Benzofuran-isatin conjugates are considered as promising compounds in cancer prevention and treatment. However, it is not known yet whether these compounds are useful to effectively treat multidrug-resistant tumors. In this study, we investigated the activity of G-5e, a novel benzofuran-isatin conjugate in a panel of cell lines exhibiting well-known drug resistance mechanisms (P-gp, BCRP, TP53, EGFR). P-glycoprotein overexpressing CEM/ADR5000 cell line displayed notable hypersensitivity (collateral sensitivity) to G-5e, which was mediated through autophagic cell death activation including downregulation of the autophagy suppressor RND2, upregulation of the autophagy inducer LC3B, and G0/G1 phase arrest during cell cycle progression. Independent of collateral sensitivity, transcriptomic analyses also revealed that G-5e caused downregulation of NF-κB and ERK1/2 pathways. Our findings highlight the potential of benzofuran-isatin conjugates to combat multidrug resistance and the role of RND2 for collateral sensitivity.

Anti-cancer drug's cytotoxicity is determined by their ability to induce predetermined cell demise, commonly called apoptosis. The cancer-causing cells are able to evade cell death, which has been affiliated with both malignancy as well as resistance to cancer treatments. In order to avoid cell death, cancerous tumour cells often produce an abundance of anti-apoptotic proteins, becoming "dependent" on them. Consequently, protein inhibitors of cell death may prove to be beneficial as pharmacological targets for the future creation of cancer therapies. This article examines the molecular routes of apoptosis, its clinical manifestations, anti-cancer therapy options that target the intrinsic mechanism of apoptosis, proteins that prevent cell death, and members of the B-lymphoma-2 subset. In addition, novel approaches to cell death are highlighted, including how curcumin mitigates chemotherapy-induced apoptosis in healthy tissues and the various ways melatonin modifies apoptosis to improve cancer treatment efficacy, particularly through the TNF superfamily. Cancer treatment-induced increases in anti-apoptotic proteins lead to drug resistance; yet, ligands that trigger cell death by inhibiting these proteins are expected to improve chemotherapy's efficacy. The potential of frequency-modulated dietary phytochemicals as a cancer therapeutic pathway, including autophagy and apoptosis, is also explored. This approach may be more efficient than inhibition alone in overcoming drug resistance. Consequently, this method has the potential to allow for lower medication concentrations, reducing cytotoxicity and unwanted side effects.

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

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

Globally, colorectal cancer (CRC) is the third most common type of cancer, and its treatment frequently includes the utilization of drugs based on antibodies and small molecules. The development of CRC has been linked to various signaling pathways, with the Wnt/β-catenin pathway identified as a key target for intervention.

We have explored the impact of imidazopyridine-tethered chalcone-C (CHL-C) in CRC models.

To determine the influence of CHL-C on apoptosis and autophagy, Western blot analysis, annexin V assay, cell cycle analysis, acridine orange staining, and immunocytochemistry were performed. Next, the activation of the Wnt/β-catenin signaling pathway and the anti-cancer effects of CHL-C in vivo were examined in an orthotopic HCT-116 mouse model.

We describe the synthesis and biological assessment of the CHL series as inhibitors of the viability of HCT-116, SW480, HT-29, HCT-15, and SNU-C2A CRC cell lines. Further biological evaluations showed that CHL-C induced apoptosis and autophagy in down-regulated β-catenin, Wnt3a, FZD-1, Axin-1, and p-GSK-3β (Ser9), and up-regulated p-GSK3β (Tyr216) and β-TrCP. In-depth analysis using structure-based bioinformatics showed that CHL-C strongly binds to β-catenin, with a binding affinity comparable to that of ICG-001, a well-known β-catenin inhibitor. Additionally, our in vivo research showed that CHL-C markedly inhibited tumor growth and triggered the activation of both apoptosis and autophagy in tumor tissues.

CHL-C is capable of inducing apoptosis and autophagy by influencing the Wnt/β-catenin signaling pathway.

