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.

Nuclear receptor coactive 4 (NCOA4) is a specific receptor for ferritinophagy, transporting ferritin to lysosomal degradation, releasing free iron, and excessive iron levels may lead to cellular redox imbalance, contributing to cell death, predominantly ferroptosis. NCOA4 is regulated by a variety of transcriptional, post-transcriptional, translational, and post-translational modifications. Targeted modulation of NCOA4-mediated ferritinophagy has been successfully used as a therapeutic strategy in several disease models. Recent evidences have elucidated that ferritinophagy and ferroptosis played a major role in heavy metals toxicity. In this review, we explored the regulatory mechanism of NCOA4 as the sole receptor for ferritinophagy from multiple perspectives based on previous studies. The significant role of ferritinophagy-mediated ferroptosis in heavy metals toxicity was discussed in detail, emphasizing the great potential of NCOA4 as a target for heavy metals toxicity.

Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients.Abbreviation: AMPK: AMP-activated protein kinase; ASOs: antisense oligonucleotides; CAD: carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; DC: dendritic cell; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; ERBB2: erb-b2 receptor tyrosine kinase 2; ESCRT: endosomal sorting complex required for transport; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; GRB2: growth factor receptor bound protein 2; LPP: lipopolyplex; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; NSCLC: non-small cell lung cancer; PADC: pancreatic ductal adenocarcinoma; PDPK1: 3-phosphoinositide dependent protein kinase 1; PI3K: phosphoinositide 3-kinase; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns(3,4,5)P3: phosphatidylinositol-(3,4,5)-trisphosphate; PtdIns(4,5)P2: phosphatidylinositol-(4,5)-bisphosphate; PTT: photothermal therapies; RAC1: Rac family small GTPase 1; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RTKs: receptor tyrosine kinases; SREBF: sterol regulatory element binding transcription factor; TFEB: transcription factor EB; TNBC: triple-negative breast cancer; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system.

Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature.

Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy.

In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

Breakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain-containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.

To develop novel PI4KIIIβ inhibitors and explore their antitumor activity, a series of 5-phenylthiazol-2-amine derivatives were synthesized by structural modifications of PIK93. Biological assay results indicated that compounds 16 and 43 exhibited superior PI4KIIIβ selective inhibitory and antiproliferative activity than PIK93. Mechanistic studies revealed that the two compounds inhibit the PI3K/AKT pathway more effectively, thereby inducing cancer cell apoptosis, cycle arrest in the G2/M phase and autophagy. Importantly, in vivo toxicity and pharmacodynamics studies showed that compounds 16 and 43 exhibited superior safety to that of commercially available PI3K/AKT axis inhibitor alpelisib, and obviously antitumor activity in small cell lung cancer H446 xenograft models. Overall, this work highlights the therapeutic potential and safety of PI4KIIIβ inhibitors 16 and 43 in the treatment of tumors, and provides candidates and viable drug development strategies for the treatment of small cell lung cancer and the development of novel PI3K/AKT axis inhibitors.

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.

Progression to castration resistance is the leading cause of death in prostate cancer patients. Long non-coding RNAs (lncRNAs) have recently become a focal point in the regulation of cancer development. However, few lncRNAs associated with castration-resistant prostate cancer (CRPC) have been reported.

Firstly, we explore the CRPC associated lncRNAs by RNA sequencing and validated using quantitative polymerase chain reaction (qRT-PCR) and RNA fluorescence in situ hybridization (RNA-FISH). The clinical significance of FLJ was evaluated in a collected cancer cohort. Functional loss assays were performed to assess the effects of FLJ on CRPC cells both in vitro and in vivo. The regulatory mechanism of FLJ was investigated using immunohistochemistry (IHC), qRT-PCR, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) assays.

FLJ is highly expressed in CRPC and is associated with higher stages and Gleason scores in prostate cancer. FLJ is strongly positively correlated with androgen receptor (AR), which acts as a transcription factor and directly binds to the FLJ promoter region to enhance its transcription. Knockdown of FLJ inhibits CRPC cell proliferation and increases sensitivity to castration and enzalutamide (ENZA) in vitro. Mechanistically, FLJ promotes castration resistance in prostate cancer cells by inhibiting AR nuclear import and cytoplasmic protein degradation, thereby activating the androgen-independent AR signaling pathway. Importantly, in vivo experiments showed that FLJ knockdown inhibited tumor growth and enhanced the therapeutic effect of ENZA.

This study identifies a novel regulatory mechanism by which lncRNA FLJ promotes CRPC progression. Sustained AR activation in CRPC acts as a transcription factor to upregulate FLJ expression. FLJ circumvents the traditional androgen-dependent survival mechanism by inhibiting AR nuclear entry and cytoplasmic protein degradation, thereby activating the AR signaling pathway. Targeting the FLJ-AR signaling axis may represent a novel therapeutic strategy for patients with castration-resistant prostate cancer.

The activation of STING1 can lead to the production and secretion of cytokines, initiating antitumor immunity. Here, we screened an ion channel ligand library and identified tetrandrine, a bis-benzylisoquinoline alkaloid, as an immunological adjuvant that enhances antitumor immunity by preventing the autophagic degradation of the STING1 protein. This tetrandrine effect is independent of its known function as a calcium or potassium channel blocker. Instead, tetrandrine inhibits lysosomal function, impairing cathepsin maturation, and autophagic degradation. Proteomic analysis of lysosomes identified TAX1BP1 as a novel autophagic receptor for the proteolysis of STING1. TAX1BP1 recognizes STING1 through the physical interaction of its coiled-coil domain with the cyclic dinucleotide binding domain of STING1. Systematic mutation of lysine (K) residues revealed that K63-ubiquitination of STING1 at the K224 site ignites TAX1BP1-dependent STING1 degradation. Combined treatment with tetrandrine and STING1 agonists promotes antitumor immunity by converting "cold" pancreatic cancers into "hot" tumors. This process is associated with enhanced cytokine release and increased infiltration of cytotoxic T-cells into the tumor microenvironment. The antitumor immunity mediated by tetrandrine and STING1 agonists is limited by neutralizing antibodies to the type I interferon receptor or CD8+ T cells. Thus, these findings establish a potential immunotherapeutic strategy against pancreatic cancer by preventing the autophagic degradation of STING1.

