Our study aims to investigate the roles of embryonic lethal abnormal vision-like 1 (ELAVL1) and long non-coding RNA (LncRNA) NEAT1 in endometrial cancer (EC), focusing on their underlying molecular mechanisms.We obtained EC cell lines (HEC-1A, Ishikawa, RL95-2, HEC-1B, and AN3CA) from ATCC. We used siRNAs (si-ELAVL1#1 and si-ELAVL1#2) and overexpression RNAs (OE ELAVL1 and OE-NEAT1) for knockdown or overexpression of ELAVL1 and LncRNA NEAT1. We also employed 3-MA (5mM) or rapamycin (100µM) to inhibit or promote autophagy. Moreover, we conducted RNA immunoprecipitation (RIP) assays to confirm the interaction between LncRNA NEAT1 and ELAVL1. Cell Counting Kit-8 (CCK-8) and transwell assays were utilized to assess cell proliferation and migration. Additionally, we measured the expression of ELAVL1 and Beclin1 through Western blotting and RT-qPCR.ELAVL1 was found to be highly expressed in EC. Furthermore, ELAVL1 promoted the proliferation, invasion, and migration of EC cells through the regulation of Beclin1-related pathways. RIP assays revealed a direct interaction between LncRNA NEAT1 and ELAVL1, with ELAVL1 stabilizing LncRNA NEAT1 mRNA in EC cells. Additionally, we observed that ELAVL1 influenced EC cell proliferation, invasion, and migration through the regulation of LncRNA NEAT1-mediated regulation of Beclin1 expression. Moreover, in an animal study, we determined that ELAVL1 influenced endometrial cancer tumor growth through its interaction with LncRNA NEAT1, which mediated Beclin1 expression in vivo.In summary, our study showed that ELAVL1 regulated the malignant behavior of endometrial cancer cells through the modulation of LncRNA NEAT1-mediated regulation of Beclin1 expression.

Hepatocellular carcinoma is a prevalent malignant tumor with a high mortality rate. Natural plants hold promise for its treatment, however, the mechanism of lysionotin induced apoptosis in liver cancer cells unclearly. This study aims to investigate the microenvironment alterations and the efficacy of lysionotin in liver cancer.

Transmission electron microscopy, and laser confocal microscopy were employed to investigate the effect of lysionotin on autophagy in HCC cells. The molecular mechanism through which lysionotin induces autophagy and autophagy-induced apoptosis was ascertained by transcriptome sequencing, immunoblotting and Hoechst 33258 staining.

RNA sequencing analysis, electron microscopy and laser confocal microscopy revealed that lysionotin initiate autophagy in liver cancer cells. Immunoblotting indicated that lysionotin markedly enhances the activation of LC3-II in HCC cells, resulting in the activation of key effector molecules ATG12, Beclin-1 and the degradation of P62. Combined with autophagy inhibitors CQ and 3-MA significantly inhibited lysionotin-induced cell apoptosis. Immunoblotting and Hoechst staining disclosed that the activation of autophagy by lysionotin might be associated with the suppression of the mTOR-AKT signaling pathway. The treatment of mTOR inhibitor RAPA and activator 1485 demonstrated that inhibiting mTOR activation significantly augments the pro-apoptotic effect of lysionotin on liver cancer cells, while mTOR activator could rescue the effect of lysionotin on cells.

The findings suggest that the activation of autophagy by lysionotin may represent one of the pivotal mechanisms underlying its therapeutic efficacy against HCC and its synergistic enhancement of RAPA's antitumor effects.

Resistance to apoptosis-inducing drugs frequently occurs in cancer cells, limiting their usefulness in ongoing cancer treatment. Despite ongoing efforts to overcome drug resistance, a definitive solution remains elusive. However, autophagy inhibition has been shown to enhance the effectiveness of some anticancer drugs and is a possible strategy for overcoming drug resistance. In this study, we demonstrate that chlorogenic acid (CGA), a natural antioxidant, significantly enhances beta-lapachone (β-Lap)-induced cell death in cancer cells. The augmented apoptosis induced by CGA is associated with activation of protein kinase A (PKA) in β-Lap-treated cells, independent of the antioxidant properties of CGA. As a result, PKA activation in cancer cells co-treated with β-Lap and CGA effectively inhibits autophagy. Notably, PKA activation leads to phosphorylation of microtubule-associated protein 1 A/1B-light chain 3 (LC3) at the serine 12 residue, causing autophagy suppression irrespective of mTORC activity. Importantly, the cell death induced by β-Lap and CGA in NQO1-overexpressing breast or lung cancers is closely linked to autophagy inhibition. These findings suggest that combining β-Lap and CGA might be a novel strategy for cancer therapy, particularly for overcoming drug resistance caused by autophagy induction in cancer cells.

Lung cancer remains a leading cause of cancer-related mortality worldwide. Its progression is intricately associated with the dynamic regulation of autophagy and RNA-binding proteins (RBPs), which play crucial roles in mRNA stability, alternative splicing, and cellular stress responses.

This review aims to systematically analyze the mechanisms through which RBPs and autophagy contribute to lung cancer progression and explore potential therapeutic strategies targeting these pathways.

We reviewed recent studies on the molecular mechanisms by which RBPs regulate tumor proliferation, metabolic adaptation, and their interaction with autophagy. The review also examines the dual roles of autophagy in lung cancer, highlighting its context-dependent effects on cell survival and death.

The interactions and regulatory networks between RBPs and autophagy involve multiple levels of regulation. RBPs can directly influence autophagy processes and act as microRNA (miRNA) sponges to regulate mRNA stability. The modulation of RBPs affects the expression of autophagy-related genes (ATGs) and autophagosome formation. Additionally, RBPs participate in complex regulatory interactions with non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other proteins.

