP1 levels were independently correlated with National Institutes of Health Stroke Scale (NIHSS) scores, hematoma volume and six-month mRS scores, and independently predicted six-month bad prognosis. A linear relationship was observed between serum NLRP1 levels and the risk of poor prognosis in a restricted cubic spline. Under the receiver operating characteristic (ROC) curve, serum NLRP levels efficiently discriminated poor prognosis. Serum NLRP1, NIHSS, and hematoma volume were merged into a prognosis prediction model, which was portrayed using a nomogram. Good performance of the model was verified using calibration curve, decision curve, and ROC curve.

Serum NLRP1 levels are elevated during the early period following ICH and are independently related to hemorrhagic severity and poor prognosis, suggesting that serum NLRP1 may represent a promising prognostic biomarker of ICH.

Autophagy plays a vital role in sustaining cellular homeostasis and its alterations have been implicated in the etiology of many diseases. Drugs development targeting autophagy began decades ago and hundreds of agents were developed, some of which are licensed for the clinical usage. However, no existing intervention specifically aimed at modulating autophagy is available. The obstacles that prevent drug developments come from the complexity of the actual impact of autophagy regulators in disease scenarios. With the development and application of new technologies, several promising categories of compounds for autophagy-based therapy have emerged in recent years. In this paper, the autophagy-targeted drugs based on their targets at various hierarchical sites of the autophagic signaling network, e.g., the upstream and downstream of the autophagosome and the autophagic components with enzyme activities are reviewed and analyzed respectively, with special attention paid to those at preclinical or clinical trials. The drugs tailored to specific autophagy alone and combination with drugs/adjuvant therapies widely used in clinical for various diseases treatments are also emphasized. The emerging drug design and development targeting selective autophagy receptors (SARs) and their related proteins, which would be expected to arrest or reverse the progression of disease in various cancers, inflammation, neurodegeneration, and metabolic disorders, are critically reviewed. And the challenges and perspective in clinically developing autophagy-targeted drugs and possible combinations with other medicine are considered in the review.

Cancer has become a global public health problem and its harmful effects have received widespread attention. Conventional treatments such as surgical resection, radiotherapy and other techniques are applicable to clinical practice, but new drugs are constantly being developed and other therapeutic approaches, such as immunotherapy are being applied. In addition to studying the effects on individual tumor cells, it is important to explore the role of tumor microenvironment on tumor cell development since tumor cells do not exist alone but in the tumor microenvironment. In the tumor microenvironment, tumor cells are interconnected with other stromal cells and influence each other, among which tumor-associated macrophages (TAMs) are the most numerous immune cells. At the same time, it was found that cancer cells have different levels of autophagy from normal cells. In cancer therapy, the occurrence of autophagy plays an important role in promoting tumor cell death or inhibiting tumor cell death, and is closely related to the environment. Therefore, elucidating the regulatory role of autophagy between TAMs and tumor cells may be an important breakthrough, providing new perspectives for further research on antitumor immune mechanisms and improving the efficacy of cancer immunotherapy.