Several studies have suggested a potential antitumor effect of 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD). To further understand the mechanism of action of this compound, we investigated its effect on the phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. We show that DMDD application significantly inhibited the proliferation of breast cancer cell lines MDA-MB-231 and ER-α positive MCF-7. Furthermore, DMDD application resulted in increased intracellular reactive oxygen species (ROS) levels, apoptosis and autophagy, whereas it downregulated the expression of PI3K, Akt and mTOR mRNA and proteins, and increased the expression of LC3II/I and p62 proteins. In a mouse breast cancer xenograft model, DMDD inhibited tumor growth. Expression analyses suggest that ROS levels were higher in DMDD treated tumor tissues, whereas immunohistochemical analyses suggest that apoptotic cells were more prevalent in the DMDD treated group compared to the control group. Taken together, our results suggest that the molecular mechanism of action of DMDD may involve the enhancement of breast cancer autophagy through the PI3K/Akt/mTOR signaling pathway by mediating ROS expression.

Niclosamide is an established anthelmintic substance and a promising candidate for treating cancer, viral infections, and other diseases. However, its solubility in aqueous media is low, and the systemic bioavailability of the commercially available chewing tablet is poor, limiting the use of niclosamide for systemic treatment. A liquid oral formulation using polyethylene glycol 400 was developed and investigated in healthy volunteers to assess safety, tolerability, and pharmacokinetics in comparison to the marketed tablet. (ClinicalTrials.gov: NCT04644705).

The study consisted of three parts: Part A was a double-blind placebo-controlled single ascending dose trial in three dose groups (200, 600, and 1600 mg) with four participants receiving either the investigational niclosamide formulation or placebo (3:1) under fasted and/or fed conditions. Part B was a crossover study comparing 1600 mg investigational niclosamide solution with the marketed 2000 mg chewing tablet in four healthy volunteers. Part C was a double-blind placebo-controlled multiple-dose trial comparing 1200 mg and 1600 mg (verum: placebo 4:2) in two dose groups with six subjects each, who received daily doses for seven days.

No serious or severe adverse events occurred. The most frequent adverse events were mild to moderate gastrointestinal reactions. There was also no apparent dependence between drug exposure levels (AUC, Cmax) and the severity and incidence of adverse events detectable. A relevant food effect was observed with a mean AUClast about 2-fold higher in fed condition compared to fasted condition. In Part B, dose-normalized Cmax and AUClast were similar for niclosamide solution and tablet. Absorption of niclosamide solution was highly variable. Some individuals showed high absorption (Cmax > 2µg/ml) whereas others did absorb only marginally. Importantly, there was no dose linearity in the range of 200 mg - 1600 mg. No signs of relevant systemic drug accumulation after multiple administrations were observed.

Overall safety and tolerability observed in healthy subjects were benign. This is also true for individuals with high absorption (Cmax > 2µg/ml), encouraging further research into niclosamide as a potential therapeutic agent. Galenic optimization, however, will remain challenging as evident from the observed exposure variability and non-linear PK. Non-linearity, if confirmed by additional data, might make niclosamide more suitable for multi-dose rather than high single dose regimens. The observed food effect should also be considered when further investigating systemic niclosamide exposures.

ClinicalTrials.gov NCT04644705.

Cervical cancer metastasis is characterized by the systemic spread of tumor cells. However, the underlying mechanism remains incompletely understood. Herein, we demonstrate that RAB33A promoted metastasis by enhancing RhoC accumulation and that higher RAB33A expression predicted poorer prognosis in patients with cervical cancer. Mechanistically, RhoC typically degraded via canonical autophagy due to the binding of two LIR motifs (LC3 interaction region) in RhoC to LC3; however, RAB33A induced non-canonical autophagy, resulting in RhoC stabilization, which facilitated pseudopodia formation and consequently cervical cancer metastasis. The fusion of RAB33A-induced autophagosomes with lysosomes was impaired, as RAB33A inactivated RAB7 by interacting with TBC1D2A, a GTPase-activating protein that targets RAB7. Our findings reveal a pivotal role of the RAB33A-RhoC axis in cervical cancer metastasis, indicating that RhoC inhibitors may be beneficial for treating cervical cancer patients with high levels of RAB33A.

Glucose metabolism plays a critical role in tumor progression. When glucose intake is insufficient and the tumor's growth rate exceeds its energy supply, tumor cells typically adapt and overcome the energy stress through compensatory mechanisms to maintain the survival of tumor cells, which may also be related to tumor recurrence or metastasis.

Different concentrations of glucose were selected as the basis for the energy stress model of gastric cancer. Then CCK-8 and flow cytometry were used to detect its effects on cell proliferation, apoptosis, and cell cycle. Differentially expressed genes (DEGs) were screened by RNA sequencing and the regulated pathways were identified by gene set enrichment analysis. The regulatory relationship between the gene PPP1R15A and its transcription factor JUN was proved by ChIP-qPCR and dual-luciferase reporter assay. The gain and loss of function assays were conducted to examine the effects of PPP1R15A under energy stress in vivo and in vitro. Potential regulatory mechanisms of PPP1R15A were further analyzed through a combination of online databases, RNA sequencing, and metabolite sequencing. The regulation of PPP1R15A on cell autophagy under energy stress was detected by western blot, transmission electron microscope, mRFP-GFP-LC3 adenovirus and laser scanning confocal microscopy.

