Thermoelectric Performance Enhancement in SnS Polycrystals Owing to Hole Doping Combined with Textured Microstructures.

Recently, the earth-abundant tin sulfide (SnS) has emerged as a promising thermoelectric material due to its phonon and electron structure similar to that of tin selenide (SnSe). However, compared with SnSe, limited progress has been achieved in the thermoelectric property enhancement of SnS. Textured SnS polycrystals with an enhanced thermoelectric performance have been developed in this work. The high carrier mobility benefited from the enhanced texture through the repressing strategy of spark plasma sintering, improving the electrical conductivity. In addition, Sn atom deficiencies in the texture sample led to an increased hole concentration, further boosting the electrical conductivity and power factor. The power factor exceeded 4.10 µW/cm·K2 at 423 K and 5.50 µW/cm·K2 at 850 K. The phonon scattering was strengthened by adjusting the multiscale microstructures including dislocations, defect clusters, etc., leading to an ultralow lattice thermal conductivity of 0.23 W/m·K at 850 K. A figure of merit zT > 1.3 at 850 K and an average zTave of 0.58 in the temperature range 373-850 K were achieved in the SnS polycrystal.

Plasticity in single-crystalline Mg3Bi2 thermoelectric material.

Most of the state-of-the-art thermoelectric materials are inorganic semiconductors. Owing to the directional covalent bonding, they usually show limited plasticity at room temperature1,2, for example, with a tensile strain of less than five per cent. Here we discover that single-crystalline Mg3Bi2 shows a room-temperature tensile strain of up to 100 per cent when the tension is applied along the (0001) plane (that is, the ab plane). Such a value is at least one order of magnitude higher than that of traditional thermoelectric materials and outperforms many metals that crystallize in a similar structure. Experimentally, slip bands and dislocations are identified in the deformed Mg3Bi2, indicating the gliding of dislocations as the microscopic mechanism of plastic deformation. Analysis of chemical bonding reveals multiple planes with low slipping barrier energy, suggesting the existence of several slip systems in Mg3Bi2. In addition, continuous dynamic bonding during the slipping process prevents the cleavage of the atomic plane, thus sustaining a large plastic deformation. Importantly, the tellurium-doped single-crystalline Mg3Bi2 shows a power factor of about 55 microwatts per centimetre per kelvin squared and a figure of merit of about 0.65 at room temperature along the ab plane, which outperforms the existing ductile thermoelectric materials3,4.

OsRCI-1-Mediated GLVs Enhance Rice Resistance to Brown Planthoppers.

Green leaf volatiles (GLVs) play pivotal roles in plant anti-herbivore defense. This study investigated whether the rice 13-lipoxygense gene OsRCI-1 is involved in GLV production and plant defense in rice. The overexpression of OsRCI-1 (oeRCI lines) in rice resulted in increased wound-induced levels of two prominent GLVs, cis-3-hexen-1-ol and cis-3-hexenal. In a previous study, we found that the overexpression of OsRCI-1 reduced the colonization by the rice brown planthopper (BPH, Nilaparvata lugens) but increased the attractiveness to the egg parasitoid Anagrus nilaparvatae compared to wild-type (WT) plants. This study found that when cis-3-hexen-1-ol, but not cis-3-hexenal, was added to WT plants, it could change the BPH's colonization preference, i.e., more BPHs preferred to colonize the oeRCI lines. The exogenous application of cis-3-hexen-1-ol or cis-3-hexenal to BPH-infested WT plants could weaken or overturn the preference of A. nilaparvatae for oeRCI lines. However, field experiments revealed that only cis-3-hexenal was attractive to the parasitoid and increased the parasitism rates of BPH eggs. These results indicate that OsRCI-1 is involved in rice GLV production and therefore modulates both direct and indirect defense in rice.

Cardioprotective effect of Cinnamamide derivative compound 10 against myocardial ischemia-reperfusion through regulating cardiac autophagy via Sirt1.