This review proposes innovative therapeutic strategies that combine RBP-targeting approaches (e.g., small molecule inhibitors, CRISPR gene editing) with autophagy modulators (e.g., mTOR inhibitors, chloroquine) to enhance treatment efficacy. Nanoparticle drug delivery systems and epigenetic regulation offer further opportunities for targeted interventions. This review lays a theoretical foundation for advancing lung cancer research and provides novel insights into synergistic therapies that target both RBPs and autophagy to improve treatment outcomes for lung cancer.

Autophagy plays a complex role in cancer progression, serving as both a tumor suppressor and a promoter, depending on the context. In triple-negative breast cancer (TNBC), a particularly aggressive subtype with limited therapeutic options, autophagy inhibition has emerged as a promising strategy to enhance the efficacy of chemotherapy. This study investigates the synergistic effects of autophagy suppression using LC3 siRNA-loaded "smart" nanoparticles (LC3siRNA-NPs) in combination with doxorubicin (DOX) to overcome chemoresistance in TNBC. We engineered a well-defined copolymer, poly[hexyl methacrylate-co-2-(dimethylamino) ethyl methacrylate-co-trimethylaminoethyl methacrylate iodide], and a PEG heteroarm beta-cyclodextrin (βCD) core star copolymer that delivers LC3 siRNA, effectively silencing the autophagy-related gene LC3. In vitro, the coadministration of LC3siRNA-NPs and DOX significantly inhibited TNBC cell proliferation, migration, and colony formation, while inducing apoptosis more effectively than either treatment alone. Mechanistically, this combination downregulated key oncogenic markers such as PARP, cyclin D1, and Src, enhancing the therapeutic outcome. In vivo, treatment with LC3siRNA-NPs and DOX in a TNBC xenograft model resulted in superior tumor growth suppression compared to that with monotherapy alone. Our findings highlight the potential of autophagy-targeting nanocarriers to improve chemotherapy outcomes and provide an effective approach to TNBC treatment by enhancing chemotherapeutic sensitivity and reducing tumor resistance.

Autophagy critically regulates cellular development while maintaining pathophysiological homeostasis. Since the autophagic process is tightly regulated by the coordination of autophagy-related proteins (ATGs), precise identification of these proteins is essential. Although current computational approaches have addressed experimental recognition's costly and time-consuming challenges, they still have room for improvement since handcrafted features inadequately capture the intricate patterns and relationships hidden in sequences. In this study, we propose PLM-ATG, a novel computational model that integrates support vector machines with the fusion of protein language model (PLM) embeddings and position-specific scoring matrix (PSSM)-based features for the ATG identification. First, we extracted sequence-based features and PSSM-based features as the inputs of six classifiers to establish baseline models. Among these, the combination of the SVM classifier and the AADP-PSSM feature set achieved the best prediction accuracy. Second, two popular PLM embeddings, i.e., ESM-2 and ProtT5, were fused with the AADP-PSSM features to further improve the prediction of ATGs. Third, we selected the optimal feature subset from the combination of the ESM-2 embeddings and AADP-PSSM features to train the final SVM model. The proposed PLM-ATG achieved an accuracy of 99.5% and an MCC of 0.990, which are nearly 5% and 0.1 higher than those of the state-of-the-art model EnsembleDL-ATG, respectively.

Colorectal cancer (CRC) is one of the aggressive malignant tumors. Studies have shown that glycolysis promotes the proliferation of colorectal cancer cells and that PYCR2 is involved in cancer progression by affecting cellular glycolysis. In addition, PYCR2 is upregulated in colorectal cancer cell lines and can affect cellular autophagy.

Si-PYCR2 was used to interfere with PYCR2 in colorectal cancer cells, and the cells were treated with the addition of autophagy inhibitor 3-MA or mTOR agonist MHY1485. The expression of LC3B was detected by immunofluorescence, and the expression of autophagy and glycolytic proteins was detected by Western blot. XF96 extracellular flux analyzer was used to detect the ECAR and OCR of the cells, and biochemical kits were used to detect the levels of glucose consumption, lactate secretion, and ATP production in the cells.

PYCR2 expression was up-regulated in colorectal cancer cell lines. si-PYCR2 interference enhanced the fluorescence intensity of LC3B in the cells, inhibited the expression of p62 proteins but enhanced the expression of ATG5, ATG7, and LC3-II/I proteins, which indicated an enhanced level of autophagy in colorectal cancer cells. In addition, PYCR2 depletion also inhibited cellular glycolysis as well as mTOR/HK2 signaling. However, the addition of 3-MA resulted in an increase in cellular ECAR while a decrease in OCR, and an increase in the levels of glucose consumption, lactate and ATP production, as well as the expressions of glycolytic proteins (GLUT1, PGK1, ENO1, PKM2), which suggested the glycolysis of cells was enhanced. In addition, MHY1485 treatment not only inhibited autophagy but also enhanced glycolysis in colorectal cancer cells.

Interference with PYCR2 corrected autophagy-dependent glycolysis levels in colorectal cancer cells via mTOR/HK2 signaling. Activation of mTOR/HK2 signaling mitigated the effects of PYCR2 depletion in colorectal cells.

Telomere maintenance is an important feature of tumor cells. Telomeric-repeat binding factor 1 interaction nuclear protein 2 (TIN2), a key member of the shelterin proteins, functions in regulating telomere structure, length and function. Our work sought to investigate the role of TIN2 in controlling gastric cancer (GC) malignant biological behaviors.

The mRNA and protein expressions were examined by qRT-PCR, western blot and immunofluorescence assays. The relative telomerase activity and telomere length were detected using the corresponding kit and qRT-PCR, respectively. The proliferation, migration and invasion abilities were detected by CCK8 and transwell assays, respectively. Cellular oxidative stress level and Fe2 + content were assessed by DCFH-DA staining and ELISA assays, respectively. The interaction between IGF2BP1/2/3 and TIN2 was analyzed by RIP and RNA pull down assays.