PPP1R15A and the transcription factor JUN were significantly upregulated by glucose deprivation (0 mM vs. 25 mM), JUN combined with the promoter of PPP1R15A and activated its expression. Both PPP1R15A and JUN were highly expressed in gastric cancer tissues and were independent risk factors for prognosis in the gastric cancer cohort. Overexpression of PPP1R15A promoted cell proliferation, inhibited apoptosis, and was involved in cell cycle arrest. Further RNA and metabolite sequencing suggested that PPP1R15A was associated with cell autophagy. In vitro experiments confirmed that both glucose deprivation and overexpression of PPP1R15A promoted the biosynthesis of autolysosome and autophagosome, and activated the cleavage of LC3 complex in gastric cancer cells. Moreover, PPP1R15A knockdown inhibited cell autophagy induced by glucose deprivation.

PPP1R15A sustained the survival of gastric cancer cells by regulating autophagy under energy stress to resist or adapt to harsh environments.

Autophagy was considered to induce resistance in chemotherapy, which was significantly associated with proliferation of cancer; however, few bibliometric studies on the relation between autophagy and chemotherapy in lung cancer are available. The aim of the present study was to provide a comprehensive overview of the knowledge structure and research hotspots of autophagy and chemotherapy in lung cancer by bibliometric analysis. Publications related to autophagy and chemotherapy in lung cancer from 2003 to 2023 were searched on the Web of Science Core Collection (WoSCC) database. The bibliometric analysis was conducted by using VOSviewers, CiteSpace, and the R package "bibliometrix." A total of 675 articles from 70 countries, led by China and the United States, were included in the analysis. The number of publications related to autophagy and chemotherapy in lung cancer is increasing year by year. Nanjing Medical University, Zhejiang University, China Medical University, and Sichuan University are among the main research institutions contributing to this field. The journal Cancers is the most popular publication in this area, with Autophagy being the most co-cited journal. These publications involve 4481 authors, with Chiu Chien-chih and Gewirtz David having published the most papers, and Noboru Mizushima being the most frequently co-cited author. Studying the relation between autophagy and chemotherapy in the occurrence and development of lung cancer, and exploring therapeutic strategies involving autophagy and chemotherapy in lung cancer, are the primary topics in this research field. "Tumor stem cells," "microRNA," and "EGFR" emerge as the primary keywords in the emerging research hotspots. Indeed, this bibliometric study provides valuable insights into the research trends and developments concerning autophagy and chemotherapy in lung cancer. By identifying recent research frontiers and highlighting hot directions, this study serves as a valuable reference for scholars interested in understanding the relationship between autophagy and chemotherapy in lung cancer. The comprehensive summary of findings offers a foundation for further exploration and advancement in this critical area of cancer research.

Nanozymes with multienzyme-like activity have sparked significant interest in anti-tumor therapy via responding to the tumor microenvironment (TME). However, the consequent induction of protective autophagy substantially compromises the therapeutic efficacy. Here, a targeted nanozyme system (Fe-Arg-CDs@ZIF-8/HAD, FZH) is shown, which enhances synergistic anti-tumor ferroptosis/apoptosis therapy by leveraging machine learning (ML). A novel ML model, termed the sequential backward Tree-Classifier for Gaussian Process Regression (TCGPR), is proposed to improve data pattern recognition following the divide-and-conquer principle. Based on this, a Bayesian optimization algorithm is employed to select candidates from the extensive search space. Leveraging this fresh material discovery framework, a novel strategy for enhancing nanozyme-based tumor therapy, has been developed. The results reveal that FZH effectively exerts anti-tumor effects by sequentially responding to the TME, having a cascade reaction to induce ferroptosis. Moreover, the endogenous elevation of high concentration nitric oxide (NO) serves as a direct mechanism for killing tumor cells while concurrently suppressing the protective autophagy induced by oxidative stress (OS), enhancing synergistic ferroptosis/apoptosis therapy. Overall, a novel strategy for improving nanozyme-based tumor therapy has been proposed, underlying the integration of ML, experiments, and biological applications.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is highly resistant to chemo- or radiation therapy, which poses a huge challenge for treatment of advanced NSCLC. Previously, we demonstrated the oncogenic role of Tudor Staphylococcal nuclease (TSN, also known as Staphylococcal nuclease domain-containing protein 1, SND1), in regulating chemoresistance in NSCLC cells. Here, we showed that silencing of SND1 augmented the sensitivity of NSCLC cells to different chemotherapeutic drugs. Additionally, the expression of PDCD4 (a tumor suppressor highly associated with lung cancer) in NSCLC cells with low endogenous levels was attenuated by SND1 silencing, implying that SND1 might function as a molecular regulator upstream of PDCD4. PDCD4 is differentially expressed in various NSCLC cells. In the NSCLC cells (A549 and H23 cells) with low expression of PDCD4, despite the downregulation of PDCD4, silencing of SND1 still led to sensitization of NSCLC cells to treatment with different chemotherapeutic agents by the inhibition of autophagic activity. Thus, a novel correlation interlinking SND1 and PDCD4 in the regulation of NSCLC cells concerning chemotherapy was revealed, which contributes to understanding the mechanisms of chemoresistance in NSCLC.