Long noncoding RNAs (lncRNAs) are implicated in pulmonary hypertension (PH) progression. However, the underlying mechanisms remain largely unknown. Although mitophagy plays a crucial role in hypoxia-induced PH pathogenesis, the role of lncRNAs in mitophagy remains unclear. Especially, the mechanism of lncRNA encoded by the mitochondrial genome in regulating mitophagy needs to be elucidated. We explored the role of lncND5 in human pulmonary artery smooth muscle cells (PASMCs) and Sugen5416 plus hypoxia (SuHx)-induced PH mouse model in vitro and in vivo. LncND5 expression and localization were detected using real-time quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH). We investigated the molecular mechanism of lncND5 using western blotting, flow cytometry, RNA immunoprecipitation, RNA pulldown, transmission electron microscopy (TEM), immunofluorescence (IF), and echocardiography. Mitochondrial lncND5 expression was decreased under hypoxia in human PASMCs. Mechanistically, in the mitochondria, lncND5 maintains complex I activity by binding with mitochondrial ADH-ubiquinone oxidoreductase chain 5 (MT-ND5) at nucleotides 1086-1159 bp, thereby regulating mitochondrial reactive oxygen species (mROS) release and alleviating mitophagy. Additionally, lncND5 regulates mitophagy via cardiolipin (CL), which regulates complex I activity, inhibiting ROS release then relieving mitophagy. In the cytoplasm, lncND5 inhibits mitophagy by directly interacting with hydroxymethylglutaryl-CoA synthase 1 (HMGCS1). Notably, lncND5 is transported from the mitochondria to the cytoplasm and is mediated by TAR DNA-binding protein 43 (TDP-43). Our findings, for the first time, reveal that lncND5 may be a potential therapeutic approach for PH.

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

Colorectal cancer (CRC) is the third most common cancer in the world, with increasing incidence and mortality rates. Standard conventional treatments for CRC are surgery, chemotherapy, and radiotherapy. Recently, immunotherapy has been introduced as a promising alternative to CRC treatment that utilizes patients' immune system to combat cancer cells. The beneficial effect of immune checkpoint inhibitors, specifically anti-PD-1/ PD-L1, has been ascribed to the abundance of DNA replication errors that result in the formation of neoantigens. Such neoantigens serve as distinct flags that amplify the immune response when checkpoint inhibitors (ICIs) are administered. DNA replication errors in CRC patients are expressed as two statuses: the first is the deficient mismatch repair (MSI-H/dMMR) with a higher overall immune response and survival rate than the second status of patients with proficient mismatch repair (MSS/pMMR). There is a limitation to using anti-PD-1/PD-L1 as it is only confined to MSI-H/dMMR, where there is an abundance of T-cell inhibitory ligands (PD-L1). This calls for investigating new therapeutic interventions to widen the scope of ICIs' role in the treatment of CRC. Autophagy modulation provides a good example. Autophagy is a cellular process that plays a crucial role in maintaining cellular homeostasis and has been studied for its impact on tumor development, progression, and response to treatment. In this review, we aim to highlight autophagy as a potential determinant in tumor immune response and to study the impact of autophagy on the tumor immune microenvironment. Moreover, we aim to investigate the value of a combination of anti-PD-1/PD-L1 agents with autophagy modulators as an adjuvant therapeutic approach for CRC treatment.

Breast cancer, particularly triple-negative breast cancer (TNBC), poses a significant threat to women's health. In tumor cells, autophagy and apoptosis are double-edged swords, playing complex roles in cancer progression and treatment. This study aimed to investigate whether Terrestrosin D (TED) exerts antitumor effects on TNBC by modulating autophagy and apoptosis, and to elucidate the underlying molecular mechanisms.

The antiproliferative and pro-apoptotic effects of TED on TNBC cells were assessed using CCK-8, EdU assay, Live/Dead staining, and flow cytometry. Autophagy was monitored through immunofluorescence and confocal microscopy. RNA sequencing was performed to identify the pathways and molecular targets involved. The anti-TNBC effects of TED were further evaluated in vivo using tumor xenograft models. Western blotting was conducted to validate the relationship between PSMD1, P53, and TED-induced antitumor activity.

TED exhibited significant antitumor effects both in vitro and in vivo. Cellular phenotypic analyses revealed that TED promoted autophagy and apoptosis. Transcriptomic analyses indicated that TED stabilizes P53 expression and activates the P53 signaling pathway by inhibiting the function of PSMD1.

TED exhibits potent antitumor effects on TNBC by promoting autophagy and apoptosis. It achieves this through PSMD1 inhibition, stabilizing P53 expression, and activating the P53 pathway. Notably, this study is the first to demonstrate that TED directly targets PSMD1, a key proteasomal regulator, thereby unveiling a novel mechanism for P53 stabilization in TNBC. These findings provide new insights into the therapeutic modulation of the PSMD1 - P53 axis by natural compounds and support the development of TED as a multi-functional agent for aggressive breast cancers.