TIN2 expression was significantly increased in GC cells compared with it in gastric mucosal epithelial cells. TIN2 knockdown could impair telomerase function and induce DNA injury in GC cells. Moreover, silencing of TIN2 greatly repressed cell proliferation, metastasis, and autophagy in GC cells. Likewise, the antioxidant capacity and Fe2+ content were enhanced after TIN2 depletion, leading to the activation of cellular ferroptosis. In terms of mechanism, TIN2 mRNA could be recognized by IGF2BP1/2/3, and its mRNA expression and stability were decreased upon IGF2BP1/2/3 was knocked down.

Knockdown of TIN2 could restrained telomerase function and the malignant abilities of proliferation, metastasis and autophagy but induced ferroptosis of GC cells, which suggested that targeting TIN2 might be a therapeutic strategy for GC.

Antibody‑drug conjugates (ADCs) are rapidly advancing the treatment of solid tumors, and Nectin‑4‑targeted ADCs have been approved by the FDA to treat certain cancers. Although Nectin‑4 is overexpressed in the tissues of patients with pancreatic cancer, whether Nectin‑4‑targeted ADCs can effectively treat pancreatic cancer remains unclear. The present study evaluated the therapeutic effects and mechanisms of Nectin‑4‑targeted ADCs in pancreatic cancer. A Nectin‑4‑directed ADC was chosen, Nectin‑4‑MMAE, which triggered apoptosis and induced cell death in the Nectin‑4‑positive pancreatic cancer cell lines BxPC‑3 and YAPC. Nectin‑4‑MMAE also induced autophagy in BxPC‑3 and YAPC cells by inactivating the AKT/mTOR pathway. The entire autophagy process was observed by electron microscopy and laser confocal microscopy. The autophagy inhibitors LY294002 and chloroquine significantly increased the lethal effects of Nectin‑4‑MMAE on BxPC‑3 and YAPC cells by inducing apoptosis. In the xenograft tumor model, Nectin‑4‑MMAE alone elicited potent antitumor effects. When Nectin‑4‑MMAE was combined with autophagy inhibitors, the tumor burden of mice was decreased compared with treatment with either drug alone. The present study confirmed the potent therapeutic effects of Nectin‑4‑MMAE against pancreatic cancer, and its unique antitumor mechanism provides new approaches to treatment.

Programmed necrosis, a controlled cell death method that bypasses resistance mechanisms that render apoptosis ineffective, is a potential cancer treatment target. Due to their diverse biological activities and low side effects, natural products are being explored as modulators of programmed necrosis pathways. This review highlights the potential of natural compounds to target cancer cells while preserving healthy tissues and their interaction with essential programmed necrosis mechanisms like ferroptosis and necroptosis. Recent developments have identified various types of programmable necrosis, including necroptosis, ferroptosis, pyroptosis, proptosis, mitochondrial permeability transition-driven necrosis, and oncosis. Natural compounds are increasingly being utilized as a primary source of anti-cancer medications, providing new cancer treatments. This review demonstrates the molecular mechanisms behind lipid peroxidation, mixed lineage kinase domain-like protein, and receptor-interacting protein kinases (RIPK1 and RIPK3) inducing cell death. Recent research has identified natural compounds like polyphenols, alkaloids, and terpenoids that can modulate pathways and benefit preclinical cancer models. The review underscores the potential of natural compounds in developing innovative cancer treatments by integrating pharmacology and cellular signaling knowledge. Integrating natural compound studies and programmed necrosis research presents a promising avenue for oncologists to overcome treatment resistance. Natural compounds have shown potential in developing programmed necrosis as a novel cancer treatment approach, enhancing therapeutic effectiveness and minimizing side effects through preclinical research, pharmacology, and molecular biology.

Bladder cancer (BC) is the most common cancer of the urinary tract. Bozepinib (BZP), a purine-derived molecule, is a potential compound for the treatment of cancer. Purinergic signaling consists of the activity of nucleosides and nucleotides present in the extracellular environment, modulating a variety of biological actions. In cancer, this signaling is mainly controlled by the enzymatic cascade involving the NTPDase/E-NPP family and ecto-5'-nucleotidase/CD73, which hydrolyze extracellular adenosine triphosphate (ATP) to adenosine (ADO). The aim of this work is to evaluate the activity of BZP in the purinergic system in BC cell lines and to compare its in vitro antitumor activity with cisplatin, a chemotherapeutic drug widely used in the treatment of BC. In this study, two different BC cell lines, grade 1 RT4 and the more aggressive grade 3 T24, were used along with a human fibroblast cell line MRC-5, a cell used to predict the selectivity index (SI). BZP shows strong antitumor activity, with notable IC50 values (8.7 ± 0.9 µM for RT4; 6.7 ± 0.7 µM for T24), far from the SI for cisplatin (SI for BZP: 19.7 and 25.7 for RT4 and T24, respectively; SI for cisplatin: 1.7 for T24). BZP arrests T24 cells in the G2/M phase of the cell cycle, inducing early apoptosis. Moreover, BZP increases ATP and ADP hydrolysis and gene/protein expression of the NPP1 enzyme in the T24 cell line. In conclusion, BZP shows superior activity compared to cisplatin against BC cell lines in vitro.