Aging and cancer are intricately linked through shared molecular processes that influence both the onset of malignancy and the progression of age-related decline. As organisms age, cellular stress, genomic instability, and an accumulation of senescent cells create a pro-inflammatory environment conducive to cancer development. Autophagy, a cellular process responsible for degrading and recycling damaged components, plays a pivotal role in this relationship. While autophagy acts as a tumor-suppressive mechanism by preventing the accumulation of damaged organelles and proteins, cancer cells often exploit it to survive under conditions of metabolic stress and treatment resistance. The interplay between aging, cancer, and autophagy reveals key insights into tumorigenesis, cellular senescence, and proteostasis dysfunction. This review explores the molecular connections between these processes, emphasizing the potential for autophagy-targeted therapies as strategies that could be further explored in both aging and cancer treatment. Understanding the dual roles of autophagy in suppressing and promoting cancer offers promising avenues for therapeutic interventions aimed at improving outcomes for elderly cancer patients while addressing age-related deterioration.

Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2-negative metastatic breast cancer (ER+/HER2- MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses. We conducted a phase I trial (NCT03774472 registered in ClinicalTrials.gov on 8/20/2018) of HCQ (400, 600, 800 mg/day) with palbociclib (75 mg/day continuous) and letrozole, using a 3 + 3 design. Primary objectives included safety, tolerability, and determining the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives included tumor response and biomarker analysis. Fourteen ER+/HER2- MBC patients were evaluable [400 mg (n = 4), 600 mg (n = 4), 800 mg (n = 6)]. Grade 3 adverse events (AEs) included hematological (3 at 800 mg), skin rash (2 at 600 mg), and anorexia (1 at 400 mg), with no serious AEs. The best responses were partial (2), stable (11), and progression (1). Tumor reductions ranged from 11% to 30%, with one 55% increase. The two partial responders sustained tumor size reductions of 30% to 55% over an extended treatment period, lasting nearly 300 days. Biomarker analysis in responders demonstrated significant decreases in Ki67, Rb, and nuclear cyclin E levels and increases in autophagy markers p62 and LAMP1, suggesting a correlation between these biomarkers and treatment response. This phase I study demonstrated that HCQ is safe and well-tolerated and the RP2D was established at 800 mg/day with continuous low-dose palbociclib (75 mg/day) and letrozole (2.5 mg/day). These findings suggest that adding HCQ could potentially enhance the efficacy of low-dose palbociclib and standard letrozole therapy, pending verification in larger randomized studies.

This study investigates the interrelationship between human telomerase reverse transcriptase (hTERT) and ferroptosis in precursor-B (pre-B) acute lymphoblastic leukemia (ALL), specifically examining how hTERT modulation affects ferroptotic cell death pathways. Given that hTERT overexpression characterizes various cancer phenotypes and elevated telomerase activity is observed in early-stage and relapsed ALL, we investigated the molecular mechanisms linking hTERT regulation and ferroptosis in leukemia cells. The experimental design employed Nalm-6 and REH cell lines under three distinct conditions: curcumin treatment, hTERT siRNA knockdown, and their combination. Cell viability and proliferation were assessed via MTT and BrdU assays at 24- and 48-hour intervals post-treatment. Ferroptotic and oxidative markers were quantified using commercial assays, while cell death parameters and gene expression were evaluated through flow cytometry and qRT-PCR analyses. Molecular docking studies were performed to evaluate protein-ligand interactions. Results demonstrated that combined curcumin treatment and hTERT knockdown significantly enhanced cytotoxicity in Nalm-6 cells compared to individual interventions. This was characterized by the upregulation of ferroptosis promoters (lipid-ROS, Fe²⁺, ACSL4) and suppression of inhibitors (GSH, GPx, SLC7A11, GPx4). The response showed cell-line specificity, with Nalm-6 cells exhibiting enhanced ferroptotic sensitivity while REH cells underwent apoptotic cell death. Molecular docking revealed strong curcumin-protein interactions (∆G = -34.24 kcal/mol for hTERT). This study establishes hTERT as a critical regulator of ferroptotic cell death in pre-B ALL, operating through redox homeostasis, iron metabolism, and lipid peroxidation pathways. The cell-type-specific responses suggest promising therapeutic strategies through combined hTERT suppression and ferroptosis induction.

Lung cancer is one of the main causes of cancer-related mortality globally, and it poses considerable therapeutic challenges. Polo-like kinase 1 (PLK1) exhibits upregulation in lung cancer, and PLK1 silencing promotes autophagy in lung cancer cells, which inhibits tumor progression. The phosphatase and tensin homolog deleted on chromosome ten (PTEN) acts as a tumor suppressor gene. This study aimed to investigate whether PTEN regulates autophagy and inhibits lung cancer-cell proliferation by suppressing PLK1.

In this study, we evaluated cell proliferation by silencing or overexpressing PLK1 and PTEN in A549 cells through 5-ethynyl-2'-deoxyuridine labeling and cloning experiments. The autophagy levels were detected through transmission electron microscopy, real-time quantitative polymerase chain reaction, and Western blot. Finally, the results of in vitro experiment were further verified using an in vivo xenograft tumor animal model.

The upregulation of PTEN suppressed PLK1 expression in lung cancer cells and reduced their proliferation rate. In addition, the overexpression of PTEN has been associated with the growth of lung cancer tumors. In parallel, the levels of autophagy of lung cancer cells rose in response to PTEN upregulation in vivo and in vitro.