Platinum-based chemotherapy is limited by drug resistance and severe adverse effects. Although the DNA damage response (DDR) is known to affect drug sensitivity across cancer types, the role of its upstream regulator ATM in modulating cisplatin (DDP) resistance remains unclear. In this study, we investigated the role of the ATM/DDR pathway to DDP resistance and proposed a potential targeted strategy. Bioinformatics analysis revealed significant overexpression of ATM and RAD51 in liver and lung cancers, which correlated with poor survival (p < 0.05). In vitro assays showed that DDP activated ATM to initiate the downstream DDR, thereby promoting chemoresistance; inhibition of ATM using KU-55933 or siRNA enhanced the anticancer effect of DDP. Among screened Shikonin derivatives, acetyl alkannin emerged as the most potent ATM-targeting analogue. Combination treatment with low-dose acetyl alkannin (2.5 μM or 2.6 μM) and DDP increased DDP sensitivity 8.0-fold in Huh-7 liver cancer cells and 22.5-fold in A549 lung cancer cells. Mechanistically, acetyl alkannin targets ATM and induces its caspase-dependent degradation, suppressing DDR signaling and promoting apoptosis. In vivo xenograft experiments confirmed the superior tumor growth inhibition of the combination treatment. These findings establish ATM-mediated DDR activation as a central mechanism of DDP resistance and identify acetyl alkannin as a candidate sensitizer for platinum-based chemotherapy.

Cell death occurs continuously throughout individual development. By removing damaged or senescent cells, cell death not only facilitates morphogenesis during the developmental process, but also contributes to maintaining homeostasis after birth. In addition, cell death reduces the spread of pathogens by eliminating infected cells. Cell death is categorized into two main forms: necrosis and programmed cell death. Programmed cell death encompasses several types, including autophagy, pyroptosis, apoptosis, necroptosis, ferroptosis, and PANoptosis. Autophagy, a mechanism of cell death that maintains cellular equilibrium via the breakdown and reutilization of proteins and organelles, is implicated in regulating almost all forms of cell death in pathological contexts. Notably, necroptosis, ferroptosis, and PANoptosis are directly classified as autophagy-mediated cell death. Therefore, regulating autophagy presents a therapeutic approach for treating diseases such as inflammation and tumors that arise from abnormalities in other forms of programmed cell death. This review focuses on the crosstalk between autophagy and other programmed cell death modalities, providing new perspectives for clinical interventions in inflammatory and neoplastic diseases.

Abnormalities in glucose metabolism have been shown to characterize malignant tumors. Glucose depletion by glucose oxidase (GOD) has shown great potential in tumor therapy by causing tumor starvation. Since 2017, nanomedicines have been designed and utilized to deliver GOD for more precise and effective glucose modulation, which can overcome intrinsic limitations of different cancer therapeutic modalities by remodeling the tumor microenvironment to enhance antitumor therapy. To date, the topic of GOD-delivering nanomedicines for enhancing tumor therapy has not been comprehensively summarized. Herein, this review aims to provide an overview and discuss in detail recent advances in GOD delivery and directly involved starvation therapy strategies, GOD-sensitized various tumor therapy strategies, and GOD-mediated multimodal antitumor strategies. Finally, the challenges and outlooks for the future progress of the emerging tumor therapeutic nanomedicines are discussed. This review provides intuitive and specific insights to a broad audience in the fields of nanomedicines, biomaterials, and cancer therapy.

Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.

Sinularin is a natural product extracted from soft coral and is shown to exhibit antitumor effects against multiple human cancers. We previously showed that Sinularin induces apoptotic cell death via stabilizing the FOXO3 protein in prostate cancer cells. In this study, we demonstrated that Sinularin triggers autophagy via two different mechanisms in prostate cancer cells. First, Sinularin reduced the S757 phosphorylation of ULK1 protein, which was mediated by mTOR, leading to ULK1 activation and autophagy initiation. Second, Sinularin enhanced the expression of autophagic protein ATG4A, which is the key regulator in the formation of autophagosome, through a FOXO3-dependent transcriptional mechanism. Next, we identified that ATG4A is a new target gene of the transcription factor FOXO3. Additionally, we also found that Sinularin-induced autophagy promoted survivin degradation and led to cell apoptosis. Taken together, these findings suggest that Sinularin induces prostate cancer cell autophagy by promoting autophagy initiation through activation of ULK1 and formation of autophagosome through the FOXO3-ATG4A pathway.

Cardiovascular diseases (CVDs) remain a global health challenge, with programmed cell death (PCD) mechanisms like apoptosis and necroptosis playing key roles in the progression. Circular RNAs (circRNAs) have recently been recognized as crucial regulators of gene expression, especially in modulating PCD. In current researches, circRNA regulation of apoptosis is the most studied area, followed by autophagy and ferroptosis. Notably, the regulatory role of circRNAs in pyroptosis and necroptosis has also begun to attract attention. From a mechanistic perspective, circRNAs influence cellular processes through several modes of action, including miRNA sponging, protein interactions, and polypeptide translation. Manipulating circRNAs and their downstream targets through inhibition or overexpression offers versatile therapeutic options for CVD treatment. Continued investigation into circRNA-mediated mechanisms may enhance our understanding of CVD pathophysiology and underscore their potential as novel and promising therapeutic targets.