Autophagy is a highly conserved catabolic pathway that is precisely regulated and plays a significant role in maintaining cellular metabolic balance and intracellular homeostasis. Abnormal autophagy is directly linked to the development of various diseases, particularly immune disorders, neurodegenerative conditions, and tumors. The precise regulation of proteins is crucial for proper cellular function, and post-translational modifications (PTMs) are key epigenetic mechanisms in the regulation of numerous biological processes. Multiple proteins undergo PTMs that influence autophagy regulation. Methylation modifications on non-histone lysine and arginine residues have been identified as common PTMs critical to various life processes. This paper focused on the regulatory effects of non-histone methylation modifications on autophagy, summarizing related research on signaling pathways involved in autophagy-related non-histone methylation, and discussing current challenges and clinical significance. Our review concludes that non-histone methylation plays a pivotal role in the regulation of autophagy and its associated signaling pathways. Targeting non-histone methylation offers a promising strategy for therapeutic interventions in diseases related to autophagy dysfunction, such as cancer and neurodegenerative disorders. These findings provide a theoretical basis for the development of non-histone-methylation-targeted drugs for clinical use.

Pancreatic cancer is an aggressive tumor, which is often associated with a poor clinical prognosis and resistance to conventional chemotherapy. Therefore, there is a need to identify new therapeutic markers for pancreatic cancer. Although KIN17 is a highly expressed DNA‑ and RNA‑binding protein in a number of types of human cancer, its role in pancreatic cancer development, especially in relation to progression, is currently unknown. The present study verified the upregulation of KIN17 in pancreatic cancer using The Cancer Genome Atlas and Gene Expression Omnibus databases (GSE15471, GSE71989 and GSE62165), and identified an association between the PI3K/Akt/mTOR pathway and patient prognosis using publicly available datasets (Gene Expression Profiling Interactive Analysis). Immunohistochemistry was performed to determine the association between KIN17 and the pathological features of clinical pancreatic cancer samples. Furthermore, knockdown of KIN17 was shown to inhibit the migration and invasion of pancreatic cancer cells, and to reverse epithelial‑mesenchymal transition in pancreatic cancer cells through downregulation of Vimentin and N‑cadherin, and upregulation of E‑cadherin. Through various cellular experiments, the role of KIIN17 was explored in PI3K/AKT/mTOR activity. KIN17 inhibition was shown to suppress the migration and invasion of pancreatic cancer cells through PI3K/AKT/mTOR‑mediated autophagy. Furthermore, combined with mTOR inhibition, dual inhibition could enhance autophagy, leading to anti‑migratory and anti‑invasion effects in pancreatic cancer. In conclusion, the present study indicated that KIN17 may have a role in carcinogenesis and could serve as a prognostic biomarker of pancreatic cancer, owing to its high expression. In addition, KIN17 may be considered a potential therapeutic target with its knockdown having an inhibitory effect on pancreatic cancer.

Chemotherapeutic drugs often fail to provide long-term efficacy due to their lack of specificity and high toxicity. To enhance the biosafety and reduce the side effects of these drugs, various nanocarrier delivery systems have been developed. In this study, we loaded the anticancer drug doxorubicin (DOX) and an MRI contrast agent into silica nanoparticles, coating them with pH-responsive and tumor cell-targeting polymers. These polymers enable the carrier to achieve targeted delivery and controlled drug release in acidic environments. This integrated diagnostic and therapeutic strategy successfully achieved both the diagnosis and treatment of liver cancer. Additionally, we demonstrated that the nanocarrier inhibits autophagic flux in liver cancer cells by targeting the autophagy-lysosome pathway and regulating the nuclear translocation of TFEB, thereby promoting tumor cell death. This novel diagnostic-integrated nanocarrier is expected to be a promising tool for targeted liver cancer treatment.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is marked by a high mortality rate, with the misregulation of long non-coding RNAs (LncRNAs) playing a key role in its development. Here, we studied the role of LINC02987 in HCC. We employed bioinformatics tools to identify LncRNAs and miRNAs that exhibit differential expression in HCC. Quantitative real-time reverse transcription PCR (RT-qPCR) and Western blot analysis were utilized to quantify gene and protein expression levels. The interaction between miR-338-3p and LINC02987 or ATG12 was confirmed through dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. We observed that LINC02987 was overexpressed in HCC tumor tissues and cell lines. Silencing of LINC02987 led to a reduction in cell viability, diminished clonogenic potential, and attenuated invasive and migratory capabilities. Also, decreasing protein level and fluorescence intensity of the autophagy-associated LC3 I/II. In HCC, miR-338-3p expression was downregulated, while inversely correlates with the overexpression of the autophagy protein ATG12. Mimicking miR-338-3p suppresses the activity of both LINC02987 and ATG12, as evidenced by reduced luciferase signals in corresponding reporter assays. Mimicking miR-338-3p suppresses the activity of both LINC02987 and ATG12, as evidenced by reduced luciferase signals in reporter assays. Transfection with si-LINC02987 decreased ATG12 expression, an effect that was partially reversed by miR-338-3p knockdown. Inhibition of miR-338-3p or overexpression of ATG12 increased LC3 I/II protein levels. Our results indicate that LINC02987 sequesters miR-338-3p, leading to increased ATG12 and promoting autophagy in HCC cells. These results highlight the potential of LINC02987 as a therapeutic target for the treatment of HCC.

Hydroxysafflor yellow A (HSYA), a natural pigment with a chalcone structure extracted from Carthamus tinctorius L. (Safflower), has been widely proven to have good efficacy on cardiovascular diseases, atherosclerosis, cancer, and diabetes. However, no study has reported on the anticancer mechanisms of Hydroxysafflor yellow A (HSYA), a principal bioactive compound in safflower. This review discusses recent developments in the physicochemical properties and sources, pharmacological effects and mechanisms, pharmacokinetic progress, and safety of HSYA, focusing on the involvement of HSYA in the regulation of related pathways and mechanisms of apoptosis, autophagy, and the tumor immune microenvironment in a variety of cancers. This can serve as a theoretical basis for further research and development of HSYA, with insights into the mechanisms of anticancer signaling pathways.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST models indicates that MEK inhibition has poor antitumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors were performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine (HQ) resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with HQ as a unique treatment approach for NF1 MPNSTs.