This study revealed that PTEN promotes the autophagy of lung cancer cells and inhibits cell proliferation and tumor growth by suppressing PLK1 expression. This finding provides a new strategy for lung cancer treatment by utilizing the autophagy-regulating effect of PTEN to inhibit lung cancer growth by targeting PLK1.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

Cancer represents an intricate and heterogeneous ailment that evolves from a multitude of epigenetic and genetic variations that disrupt normal cellular function. The WNT/β-catenin pathway is essential in maintaining the balance between cell renewal and differentiation in various tissues. Abnormal activation of this pathway can lead to uncontrolled cell growth and initiate cancer across a variety of tissues such as the colon, skin, liver, and ovary. It enhances characteristics that lead to cancer progression, including angiogenesis, invasion and metastasis. Processes like autophagy and apoptosis which regulate cell death and play a crucial role in maintaining cellular equilibrium are also intimately linked with WNT/ β-catenin pathway. Thus, targeting WNT pathway has become a key strategy in developing antitumor therapies. Employing small molecule inhibitors has emerged as a targeted therapy to improve the clinical outcome compared to conventional cancer treatments. Many strategies using small molecule inhibitors for modulating the WNT/β-catenin pathway, such as hindering WNT ligands' secretion or interaction, disrupting receptor complex, and blocking the nuclear translocation of β-catenin have been investigated. These interventions have shown promise in both preclinical and clinical settings. This review provides a comprehensive understanding of the role of WNT/β-catenin signalling pathway's role in cancer, emphasizing its regulation of autophagy and apoptosis. Our goal is to highlight the potential of specific small molecule inhibitors targeting this pathway, fostering the development of novel, tailored cancer treatments.

Macroautophagy/autophagy is a highly conserved evolutionary mechanism involving lysosomes for the degradation of cytoplasmic components including organelles. The constitutive, basal level of autophagy is fundamental for preserving cellular homeostasis; however, alterations in autophagy can cause disease pathogenesis, including cancer. The role of autophagy in cancer is particularly complicated, since this process acts both as a tumor suppressor in precancerous stages but facilitates tumor progression during carcinogenesis and later stages of cancer progression. This shift between anti-tumor and pro-tumor roles may be influenced by genetic and environmental factors modulating key pathways such as those involving autophagy-related proteins, the PI3K-AKT-MTOR axis, and AMPK, which often show dysregulation in tumors. Autophagy regulates various cellular functions, including metabolism of glucose, glutamine, and lipids, cell proliferation, metastasis, and several types of cell death (apoptosis, ferroptosis, necroptosis and immunogenic cell death). These multifaceted roles demonstrate the potential of autophagy to affect DNA damage repair, cell death pathways, proliferation and survival, which are critical in determining cancer cells' response to chemotherapy. Therefore, targeting autophagy pathways presents a promising strategy to combat chemoresistance, as one of the major reasons for the failure in cancer patient treatment. Furthermore, autophagy modulates immune evasion and the function of immune cells such as T cells and dendritic cells, influencing the tumor microenvironment and cancer's biological behavior. However, the therapeutic targeting of autophagy is complex due to its dual role in promoting survival and inducing cell death in cancer cells, highlighting the need for strategies that consider both the beneficial and detrimental effects of autophagy modulation in cancer therapy. Hence, both inducers and inhibitors of autophagy have been introduced for the treatment of cancer. This review emphasizes the intricate interplay between autophagy, tumor biology, and immune responses, offering insights into potential therapeutic approaches that deploy autophagy in the cancer suppression.

Metabolic reprogramming is a hallmark of cancer, characterized by a high dependence on glycolysis and an enhanced utilization of acetate as an alternative carbon source. ACSS2 is a critical regulator of acetate metabolism, playing a significant role in the development and progression of various malignancies. ACSS2 facilitates the conversion of acetate to acetyl-CoA, which participates in multiple metabolic pathways and functions as an epigenetic regulator of protein acetylation, thereby modulating key cellular processes such as autophagy. However, the roles and intrinsic connections of ACSS2, glycolysis, protein acetylation, and autophagy in ovarian cancer (OC) remain to be elucidated.

Utilizing clinical specimens and online databases, we analysed the expression of ACSS2 in OC and its relationship with clinical prognosis. By knocking down ACSS2, we evaluated its effects on the malignant phenotype, acetate metabolism, glycolysis, and autophagy. The metabolic alterations in OC cells were comprehensively analysed using Seahorse assays, transmission electron microscopy, membrane potential measurements, and stable-isotope labeling techniques. CUT&TAG and co-immunoprecipitation techniques were employed to explore the deacetylation of autophagy-related proteins mediated by ACSS2 via SIRT1. Additionally, through molecular docking, transcriptome sequencing, and metabolomics analyses, we validated the pharmacological effects of paeonol on ACSS2 and the glycolytic process in OC cells. Finally, both in vitro and in vivo experiments were performed to investigate the impact of paeonol on autophagy and its anti-OC effects mediated through the ACSS2/SIRT1 deacetylation axis.

ACSS2 is significantly upregulated in OC and is associated with poor prognosis. Knockdown of ACSS2 inhibits OC cells proliferation, migration, invasion, angiogenesis, and platinum resistance, while reducing tumour burden in vivo. Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK2. This glycolytic reduction promotes the translocation of ACSS2 from the cytoplasm to the nucleus, leading to increased expression of the deacetylase SIRT1. SIRT1 mediates the deacetylation of autophagy-related proteins, such as ATG5 and ATG2B, thereby significantly activating autophagy in OC cells and exerting antitumor effects. Paeonol inhibits acetate metabolism and glycolysis in OC cells by targeting ACSS2. Paeonol activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation axis, demonstrating inhibition of OC in vitro and in vivo.

Pae can serve as an effective, low-toxicity, multi-targeted drug targeting ACSS2 and glycolysis. It activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation signalling cascade, thereby exerting anti-OC effects. Our study provides new insights into the malignant mechanisms of OC and offers a novel strategy for its treatment.