Acute myeloid leukemia (AML) is the most prevalent kind of acute leukemia in adults. Despite the availability of new targeted therapies, AML remains connected with a poor prognosis and decreased rate of survival. Tubeimoside I (TBMS1), a critical compound extracted from Bolbostemma paniculatum, has demonstrated potential anticancer effects in lung and colorectal cancers. Nevertheless, the TBMS1 anticancer pathway against AML is still elusive. This study aimed to explore the potential role of TBMS1 in anti-AML and its molecular mechanism. In vitro, TBMS1 treatment suppressed AML cells proliferation, induced apoptosis, and mitochondrial damage, and elevated ROS levels. Network pharmacological analysis suggested, and subsequent studies confirmed, that TBMS1 induced mitophagy in AML cells by modulating the PINK1/Parkin/Mfnh2 signaling pathway, an effect that was effectively reversed following PINK1 knockdown. In vivo, TBMS1 treatment suppressed the proliferation of AML cells after 21 days, improved the survival rates of nude mice, and showed no evident organ toxicity. These evidences suggest that TBMS1 may have significant therapeutic potential in treating AML.

Oral squamous cell carcinoma (OSCC) is a prevalent type of head and neck neoplasm distinguished by a high risk of metastasis and a poor prognosis. Nevertheless, the fundamental mechanisms of OSCC cell proliferation and metastasis remain poorly understood. Autophagy, as the principal intracellular degradation system, has been implicated in OSCC progression; however, its underlying mechanism remains unclear. In this study, transcriptomic sequencing analysis was performed using both The Cancer Genome Atlas (TCGA) database and samples from OSCC patients and revealed significant upregulation of EPHB2 expression, which is positively correlated with OSCC metastasis and a poor prognosis. In subsequent studies, we observed that the knockdown of EPHB2 resulted in the blockade of autophagic flux due to impaired lysosomal function, leading to inhibited proliferation, migration, and invasion in OSCC cells. Furthermore, the knockdown of EPHB2 significantly suppressed the expression of VPS4A, a key mediator that facilitates autolysosomal degradation. The overexpression of VPS4A restored lysosomal function and autophagic flux, thereby attenuating the inhibitory effects of EPHB2 knockdown on OSCC cell progression. The findings of this study demonstrate that the molecular mechanism underlying EPHB2 regulation of autophagic flux to promote OSCC progression is by regulating VPS4A activity and that EPHB2 may be a diagnostic biomarker and therapeutic target for OSCC prevention and treatment.

The lysosome is transformed from a major degradative site to a dynamic regulator of cellular homeostasis. Cancer cells with altered redox environments could be exploited as potential targets for cancer therapy. The thioredoxin (Trx) system, which includes thioredoxin reductases (TrxRs), is a promising target for cancer drug development. Here, by identifying the natural product isowalsuranolide (Hdy-7), we showed that lysosomal biogenesis and autophagy are elicited by Hdy-7 via the inhibition of TrxRs. The attenuation of cellular TrxR activity led to the accumulation of ROS, which are indispensable for p53 activation and subsequent lysosomal biogenesis mediated by the transcription factor TFEB/TFE3. Knockdown of TrxR1/2 led to activation of TFEB/TFE3, thereafter increasing lysosomal biogenesis. Treatment with the ROS scavenger NAC or knockdown of p53 or SESN2 led to attenuation of the nuclear translocation of TFEB/TFE3, lysosomal biogenesis, and autophagic flux, suggesting that the TrxR1/2-p53-TFEB/TFE3 axis plays a role in maintaining lysosomal homeostasis under stress conditions other than starvation. Surprisingly, pharmacological inhibition or genetic ablation of autophagy prevented Hdy-7-induced cell death, suggesting that Hdy-7-induced autophagy is detrimental to cancer cells. Our study revealed that Hdy-7 induces ROS-mediated lysosomal biogenesis and retards cell growth by targeting TrxR1/2. This study highlights the lysosome as a regulatory hub for cellular homeostasis and as an attractive therapeutic target for a variety of lysosome-related diseases, including cancer.

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.

Persistent upregulation of autophagy contributes to tumour cells' resistance to EGFR-TKI therapy, and hence, inhibiting autophagy could be a valuable strategy for overcoming such resistance.

This study investigated the effects of liensinine in EGFR-TKI resistant lung adenocarcinoma (LUAD) and to explore the underlying mechanism.