Hepatocellular carcinoma (HCC) is a globally prevalent malignancy accompanied by high incidence, poor outcomes, and high mortality. Anthocyanins can inhibit tumor proliferation, migration, invasion, and promote apoptosis. Moreover, autophagy-related genes (ARGs) may play vital roles in HCC progression. This study aimed to decipher the mechanisms through which anthocyanins influence HCC via ARGs and to establish a novel prognostic model.

Based on data from public databases, differential analysis and the Venn algorithm were employed to detect intersecting genes among differentially expressed genes (DEGs), anthocyanin- related targets, and ARGs. Consensus clustering was implemented to delineate molecular subtypes of HCC. The prognostic model was developed by Cox regression analyses. CIBIRSORT was engaged to assess the immune cell infiltration. Kaplan-Meier (KM) analysis and receiver operating characteristic (ROC) curve were utilized to evaluate the predictive efficiency of the prognostic signature.

A total of 36 intersecting genes were identified from overlapping 1524 ARGs, 537 anthocyanin- related targets, and 5247 DEGs. Consensus clustering determined three molecular subtypes (cluster 1, cluster 2, and cluster 3). Cluster 1 showed worse outcomes and remarkably higher abundances of plasma cells and T follicular helper cells. Furthermore, four prognostic signatures (KDR (Kinase insert domain receptor), BAK1 (BCL2 antagonist/killer 1), HDAC1 (Histone deacetylase 1), and CDK2 (Cyclin-dependent kinase 2)) were identified and showing substantial predictive efficacy.

This investigation identified three molecular subtypes of HCC patients and proposed a promising prognostic signature comprising KDR, BAK1, HDAC1, and CDK2, which could supply further robust evidence for additional clinical and functional studies.

Autophagy is a conservative lysosome-dependent material catabolic pathway, and exists in all eukaryotic cells. Autophagy controls cell quality and survival by eliminating intracellular dysfunction substances, and plays an important role in various pathophysiology processes. Erectile dysfunction (ED) is a common male disease. It is resulted from a variety of causes and pathologies, such as diabetes, hypertension, hyperlipidemia, aging, spinal cord injury, or cavernous nerve injury caused by radical prostatectomy, and others. In the past decade, autophagy has begun to be investigated in ED. Subsequently, an increasing number of studies have revealed the regulation of autophagy contributes to the recovery of ED, and which is mainly involved in improving endothelial function, smooth muscle cell apoptosis, penile fibrosis, and corpus cavernosum nerve injury. Therefore, in this review, we aim to summarize the possible role of autophagy in ED from a cellular perspective, and we look forward to providing a new idea for the pathogenesis investigation and clinical treatment of ED in the future.

Definitive chemoradiotherapy (CRT) is a cornerstone of treatment for locoregionally advanced head and neck cancer (HNC). Research is ongoing on how to improve the tumor response to treatment and limit normal tissue toxicity. A major limitation in that regard is the growing occurrence of intrinsic or acquired treatment resistance in advanced cases. In this review, we will discuss how overexpression of efflux pumps, perturbation of apoptosis-related factors, increased expression of antioxidants, glucose metabolism, metallotheionein expression, increased DNA repair, cancer stem cells, epithelial-mesenchymal transition, non-coding RNA and the tumour microenvironment contribute towards resistance of HNC to chemotherapy and/or radiotherapy. These mechanisms have been investigated for years and been exploited for therapeutic gain in resistant patients, paving the way to the development of new promising drugs. Since in vitro studies on resistance requires a suitable model, we will also summarize published techniques and treatment schedules that have been shown to generate acquired resistance to chemo- and/or radiotherapy that most closely mimics the clinical scenario.

Macroautophagy (autophagy) involves the formation of phagophores that mature into autophagosomes. The impact of inhibiting autophagosome closure remains unclear. Here, we report the generation and analysis of mice with impaired autophagosome closure by targeting the ubiquitin E2 variant-like (UEVL) β strands of the endosomal sorting complex required for transport (ESCRT) I subunit VPS37A. The VPS37A UEVL mutation (Δ43-139) impairs bulk autophagic flux without disrupting ESCRT-I complex assembly and endosomal function. Homozygous mutant mice exhibit signs of autophagy impairment, including p62/SQSTM1 and ubiquitinated protein accumulation, neuronal dysfunction, growth retardation, antioxidant gene upregulation, and tissue abnormalities. However, about half of the mutant neonates survive to adulthood without severe liver injury. LC3 proximity proteomics reveals that the VPS37A UEVL mutation leads to active TANK-binding kinase 1 (TBK1) accumulation on phagophores, resulting in increased p62 phosphorylation and inclusion formation. These findings reveal a previously unappreciated role of LC3-conjugated phagophores in facilitating protein aggregation and sequestration, potentially alleviating proteotoxicity.