Mitochondria and lysosomes regulate a multitude of biological processes that are essential for the maintenance of nutrient and metabolic homeostasis and overall cell viability. Recent evidence reveals that these pivotal organelles, similarly to others previously studied, communicate through specialized membrane contact sites (MCSs), hereafter referred to as mitochondria-lysosome contacts (or MLCs), which promote their dynamic interaction without involving membrane fusion. Signal integration through MLCs is implicated in key processes, including mitochondrial fission and dynamics, and the exchange of calcium, cholesterol, and amino acids. Impairments in the formation and function of MLCs are increasingly associated with age-related diseases, specifically neurodegenerative disorders and lysosomal storage diseases. However, MLCs may play roles in other pathological contexts where lysosomes and mitochondria are crucial. In this review, we introduce the methodologies used to study MLCs and discuss known molecular players and key factors involved in their regulation in mammalian cells. We also argue other potential regulatory mechanisms depending on the acidic lysosomal pH and their impact on MLC's function. Finally, we explore the emerging implications of dysfunctional mitochondria-lysosome interactions in disease, highlighting their potential as therapeutic targets in cancer.

Pediatric gliomas are the most common brain tumor in children, encompassing both low-grade glioma (pLGG) and high-grade glioma (pHGG). Alterations in the RAS/MAPK pathway are the driver event in the majority of pLGG and account for a subset of pHGG. Identification of these alterations has resulted in the transition to targeted therapy as a treatment option.

In pLGG, multiple trials have demonstrated superior outcomes using targeted therapy compared to traditional chemotherapy regimens. This has transformed care for these patients over the past decade with targeted therapy moving into front-line treatment regimens in certain scenarios. Despite these advances, novel targeted therapy approaches continue to present unique challenges to patient care, including optimal duration of therapy, distinct toxicity profiles and the unknown potential impact on the natural history of disease. While targeted therapy has revolutionized treatment of pLGG, additional questions remain in regard to pHGG including the role of targeted therapy in combination with other treatments, such as chemotherapy/radiation, and mechanisms of resistance. These developments are promising treatment options for pediatrics gliomas, enabling a move towards precision medicine.

Herein, we review the role of RAS/MAPK targeted therapy for treatment of pediatric glioma along with the current controversies and outstanding questions.

Background/Objectives: Preclinical studies have shown that the anti-malarial drug hydroxychloroquine (HCQ) improves the anti-cancer effects of various therapeutic agents by impairing autophagy. These findings are difficult to translate in vivo as reaching an effective HCQ concentration at the tumor site for extended times is challenging. Previously, we found that free HCQ in combination with gefitinib (Iressa®, ZD1839) significantly reduced tumor volume in immunocompromised mice bearing gefitinib-resistant JIMT-1 breast cancer xenografts. Here, we sought to evaluate whether a liposomal formulation of HCQ could effectively modulate autophagy in vivo and augment treatment outcomes in the same tumor model. Methods: We developed two liposomal formulations of HCQ: a pH-loaded formulation and a formulation based on copper complexation. The pharmacokinetics of each formulation was evaluated in CD1 mice following intravenous administration. An efficacy study was performed in immunocompromised mice bearing established JIMT-1tumors. Autophagy markers in tumor tissue harvested after four weeks of treatment were assessed by Western blot. Results: The liposomal formulations engendered ~850-fold increases in total drug exposure over time relative to the free drug. Both liposomal and free HCQ in combination with gefitinib provided comparable therapeutic benefits (p > 0.05). An analysis of JIMT-1 tumor tissue indicated that the liposomal HCQ and gefitinib combination augmented the inhibition of autophagy in vivo compared to the free HCQ and gefitinib combination as demonstrated by increased LC3-II and p62/SQSTM1 (p62) protein levels. Conclusions: The results suggest that liposomal HCQ has a greater potential to modulate autophagy in vivo compared to free HCQ; however, this did not translate to better therapeutic effects when used in combination with gefitinib to treat a gefitinib-resistant tumor model.

Lung adenocarcinoma (LUAD) is a major contributor to cancer-related deaths, distinguished by its pronounced tumor heterogeneity and persistent challenges in overcoming drug resistance. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to dissect the roles of programmed cell death (PCD) pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis, in shaping LUAD heterogeneity, immune infiltration, and prognosis. Among these, ferroptosis and pyroptosis were most significantly associated with favorable survival outcomes, highlighting their potential roles in enhancing anti-tumor immunity. Distinct PCD-related LUAD subtypes were identified, characterized by differential pathway activation and immune cell composition. Subtypes enriched with cytotoxic lymphocytes and dendritic cells demonstrated improved survival outcomes and increased potential responsiveness to immunotherapy. Drug sensitivity analysis revealed that these subtypes exhibited heightened sensitivity to targeted therapies and immune checkpoint inhibitors, suggesting opportunities for personalized treatment strategies. Our findings emphasize the interplay between PCD pathways and the tumor microenvironment, providing insights into the mechanisms underlying tumor drug resistance and immune evasion. By linking molecular and immune features to clinical outcomes, this study highlights the potential of targeting PCD pathways to enhance therapeutic efficacy and overcome resistance in LUAD. These results contribute to a growing framework for developing precise and adaptable cancer therapies tailored to specific tumor characteristics.