CCK-8 assay, colony formation, EdU assay and apoptosis assays were conducted for investigating the effect of EGFR-TKI and liensinine combination treatment in LUAD. Furthermore, autophagic flux were detected by western blot, fluorescence assays and TEM. In addition, by employing a DARTS approach, a CETSA assay, and SPR analysis, we identified DRP1 as a target of liensinine. Finally, by establishing a xenograft model of the disease, the impact of combination treatment in vivo was assessed.

In vitro and in vivo experiments revealed that the novel autophagy inhibitor liensinine enhanced the sensitivity of LUAD to EGFR-TKIs. This effect was achieved by inhibiting autophagic flux. We then examined whether liensinine inhibits autophagic flux through the impairment of autophagosome and autolysosome degradation. Furthermore, we identified DRP1 as a target of liensinine. The activation of DRP1 by liensinine through dephosphorylation at Ser637 promotes the accumulation of autophagosomes and autolysosomes while simultaneously blocking autophagic flux, thereby enhancing the cancer cell-killing effects of EGFR-TKIs.

Our study validated the efficacy of liensinine in overcoming EGFR-TKI resistance and elucidated the mechanism underlying liensinine's inhibition of autophagy.

Acute myeloid leukaemia (AML) is a prevalent haematologic malignancy characterized by significant heterogeneity. Despite the application of aggressive therapeutic approaches, AML remains associated with poor prognosis. Circular RNAs (circRNAs) constitute a unique class of single-stranded RNAs featuring covalently closed loop structures that are ubiquitous across species. These molecules perform crucial regulatory functions in the pathogenesis of various diseases through diverse mechanisms, including acting as miRNA sponges, interacting with DNA or proteins, and encoding functional proteins/polypeptides. Recently, numerous circRNAs have been confirmed to have aberrant expression patterns in AML patients. In particular, certain circRNAs are closely associated with specific clinicopathological characteristics and thus have great potential as diagnostic/prognostic biomarkers and therapeutic targets in AML. Herein, we systematically summarize the biogenesis, degradation, and functional mechanisms of circRNAs while highlighting their clinical relevance. We also outline a series of online databases and analytical tools available to facilitate circRNA research. Finally, we discuss the current challenges and future research priorities in this evolving field.

Dysregulated autophagy has been implicated in the pathogenesis of numerous diseases, including cancer. Despite extensive research on the underlying mechanisms of autophagy, the involvement of long non-coding RNAs (lncRNAs) remains poorly understood. Here, we demonstrate that a previously identified lncRNA, HITT (HIF-1α inhibitor at the translation level), is closely associated with biological processes such as autophagy through unbiased bioinformatic analysis. Subsequent studies demonstrate that HITT is increased by several autophagic stimuli, including PI-103, a potent inhibitor of PI3K and mTOR. This is caused by a reduction in the binding between HITT and AGO2, resulting in a reduction in the activity of miR-205 towards HITT degradation. Increased HITT then binds to a key autophagy protein, Autophagy-related 5 (ATG5), and inhibits autophagosome formation by preventing the formation of the ATG12-ATG5-ATG16L1 complex. This results in HITT sensitizing PI-103-mediated cell death both in vitro and in vivo in nude mice by attenuating protective autophagy. The data presented herein demonstrate that HITT is a newly identified RNA regulator of autophagy and that it can be used to sensitize the colon cancer response to cell death by blocking the protective autophagy.

Pancreatic ductal adenocarcinoma is a highly aggressive cancer with a low survival rate. Thus, efforts are needed to develop more effective treatments. Herein, we propose utilizing magnetic nanoparticles (MNP) for the concurrent delivery of gemcitabine and miRNA34a mimic to target pancreatic cancer cells. The MNP were functionalized with disulfide bonds to selectively release their cargo inside tumor cells. The incorporation of the miRNA34a mimic increased the sensitivity of cells to gemcitabine, especially in BxPC-3 cells. Additionally, the miRNA34a sequence was modified with locked nucleic acids (LNA) to increase stability. The resulting LNA34a showed a stronger cytotoxic effect when combined with gemcitabine, even in PANC-1 cells, which are resistant to the drug. Notably, the modified MNP exhibited less toxicity than their free counterparts when incubated with HaCaT cells, a model of healthy keratinocytes. Additionally, the combined delivery of miRNA34a mimics and gemcitabine using MNP elicited a synergistic cytotoxic effect against pancreatic cancer cells through magnetic hyperthermia. The intratumoral administration of the modified MNP in subcutaneous xenografts of BxPC-3 cells resulted in a sustained increase in temperature when an alternating magnetic field was applied. Notably, the treatment with the MNP functionalized with GEM and LNA34a led to significant changes in the expression of NOTCH1 and NOTCH2 in the tumor, which are direct targets of miRNA34a, as well as HSP70, which is related to the cellular response to stressors like heat.