Drug resistance and recurrence are still the bottlenecks in the clinical treatment of ovarian cancer (OC), seriously affecting patients' prognosis. Therefore, it is an urgent challenge for OC to be overcome towards precision therapy by studying the mechanism of OC drug resistance, finding new drug resistance targets and developing new effective treatment strategies. In this study, we found that lncRNA LOC730101 played an essential role in attenuating drug resistance in OC. LOC730101 was significantly down-regulated in platinum-resistant ovarian cancer tissues, and ectopic overexpression of LOC730101 substantially increased chemotherapy-induced apoptosis. Mechanistically, LOC730101 specifically binds to BECN1 and inhibits the formation of autophagosome BECN1/VPS34 by reducing phosphorylation of BECN1, thereby inhibiting autophagy and promoting drug sensitivity in ovarian cancer cells following treatment with cisplatin and PARP inhibitors. Moreover, LOC730101 inhibits the expression and activity of RNF168 via p62, which in turn affects H2A ubiquitination-mediated DNA damage repair and promotes drug sensitivity in ovarian cancer cells. Our findings demonstrated that LOC730101 played an important role in regulating the formation of the autophagic complex and that inhibition of autophagy significantly enhances the drug sensitivity of OC. And LOC730101 may be used as a prognostic marker to predict the sensitivity of OC to platinum and PARP 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 most important issues in acute myeloid leukemia are preventing relapse and treating relapse. Although the remission rate has improved to approximately 80%, the 5-year survival rate is only around 30%. The main reasons for this are the high relapse rate and the limited treatment options. In chronic myeloid leukemia patients, when a deep molecular response is achieved for a certain period of time through tyrosine kinase inhibitor treatment, about half of them will reach treatment-free remission, but relapse is still a problem. Therefore, potential therapeutic targets for myeloid leukemias are eagerly awaited. Autophagy suppresses the development of cancer by maintaining cellular homeostasis; however, it also promotes cancer progression by helping cancer cells survive under various metabolic stresses. In addition, autophagy is promoted or suppressed in cancer cells by various genetic mutations. Therefore, the development of therapies that target autophagy is also being actively researched in the field of leukemia. In this review, studies of the role of autophagy in hematopoiesis, leukemogenesis, and myeloid leukemias are presented, and the impact of autophagy regulation on leukemia treatment and the clinical trials of autophagy-related drugs to date is discussed.

Autophagy is a cellular recycling process that is associated with tumor growth, anti-tumor immune responses, and therapy resistance in colorectal cancer (CRC). In this report, we identify the small GTPase Rab27B to control the autophagy process in CRC. Depletion of Rab27B showed an abnormal accumulation of autophagy vesicles and increased autophagy markers in CRC cells, indicating autophagy dysregulation. Image analysis indicated that autophagy flux is blocked at the autophagosome/lysosome fusion step when Rab27B is lost. While Rab27B deficient cells are proficient at growth under 2D in vitro conditions, cell growth was significantly impacted in both in vitro 3D growth and in vivo tumorigenesis studies. Together, these results demonstrate a new role of Rab27B in the autophagy trafficking process in CRC and identify Rab27B as a potential therapeutic target for CRC.

NNK, formally known as 4-(methyl nitrosamine)-1-(3-pyridyl)-1-butanoe, is a potent chemical carcinogen prevalent in cigarette smoke and is a key contributor to the development of human lung adenocarcinomas. On the other hand, autophagy plays a complex role in cancer development, acting as a "double-edged sword" whose impact varies depending on the cancer type and stage. Despite this, the relationship between autophagy and NNK-induced lung carcinogenesis remains largely unexplored. Our current study uncovers a marked reduction in p62 protein expression in both lung adenocarcinomas and lung tissues of mice exposed to cigarette smoke. Interestingly, this reduction appears to be contingent upon the activity of extrahepatic cytochrome P450 (CYP450), revealing that NNK metabolic activation by CYP450 enzyme escalates its potential to induce p62 downregulation. Further mechanistic investigations reveal that NNK suppresses autophagy by accelerating the degradation of p62 mRNA, thereby promoting the malignant transformation of human bronchial epithelial cells. This degradation process is facilitated by the hypermethylation of the Human antigen R (HuR) promoter, resulting in the transcriptional repression of HuR - a key regulator responsible for stabilizing p62 mRNA through direct binding. This hypermethylation is triggered by the activation of ribosomal protein S6, which is influenced by NNK exposure and subsequently amplifies the translation of DNA methyltransferase 3 alpha (DNMT3a). These findings provide crucial insights into the nature of p62 in both the development and potential treatment of tobacco-related lung cancer.

Autophagy is a crucial mechanism for recycling intracellular materials, and under normal metabolic conditions, it is maintained at low levels in cells. However, when nutrients are deficient or under hypoxic conditions, the level of autophagy significantly increases. Particularly in cancer cells, which grow more rapidly than normal cells and tend to grow in a three-dimensional manner, cells inside the cell mass often face limited oxygen supply, leading to inherently higher levels of autophagy. Therefore, the initial development of anticancer drugs targeting autophagy was based on a strategy to suppress these high levels of autophagy. However, anticancer drugs that inhibit autophagy have not shown promising results in clinical trials, as it has been revealed that autophagy does not always play a role that favors cancer cell survival. Hence, this review aims to suggest anticancer strategies based on the changes in the role of autophagy according to survival conditions and tumorigenesis stage.

Autophagy is a fundamental pillar of cellular resilience, indispensable for maintaining cellular health and vitality. It coordinates the meticulous breakdown of cytoplasmic macromolecules as a guardian of cell metabolism, genomic integrity, and survival. In the complex play of biological warfare, autophagy emerges as a firm defender, bravely confronting various pathogenic, infectious, and cancerous adversaries. Nevertheless, its role transcends mere defense, wielding both protective and harmful effects in the complex landscape of disease pathogenesis. From the onslaught of infectious outbreaks to the devious progression of chronic lifestyle disorders, autophagy emerges as a central protagonist, convolutedly shaping the trajectory of cellular health and disease progression. In this article, we embark on a journey into the complicated web of molecular and immunological mechanisms that govern autophagy's profound influence over disease. Our focus sharpens on dissecting the impact of various autophagy-associated proteins on the kaleidoscope of immune responses, spanning the spectrum from infectious outbreaks to chronic lifestyle ailments. Through this voyage of discovery, we unveil the vast potential of autophagy as a therapeutic linchpin, offering tantalizing prospects for targeted interventions and innovative treatment modalities that promise to transform the landscape of disease management.