The increasing prevalence of chronic diseases and their associated morbidities demands a deeper understanding of underlying mechanism and causative factors, with the hope of developing novel therapeutic strategies. Autophagy, a conserved biological process, involves the degradation of damaged organelles or protein aggregates to maintain cellular homeostasis. Disruption of this crucial process leads to increased genomic instability, accumulation of reactive oxygen species (ROS), decreased mitochondrial functions, and suppression of ubiquitination, leading to overall decline in quality of intracellular components. Such deregulation has been implicated in a wide range of pathological conditions such as cancer, cardiovascular, inflammatory, and neurological disorders. This review explores the role of long non-coding RNAs (lncRNAs) as modulators of transcriptional and post-transcriptional gene expression, regulating diverse physiological process like proliferation, development, immunity, and metabolism. Moreover, lncRNAs are known to sequester autophagy related microRNAs by functioning as competing endogenous RNAs (ceRNAs), thereby regulating this vital process. In the present review, we delineate the multitiered regulation of lncRNAs in the autophagic dysfunction of various pathological diseases. Moreover, by highlighting recent findings on the modulation of lncRNAs in different stages of autophagy, and the emerging clinical landscape that recognizes lncRNAs in disease diagnosis and therapy, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in clinical settings of different stages of autophagic process by regulating ATG and its target genes. This focus on lncRNAs could lead to breakthroughs in personalized medicine, offering new avenues for diagnosis and treatment of complex diseases.

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.

Proteolysis of hydrophobic helices is required for complete breakdown of every transmembrane protein trafficked to the lysosome and sustains high rates of endocytosis. However, the lysosomal mechanisms for degrading hydrophobic domains remain unknown. Combining lysosomal proteomics with functional genomic data mining, we identify Lysosomal Leucine Aminopeptidase (LyLAP; formerly Phospholipase B Domain-Containing 1) as the hydrolase most tightly associated with elevated endocytic activity. Untargeted metabolomics and biochemical reconstitution demonstrate that LyLAP is not a phospholipase, but a processive monoaminopeptidase with strong preference for N-terminal leucine - an activity necessary and sufficient for breakdown of hydrophobic transmembrane domains. LyLAP is upregulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake, and its ablation led to buildup of undigested hydrophobic peptides, which compromised lysosomal membrane integrity and inhibited PDA cell growth. Thus, LyLAP enables lysosomal degradation of membrane proteins, and may represent a vulnerability in highly endocytic cancer cells.

LyLAP degrades transmembrane proteins to sustain high endocytosis and lysosomal membrane stability in pancreatic cancer.

Skin carcinoma, which includes basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, is influenced by various factors such as genetic predisposition, chemical exposures, immune system imbalances, and ultraviolet (UV) radiation. This review delves into the mechanisms behind the development of these cancers, exploring the therapeutic potential of microbial, plant derived compounds and nanoparticles in advancing skin cancer treatments. Special attention is given to the cytotoxic effects of anti-neoplastic agents from microbial sources on different cancer cell lines, particularly melanoma. Additionally, the review highlights the role of phytochemicals - such as quercetin, resveratrol, and curcumin alongside vitamins, terpenoids, and sulforaphane, in management of skin cancers through mechanisms like apoptosis induction and cell cycle regulation. Recent advancements in nanotechnology-based drug delivery systems, including NP and microemulsion formulations, are also discussed for their enhanced ability to specifically target cancer cells. The diverse roles of NPs in skin cancer therapy, especially in terms of targeted drug delivery and immune modulation, are reviewed. These innovative NPs formulations have showed improved skin penetration and tumor-specific delivery, reduced systemic toxicity and enhanced therapeutic effectiveness.

Diverse agents targeting (macro)autophagy, a critical metabolic stress response in cancer cells, have been proposed for cancer therapy. In previous studies, we showed that NNC-55-0396 (NNC) induces glioblastoma cell death by activating the Unfolded Protein Response (UPR) of ER stress and increasing cytosolic Ca2+ levels. Here, we report that NNC affects both ends of the autophagy process, causing extensive cytoplasmic vacuolation. Our results show that: (1) NNC induces autophagy downstream of UPR and Ca2+ signaling pathways, thus silencing IRE1α/JNK1 or inhibiting Ca2+/IP3R signaling prevents NNC-induced vacuolation. (2) Silencing ATG5 delays cell death, indicating that autophagy induction plays a role in NNC's cytotoxic effects. (3) NNC and other Ca2+-mobilizing agents transcriptionally upregulate p62/SQSTM1, an autophagosome cargo receptor, highlighting a role for this protein in the response to NNC. (4) Studies using tandem fluorescent-tagged LC3 and electron microscopy, however, further reveal that NNC blocks late-stage autophagy that leads to enlarged degradative compartments accumulating ubiquitin-tagged cargoes. (5) Finally, NNC impedes pro-cathepsin-B processing, an effect that is reversed with a weak acid co-treatment, suggesting that lysosomal dysfunction due to increased intraluminal pH is the underlying cause of the autophagy blockade. Together, these findings underscore a multi-level dysregulation of autophagy that contributes to NNC's anti-tumoral effects.

Although accounting for only a small amount of skin cancers, melanoma contributes prominently to skin cancer-related deaths, which are mostly caused by metastatic diseases, and lymphatic metastasis constitutes the main route. In this review, we concentrate on the metabolic mechanisms of tumor lymph node (LN) metastasis in melanoma. Two hypotheses of melanoma LN metastasis are introduced, which are the premetastatic niche (PMN) and parallel progression model. Dysregulation of oxidative stress, lactic acid concentration, fatty acid synthesis, amino acid metabolism, autophagy, and ferroptosis construct the metabolic mechanisms in LN metastasis of melanoma. Moreover, melanoma cells also promote LN metastasis by interacting with non-tumor cells through metabolic reprogramming in TIME. This review will deepen our understanding of the mechanism of lymph node metastasis in melanoma.