With the rise of immunotherapy, the treatment approach for non-small cell lung cancer (NSCLC) has undergone revolutionary changes. However, the prognosis for NSCLC patients has not been significantly improved due to the development of acquired drug resistance. Therefore, there is an urgent need to develop new and more effective drugs for treating NSCLC or improving tumor treatment resistance. Traditional Chinese medicine (TCM) has been gradually incorporated into the combined treatment of NSCLC. Its active components (also known as natural products) exhibit novel structures, multi-target effects, diverse pathways, minimal toxicity, and varied biological activities, which play a therapeutic role in various diseases. Thus, natural products hold great potential for future clinical applications.

Screening main traditional plants widely used in NSCLC and their derived natural products, as well as exploring the mechanisms by which these natural products act on NSCLC-particularly focusing on their applications-can provide valuable insights for the development of therapeutic drugs targeting NSCLC.

A comprehensive, computerized literature search was conducted in PubMed, Embase, Web of Science, Cochrane Library, CNKI Scholar, the American Chemical Abstracts, and Wanfang Database up to June 2024, using the following keywords: "traditional Chinese medicine", "herbal medicine", "medicinal plants", and "herbal", paired with terms such as "non-small cell lung cancer", "therapy", "natural products", and "active ingredient".

Summarizing current research findings, we discovered eleven medicinal plants containing a total of fourteen natural products. Natural products have a significant impact on tumor progression in NSCLC, including apotosis, autophagy, pyrotosis, cell-cycle arrest and metasis. Moreover, natural products can modulate the activities of various immune cells and reshape the immune microenvironment. Combined with conventional cancer treatments, natural products demonstrate promising therapeutic effects and effectively reverse drug resistance. Furthermore,the use of nano-drug delivery systems to address limitations associated with natural products.

This review summarizes eleven medicinal plants containing a total of fourteen natural products that can enhance NSCLC treatment and indicates their action mechanisms. Furthermore, we also discuss limitations of natural products and explore the use of nano-drug delivery systems to address limitations associated with natural products.

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.

Circular RNAs (circRNAs) are pivotal regulators in cancer, and circFOXP1 has been implicated in tumorigenesis. This study explores the exosome-mediated transfer of circFOXP1 and its functional protein product, p196, in hepatocellular carcinoma (HCC) progression.

HCC circRNA datasets were obtained from the Gene Expression Omnibus (GEO) databases, and circRNAs were validated via qRT-PCR and Sanger sequencing. Exosomes were isolated via ultracentrifugation and characterized by TEM/NTA. RIP, Co-IP, RNA pull-down and in vitro binding assays were employed to determine molecular interactions. Loss- and gain-of-function assays were employed to evaluate the effects of circFOXP1, KHDRBS3 and ULK1 on the proliferation, and invasion abilities of HCC cells both in vitro and in vivo.

CircFOXP1, which encoded a 196-amino acid protein, p196, was highly expressed in HCC tissues and cells and secreted via exosomes. Overexpression of p196 enhanced HCC cell proliferation, invasion, and autophagy flux in vitro, while knockdown produced opposite effects. Mechanistically, p196 directly bound KHDRBS3 through its D2 domain, forming a complex that stabilized ULK1 mRNA, thereby increasing ULK1 protein levels, activating autophagy and accelerating tumor progression.

Our findings indicated that circFOXP1-encoded p196 plays a role as a tumor promoter, contributing to the malignant progression of HCC. Targeting the circFOXP1/p196-KHDRBS3-ULK1 axis presents a promising therapeutic strategy for HCC, with potential applications in biomarker development and combination therapies.

Cancer remains the leading cause of death worldwide. The treatment of cancer has become increasing complex. Current treatment options for cancer include surgical resection, chemotherapy, radiotherapy, nanomedicine, and immunotherapy. Recent experimental and clinical studies have provided substantial evidence supporting the potential use of melatonin as a preventive and therapeutic agent in oncology. Melatonin (N-acetyl-5-methoxy-tryptamine), a pleiotropic and multitasking molecule, is secreted from the pineal gland during the night under normal light-dark conditions. Beyond its role in circadian regulation, melatonin exhibits antioxidant, anti-aging, immunomodulatory, and anti-cancer properties. Melatonin exerts significant apoptotic, angiogenic, oncostatic, and anti-proliferative effects on a variety of cancer cells. This review discusses the influence of melatonin on cancer cells through mechanisms involving cell cycle regulation, stimulation of apoptosis, autophagy induction, epigenetic modification, and transcriptional regulation.