High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecological cancer. Genetic studies have revealed gene copy number alterations (CNAs) frequently occurred in HGSOC pathogenesis, however the function and mechanism of CNAs for microRNAs are still not fully understood. Here, we show the dependence on gene copy number amplification of MIR937 that enhances cell autophagy and dictates HGSOC proliferative activity. Data mining of TCGA database revealed MIR937 amplification is correlated with increased MIR937 expression and cell proliferation of HGSOC. Deletion of MIR937 in HGSOC cells led to impaired autophagy and retarded cell proliferation, and the extent for its inhibitory effects scaled with the degree of MIR937 copy loss. Rescue assay confirmed miR-937-5p, a mature product of MIR937, was sufficient to restore its oncogenic function. Mechanistically, MIR937 amplification raised the expression of miR-937-5p, enhanced its binding to 3' UTR of FBXO16 transcript, and thereby restricting FBXO16 degradative effects on ULK1. Our results demonstrate that MIR937 amplification augments cell autophagy and proliferation, and suggest an alternative strategy of MIR937/FBXO16/ULK1 targeting for HGSOC treatment.

5-Fluorouracil (5-FU) is the leading chemotherapeutic drug used to treat hepatocellular carcinoma, one of the major cancer diseases after atherosclerosis. Because of chemo-resistance, the success rate of treatment declines with time due to continuous drug exposure. Though autophagy induction is majorly responsible for acquired resistance, the exact role of this evolutionary conserved mechanism is unknown in cancer cell survival and suppression. The usual practice involves the combinatorial use of chemotherapeutic drugs with autophagy inhibitors like Chloroquine and Bafilomycin A, while neglecting the side effects caused by autophagy impairment in healthy cells. Starvation is a well-known physiological inducer of autophagy. In this study, by caloric modulation, we tried to circumvent the resistance imposed by prolonged drug exposure and investigated the effect of 5-FU in nutrient-sufficient and deficient conditions. Our findings show a substantial correlation between autophagy and increased cancer cell death in the presence of 5-FU, with negligible effects on normal cells. Experimental data revealed that nutritional deprivation augmented cell death in the presence of 5-FU through mitochondrial membrane damage and excessive reactive oxygen species (ROS) production, initiating apoptosis. Lipidation study also unveiled that under such combinatorial treatment cellular metabolism shifts from glucose to lipid biosynthesis. Overall, our experimental findings suggest that nutritional deprivation in combination with chemotherapeutic medication can be a new effective strategy to control hepatocellular carcinoma.

Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.

Cancer remains a current active problem of modern medicine, a process during which cell growth and proliferation become uncontrolled. However, the role of autophagy in the oncological processes is counterintuitive and, at the same time, increasingly influential on the formation, development, and response to therapy of oncological diseases. Autophagy is a vital cellular process that removes defective proteins and organelles and supports cellular homeostasis. Autophagy can enhance the ability to form new tumors and suppress this formation in cancer. The dual potential of apoptosis may be the reason for this duality in either promoting or impeding the survival of cancer cells, depending on the situation, including starvation or treatment stress. Furthermore, long non-coding RNA NEAT1, which has been linked to several stages of carcinogenesis and in all forms of the illness, has drawn attention as a major player in cancer biology. NEAT1 is a structural portion of nuclear paraspeckles and has roles in deactivating expression in both transcriptional and post-transcriptional levels. NEAT1 acts in carcinogenesis in numerous ways, comprising interactions with microRNAs, the influence of gene articulation, regulation of epigenetics, and engagement in signalling cascades. In addition, the complexity of NEAT1's role in cancer occurrence is amplified by its place in regulating cancer stem cells and the tumor microenvironment. NEAT1's interaction with autophagy further complicates the already complicated function of this RNA in cancer biology. NEAT1 has been linked to autophagy in several types of cancer, influencing autophagy pathways and altering its stress response and tumor cell viability. Understanding the interrelation between NEAT1, autophagy, and cancer will enable practitioners to identify novel treatment targets and approaches to disrupt oncogenic processes, reduce the occurrence of treatment resistance, and increase patient survival rates. Specialized treatment strategies and regimens are thus achievable. In the present review, the authors analyze sophisticated relationship schemes in cancer: The NEAT1 pathway and the process of autophagy.

Eph receptor B2 (EPHB2) is overexpressed in some tumors and relevant to unfavorable outcomes of tumor patients. By searching Gene Expression Profiling Interactive Analysis and KM Plot websites, we discovered that EPHB2 was highly expressed in patients with esophageal cancer, leading to poor prognosis. However, the role and molecular mechanism of EPHB2 in esophagus cancer is unknown. Our study aims to unveil the underlying mechanism by which EPHB2 modulates the biological properties of esophagus cancer cells. After si-EPHB2 transfection, the malignant biological properties of esophagus cancer cells were determined by several biological experiments. IWP-4 was applied to block Wnt/β-catenin signaling pathway. The expressions of autophagy and Wnt/β-catenin signaling pathway relevant molecules were tested by western blot assay. An increased expression of EPHB2 was happened in esophagus cancer samples and loss of EPHB2 diminished esophagus cancer cells proliferation, migration, and invasion. Moreover, our data showed that depletion of EPHB2 blocked the autophagy and in-activated Wnt/β-catenin signaling pathway in esophagus cancer cells. While, IWP-4 treatment inhibited the autophagy and limited esophagus cancer cells proliferation, migration, and invasion. Moreover, EPHB2 knocked down strengthened the effect of IWP-4 treatment in regulating esophagus cancer cells proliferation, migration, and invasion. Finally, we illustrated that EPHB2 regulated the biological properties of esophagus cancer cells by modulating autophagy and Wnt/β-catenin signaling pathway. Our study illustrated that EPHB2 might be a worthwhile target considering for the treatment of esophagus cancer.