Lung carcinoma, predominantly manifested as non-small cell lung cancer (NSCLC), significantly contributes to oncological mortality, underscoring an imperative for novel therapeutic paradigms. Amidst this context, the present investigation delineates the synergistic potentiation of doxorubicin (DOX)-a canonical chemotherapeutic-by Ursodeoxycholic acid (UDCA), a compound with a historical pedigree in hepatobiliary medicine, now repositioned within oncological pharmacotherapy due to its dichotomous cellular modulation-affording cytoprotection to non-malignant epithelia whilst eliciting apoptotic cascades in neoplastic counterparts. This study, through a rigorous methodological framework, elucidates UDCA's capacity to inhibit NSCLC cellular proliferation and induce apoptosis, thereby significantly amplifying DOX's chemotherapeutic efficacy. Notably, the co-administration of UDCA and DOX was observed to attenuate DOX-induced autophagy via the modulation of the TGF-β/MAPK signaling axis, a pathway pivotal in mediating cellular survival and autophagic mechanisms. Such findings not only underscore the therapeutic potential of UDCA as a chemosensitizer but also illuminate the molecular underpinnings of its modulatory effects, thereby contributing to the corpus of knowledge necessary to surmount chemoresistance in NSCLC. The implications of this research are twofold: firstly, it offers a compelling evidence base for the clinical reevaluation of UDCA in combinatory chemotherapeutic regimens; secondly, it posits a novel mechanistic insight into the modulation of chemotherapeutic efficacy and resistance. Collectively, these insights advocate for the expedited clinical translation of UDCA-DOX synergy, potentially heralding a paradigm shift in the management of NSCLC, thereby addressing a critical lacuna in contemporary oncological therapy.

Autophagy has gained importance in the context of ferroptosis. Nevertheless, a deeper understanding of the regulatory mechanism governing autophagy-dependent ferroptosis is necessary. Cytoglobin (CYGB), a member of the globin family, exhibits antifibrotic effects, regulates cellular reactive oxygen species, and stimulates tumor inhibition. Herein, we present further insights into the role of CYGB in ferroptosis regulation. Our investigation confirmed that CYGB impedes cell proliferation and migration. Furthermore, a significant association between CYGB and the lysosomal pathway was suggested based on the RNA sequencing data analysis. Elevated lysosomal signal and colocalization of CYGB with lysosome-associated membrane glycoprotein 1 (LAMP1) were observed. Moreover, upregulated autophagy and augmented ferroptosis induced by RSL3 were confirmed in CYGB-overexpression cells with an obviously increased colocalization of nuclear receptor coactivator 4 (NCOA4) and LC3B. The autophagy inhibitor bafilomycin or chloroquine alleviated autophagy-dependent degradation of ferritin protein under RSL3 treated condition. Additionally, a colocalization of CYGB with the transferrin receptor (TFR) was confirmed. Our results demonstrate an important functional pathway by which CYGB regulates ferroptosis through TFR-binding and autophagic degradation of ferritin, and provide a potential pathway for the treatment of colorectal cancer.

Pancreatic cancer, characterized by a dismal prognosis and limited treatment options, persists as a formidable challenge in oncology. Trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugates have achieved great success in solid tumors such as breast cancer and uroepithelial carcinoma. However, their efficacy against pancreatic cancer was insufficient in clinical trials, necessitating an imperative exploration of underlying mechanisms and new therapeutic strategies. In this study, we indicated that αTROP2-MMAE, an antibody-drug conjugate targeting TROP2, induced apoptosis through the caspase-9/PARP pathway and exerted potent antitumor effects against TROP2-positive pancreatic cancer. Simultaneously, RNA sequencing suggested significant changes in autophagy after αTROP2-MMAE treatment. The formation of autophagosomes and activation of autophagic flux were markedly induced through mechanisms associated with suppressing the activation of the Akt/mTOR pathway. The addition of pharmacological inhibitors of autophagy enhanced the cytotoxicity and apoptosis caused by αTROP2-MMAE, revealing the cytoprotective role of autophagy in TROP2-positive pancreatic cancer. In the subcutaneous xenograft model using BxPC3 cells, the combined administration of αTROP2-MMAE and an autophagy inhibitor elevated the tumor inhibition rate of αTROP2-MMAE from 71.6 % to 99.0 %, resulting in the eradication of tumors in half of the mice. Collectively, our research demonstrated for the first time the cytoprotective role of autophagy in TROP2-targeted antibody-drug conjugate therapy for pancreatic cancer, providing new perspectives for mechanistic exploration and therapeutic strategies in the treatment of pancreatic cancer.

Autophagy plays an important role in maintaining the stability of intracellular environment, abnormal autophagy is associated with the occurrence and progression of cancer, the role of STIM1 in regulating cancer autophagy remains controversial, and its clinical relevance is unclear. Our study aimed to investigate the effect and mechanism of STIM1 on cervical cancer, thus to provide new molecular therapeutic targets for cervical cancer in clinic.

We collected CIN III, FIGO IB and IIA fresh Specimens without chemotherapy from patients in Renmin Hospital of Hubei University of Medicine (n = 10). STIM1, TFEB and autophagy related proteins of different stage tissues were detected. In vitro, SKF96365 and AncoA4 were used to inhibit STIM1-administrated Ca2+ entry of SiHa cells, Cyclosporine A (calcineurin inhibitors) were used to inhibit CaN/TFEB pathway, Ad-mCherry-GFPLC3B was used to detect autophagy flux, shSTIM1 was used to knockdown STIM1 expression.

The expression levels of STIM1, TFEB and autophagy related proteins were positively correlated with the progression of cervical cancer. Inhibition of STIM1-mediated SOCE can decrease proliferation and migration, and promoted the apoptosis of cervical cancer cells. Knockdown STIM1 can inhibit autophagy and TFEB nuclear translocation.

STIM1 can promote autophagy and accelerate cervical cancer progression by increasing TFEB nuclear translocation of cervical cancer cells.