Non-coding RNAs (ncRNAs), as critical regulators of gene expression, play a pivotal role in the modulation of pyroptosis and exhibit a close association with a wide range of diseases. Pyroptosis is a form of programmed cell death mediated by inflammasomes, characterized by cell membrane perforation, release of inflammatory cytokines, and a robust immune response. Recent studies have revealed that ncRNAs influence the initiation and execution of pyroptosis by regulating the expression of pyroptosis-related genes or modulating associated signaling pathways. This review systematically summarizes the molecular mechanisms and applications of ncRNAs in diseases such as cancer, infectious diseases, neurological disorders, cardiovascular diseases, and metabolic disorders. It further explores the potential of ncRNAs as diagnostic biomarkers and therapeutic targets, elucidates the intricate interactions among ncRNAs, pyroptosis, and diseases, and provides novel strategies and directions for the precision treatment of related diseases.

Osteosarcoma (OS) remains a challenging malignancy with poor prognosis, especially in metastatic or recurrent cases. Despite progress, the molecular mechanisms driving OS, particularly the regulation of autophagy, are not fully understood. Here, through integrated analysis of single-cell and transcriptomic data, we identify a novel long non-coding RNA (lncRNA), OLMALINC, as a critical autophagy regulator in OS. OLMALINC is significantly upregulated in OS tissues, with its expression correlating to poor clinical outcomes. Functional studies show that altering OLMALINC expression impacts OS cell progression and autophagy. Mechanistically, transcriptome analysis and RNA immunoprecipitation reveal Ubiquitin-Specific Peptidase 1 (USP1) as a direct downstream target of OLMALINC. The OLMALINC-USP1 axis inhibits autophagy and activates the hypoxia-inducible factor 1 (HIF-1α) pathway, promoting OS progression. Therapeutically, combining the USP1 inhibitor ML-323 with doxorubicin demonstrated synergistic anti-tumor effects in vitro and in vivo, enhancing autophagy and apoptosis while inhibiting tumor growth. These findings uncover a novel OLMALINC-USP1-HIF-1α axis in OS progression and highlight the potential of combining autophagy modulation with chemotherapy for improved therapeutic outcomes.

Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and its subsequent delivery to lysosomes for degradation and recycling. In Caenorhabditis elegans, autophagy participates in diverse processes such as stress resistance, cell fate specification, tissue remodeling, aging, and adaptive immunity. Genetic screens in C. elegans have identified a set of metazoan-specific autophagy genes that form the basis for our molecular understanding of steps unique to the autophagy pathway in multicellular organisms. Suppressor screens have uncovered multiple mechanisms that modulate autophagy activity under physiological conditions. C. elegans also provides a model to investigate how autophagy activity is coordinately controlled at an organismal level. In this chapter, we will discuss the molecular machinery, regulation, and physiological functions of autophagy, and also methods utilized for monitoring autophagy during C. elegans development.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent growth. Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux and dependency, and concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK-MAPK pathway inhibitors can synergistically block PDAC growth. However, CQ is limited in terms of specificity and potency. To find alternative anti-autophagy strategies, in this study, we performed a CRISPR-Cas9 loss-of-function screen in PDAC cell lines that identified the lipid kinase phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) as a growth-promoting gene. PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment. PIKfyve inhibition caused lysosomal dysfunction, reduced autophagic flux, and led to the accumulation of autophagy-related proteins. Furthermore, PIKfyve inhibition blocked the compensatory increases in autophagic flux associated both with MEK inhibition and with direct RAS inhibition. Accordingly, combined inhibition of PIKfyve and the RAS-MAPK pathway showed robust growth suppression across a panel of KRAS-mutant PDAC models. Growth suppression was due, in part, to potentiated cell-cycle arrest and induction of apoptosis following loss of inhibitor of apoptosis proteins. These findings indicate that concurrent inhibition of RAS and PIKfyve is a synergistic, cytotoxic combination that may represent a therapeutic strategy for PDAC. Significance: PIKfyve inhibition effectively blocks autophagy in multiple models of KRAS-mutant pancreatic cancer and can synergize with inhibitors of members of the RAS-MAPK pathway, providing an effective combination strategy for pancreatic cancer.

In recent years, significant progress has been made in the management of genitourinary cancers, primarily due to advancements in surgical techniques, the emergence of targeted therapy and immunotherapy, and the refinement of chemotherapy agents. However, despite the expanding arsenal of treatment modalities, some patients still face challenges associated with drug resistance, which hinders efforts to improve survival rates. Circular RNAs (circRNAs) are covalently closed RNA molecules with a stable structure and a unique ability to form reverse splicing loops. Increasing evidence suggests that abnormal expression of circRNAs is significantly correlated with the occurrence of genitourinay cancers, indicating their potentials as diagnostic and prognostic biomarkers, as well as new targets for treatment. Although research on circRNAs in genitourinary cancers has progressed, it is still in the preliminary stage. This review summarizes the properties and functions of circRNAs, focusing on their molecular and cellular mechanisms involved in mediating cancer-related drug resistance in the genitourinary system, including autophagy, epithelial-mesenchymal transition, and glycolysis, etc. The clinical potential of circRNAs in regulating drug resistance is also carefully discussed.