Clinical translation of autophagy modulators is tied to thoroughly acquainted with the precise state of this process and its regulators in a particular cancer. LC3Av1 is a marker of autophagosome membrane that has been contributed with pathobiology of myriad of human cancers. In the present study, we examined the effect of promoter methylation and miR-155 and LncRNA-GAS5 (GAS5) expression levels on transcription of LC3Av1 in AML patients. The study included 60 patients with de novo AML and 20 subjects with normal bone marrow cellular composition. Methylation-Sensitive high resolution melting (MS-HRM) was performed for analysis of LC3Av1 CpG island methylation and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for assessing LC3Av1, GAS5 and miR-155 expression levels. There was a significant elevation in the expression level of miR-155 and repression of LC3Av1 in AML samples. We found that LC3Av1 downregulation was negatively associated with its CpG island hypermethylation and miR-155 expression. Aging leads to overexpression of LC3Av1. GAS5 neither was differently expressed in AML patients compared to control samples nor has been related to LC3Av1 expression. The present study revealed that epigenetic changes like DNA methylation and alteration of miR-155 have a pivotal role in repression of autophagy marker LC3Av1, which potentially could provide the important clues of prognostic and therapeutic targets. The optimal strategies for clinical implementation of autophagy in AML is yet to be fully achieved and deserve further studies.

The online version contains supplementary material available at 10.1007/s12288-024-01765-3.

Clear cell renal cell carcinoma (ccRCC) is known as the most common and malignant histologic subtype of renal carcinoma. Sorting nexin 4 (SNX4) plays a regulatory role in recycling from endosomes to the plasma membrane and promotes autophagosome assembly and transport, which may exert the cancerous growth and progression. This study aimed to assess the biological role of SNX4 in ccRCC and their clinical association via public biological data platforms combined with experimental verification.

In our study, we analyzed the mRNA and protein expression of SNX4 in ccRCC under different clinicopathological characteristics through The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases. We used the Gene Expression Profiling Interactive Analysis (GEPIA) platform to conduct the survival analysis and figure out the immune cell infiltration level under different expression levels of SNX4 combined with Tumor Immune Estimation Resource (TIMER) database. Furthermore, we predicted competing endogenous RNA (ceRNA) regulatory network using TargetScan, miRDB, starBase and miRTarBase online databases. We totally collected six paired ccRCC tissues and adjacent tissues and applied quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) to detect the expression of SNX4 in the collected clinical specimens.

The mRNA and protein expression level of SNX4 was significantly lower in ccRCC than those in normal tissues. The results proposed that lower SNX4 was expressed in patients with higher histologic grade and in male patients. Kaplan-Meier analysis demonstrated that lower mRNA expression level of SNX4 was correlated with poorer prognosis. SNX4 had positive correlation with immune cell infiltrating levels and programmed cell death-ligand 1 (PD-L1) expression. Furthermore, we constructed the SNX4/miR-221-3p/miR-222-3p/DHRS4-AS1 axis, which may be the underlying ceRNA interaction network. Finally, we verified the reduced expression of SNX4 in ccRCC by qRT-PCR and WB.

The expression of SNX4 in ccRCC was lower than adjacent tissues and its downregulated expression was associated with poor prognosis of ccRCC patients. SNX4 may exert critical roles in the tumorigenesis, development and migration of ccRCC via various mechanisms.

Hydroxychloroquine sulfate (HCQ) is currently being repurposed for cancer treatment. The antitumor mechanism of HCQ is inhibition of cellular autophagy, but its therapeutic potential is severely limited by poor solubility, lack of tumor targeting and lower cellular uptake. Therefore, utilization of human H-chain apoferritin (HFn) composed only of heavy subunits is an attractive approach for tumor targeting drug delivery. This study focused on pH-triggered encapsulation of HCQ within the inner cavity of HFn to form HFn@HCQ nanoparticles for tumor-targeted drug delivery. Characterization using a range of techniques has been used to confirm the successful establishment of HFn@HCQ. HFn@HCQ exhibited pH-responsive release behavior, with almost no drug release at pH 7.4, but 80% release at pH 5.0. Owing to its intrinsic binding to transferrin receptor 1 (TfR1), HFn@HCQ was significantly internalized through TfR1-mediated endocytosis, with a 4.4-fold difference of internalization amount across cell lines. Additionally, HFn@HCQ enhanced the antitumor effect against four different cancer cell lines when compared against HCQ alone, especially in TfR1 high-expressing cells, where the inhibitory effect was 3-fold higher than free HCQ. The autophagy inhibition of HFn@HCQ has been demonstrated, which is a major pathway to induce cancer cell death. According to current findings, HFn based drug delivery is a promising strategy to target and kill TfR1 overexpressing tumor cells.

Lidamycin (LDM) has been confirmed to have a strong anti-pancreatic cancer effect and can affect the mitochondrial function of pancreatic cancer cells. Mitofusin-2 (Mfn2) is located in the outer membrane of mitochondria, and Mfn2 is currently believed to play a role in cancer inhibition in pancreatic cancer. In order to explore whether the anti-pancreatic cancer effect of LDM is related to Mfn2-mediated mitophagy, Bioinformatics and in vitro cell experiments are used for experimental research. The experimental results demonstrated that Mfn2 is correlated with mitochondrial autophagy in pancreatic cancer. Lidamycin can increase the expression of Mfn2 in pancreatic cancer and affect the process of EMT, affect the level of reactive oxygen species and mitochondrial membrane potential, and increase the expression of mitochondrial autophagy marker proteins BNIP3L and Beclin1. These results demonstrate that Mfn2 affects mitophagy in pancreatic cancer cells by regulating the expression of Mfn2.

Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.

Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.