Pancreatic cancer remains fatal because of resistance to chemo-, radio-, and immunotherapies. Carbon-ion radiotherapy (CIRT) has been beneficial for patients with pancreatic cancer. The purpose of this study was to identify the mechanism by which CIRT exerts its anticancer activity, particularly in combination with immunotherapy.

We implanted murine pancreatic cancer cells treated with CIRT and autophagy inhibitor HCQ (CIRT+HCQ) into syngeneic mice, followed by the application of a regulatory T (Treg) cell blockade using immune-checkpoint inhibitors. We compared CIRT+HCQ-treated tumors with those implanted without any treatment. Further, we also implanted CIRT+HCQ-treated pancreatic tumors into CD8+ T cell-depleted mice. To characterize immunological alterations, we conducted immunohistology and flow cytometry of implanted tumors.

CIRT+HCQ-treated tumors exhibited reduced growth, higher numbers of CD8+ T cells, and lower numbers of Treg cells compared with control tumors. CD8+ T cell depletion restored growth in CIRT+HCQ-treated tumors. A Treg blockade resulted in greater tumor growth remission and elevated levels of intratumor CD8+ T cells in mice bearing CIRT+HCQ-treated tumors but not in mice bearing control tumors.

Treg cell-targeted therapy exerted an anticancer effect in mice bearing CIRT+HCQ-treated tumors but not in those bearing untreated pancreatic tumors by activating cancer-specific CD8+ T cells.

Colorectal cancer (CRC) is among the most malignant pathologies worldwide. A major factor contributing to the poor prognosis of neoplastic diseases is the development of drug resistance. It significantly reduces the utility of most therapeutic protocols and necessitates the search for novel biomarkers and treatment strategies to combat cancer. An evolutionarily conserved catabolic mechanism, autophagy maintains nutrient recycling and metabolic adaptation and is also closely related to carcinogenesis, playing a dual role. Autophagy inhibition can limit the growth of tumors and improve the response to cancer therapeutics. Lysosomes, key players in autophagy, are also considered promising targets for anticancer treatment. There are still insufficient data on the role of poorly studied glycoproteins related to autophagy, such as the lysosome-associated membrane glycoproteins (LAMPs). They can act as multifunctional molecules involved in a multitude of processes like autophagy and cancer development. In the current review, we summarize the recent data on the double-faceted role of autophagy in cancer with a focus on drug resistance in CRC and on the roles of lysosomes and LAMPs in these interconnected processes. Several lysosomotropic drugs are discussed as options to overcome cancer cell chemoresistance. The complex networks that underline defined autophagic pathways in the context of CRC carcinogenesis and the role of autophagy, especially of LAMPs as drivers of drug resistance, are outlined.

The tumor microenvironment (TME) of gliomas comprises glioma cells and surrounding cells, such as astrocytes, macrophages, T cells, and neurons. In the TME, glioma cells can activate normal human astrocytes (NHAs) through the secretion of exosomes and the activation of astrocytes can further improve the progression of glioma, leading to a poor prognosis for patients. However, the molecular mechanisms underlying NHAs activation by gliomas remain largely unknown. It this study, glioma-derived exosomes (GDEs) play an important role in the modulation of autophagy and activation of NHAs. Compared with normoxic GDEs, hypoxic glioma-derived exosomes (H-GDEs) further improved autophagy and activation of astrocytes, which strongly promoted the progression of glioma cells. In an miRNA array between two types of exosomes from gliomas, miR-423-3p was highly expressed in H-GDEs and played an important role in autophagy, resulting in the activation of NHAs. The mechanism by which hypoxic glioma cells react with NHAs to create an immunosuppressive microenvironment was identified and 15d-PGJ2 was established as an effective inhibitor of miR-423-3p to suppress NHAs activation. These findings provide new insights into the diagnosis and treatment of gliomas by targeting autophagy and miR-423-3p expression.

Melanoma, one of the most lethal cancers, demands urgent and effective treatment strategies. However, a successful therapeutic approach requires a precise understanding of the mechanisms underlying melanoma initiation and progression. This review provides an overview of melanoma pathogenesis, identifies current pathogenic factors contributing to mortality, and explores targeted therapy and checkpoint inhibitor therapy. Furthermore, we examine melanoma classification and corresponding therapies, along with advancements in various cell death mechanisms for melanoma treatment. We also discuss the current treatment status along with some drawbacks encountered during research stages such as resistance and metastasis.