BACKGROUND AND PURPOSE: Our previous research discovered that cinnamamide derivatives are a new type of potential cardioprotective agents myocardial ischemia-reperfusion (MIR) injury, among which Compound 10 exhibits wonderful beneficial action in vitro. However, the exact mechanism of Compound 10 still needs to be elucidated. EXPERIMENTAL APPROACH: The protective effect of Compound 10 was determined by detecting the cell viability and LDH leakage rate in H9c2 cells subjected to H2O2. Alterations of electrocardiogram, echocardiography, cardiac infarct area, histopathology and serum myocardial zymogram were tested in MIR rats. Additionally, the potential mechanism of Compound 10 was explored through PCR. Network pharmacology and Western blotting was conducted to monitor levels of proteins related to autophagic flux and mTOR, autophagy regulatory substrate, induced by Compound 10 both in vitro and in vivo, as well as expressions of Sirtuins family members. KEY RESULTS: Compound 10 significantly ameliorated myocardial injury, as demonstrated by increased cell viability, decreased LDH leakage in vitro, and declined serum myocardial zymogram, ST elevation, cardiac infarct area and improved cardiac function and microstructure of heart tissue in vivo. Importantly, Compound 10 markedly enhanced the obstruction of autophagic flux and inhibited excessive autophagy initiation against MIR by decreased ATG5, Rab7 and increased P-mTOR and LAMP2. Furthermore, Sirt1 knockdown hindered Compound 10's regulation on mTOR, leading to interrupted cardiac autophagic flux. CONCLUSIONS AND IMPLICATIONS: Compound 10 exerted cardioprotective effects on MIR by reducing excessive autophagy and improving autophgic flux blockage. Our work would take a novel insight in seeking effective prevention and treatment strategies against MIR injury.

Efficient Glucose Isomerization to Fructose using Photoregenerable MgSnO3 Catalyst with Cooperative Acid-Base Sites.

The isomerization of glucose to fructose plays a crucial role in the food industry and the production of biomass-derived chemicals in biorefineries. However, the catalyst used in this reaction suffers from low selectivity and catalyst deactivation due to carbon or by-product deposition. In this study, MgSnO3 catalyst, synthesized via a facile two-step process involving hydrothermal treatment and calcination, was used for glucose isomerization to fructose. The catalyst demonstrated outstanding catalytic performance, achieving a fructose equilibrium yield of 29.8 % with a selectivity exceeding 90 % under mild conditions owing to its acid-base interaction. Notably, spent catalysts can be regenerated by photoirradiation to remove surface carbon, thereby avoiding the changes in properties and subsequent loss of activity associated with conventional calcination regeneration method. This novel approach eliminates the energy consumption and potential structural aggregation associated with traditional calcination regeneration methods. The acid-base active sites of the catalyst, along with their corresponding catalytic reaction mechanism and photoregeneration mechanism were investigated. This study presents a demonstration of the comprehensive utilization of catalytic material properties, i. e., acid-base and photocatalytic functionalities, for the development of a green and sustainable biomass thermochemical conversion system.

YBX1 Promotes Esophageal Squamous Cell Carcinoma Progression via m5C­Dependent SMOX mRNA Stabilization.

The modification and recognition of 5-methylcytosine (m5C) are involved in the initiation and progression of various tumor types. However, the precise role and potential mechanism of Y-box-binding protein 1 (YBX1) in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, it is found that YBX1 is frequently upregulated in ESCC compared with matched nontumor tissues. Gain- and loss-of-function assays show that YBX1 promoted the proliferation and metastasis of ESCC cells both in vitro and in vivo. Functional studies revealed that NOP2/Sun RNA methyltransferase family member 2 (NSUN2) is a critical RNA methyltransferase that facilitates YBX1-mediated ESCC progression. Mechanistically, integrated analysis based on RNA immunoprecipitation sequencing (RIP-seq) and m5C methylated RNA immunoprecipitation and sequencing (MeRIP-seq) assays identified spermine oxidase (SMOX) as a target gene containing an m5C site in its coding sequence (CDS) region, which coincided well with the binding site of YBX1. Overexpression of SMOX-WT but not SMOX-Mut partially restored the proliferation and invasion ability of ESCC cells curbed by YBX1 knockdown. Moreover, YBX1 activated the mTORC1 signaling pathway by stabilizing SMOX mRNA. The study reveals that YBX1 promotes ESCC development by stabilizing SMOX mRNA in an m5C-dependent manner, thus providing a valuable therapeutic target for ESCC.

Wnt/ß-catenin-driven EMT regulation in human cancers.

Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial-mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/ß-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3ß that destructs ß-catenin, while ligand-receptor interaction impairs GSK-3ß function to increase ß-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/ß-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance ß-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/ß-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/ß-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression.

Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer.

BACKGROUND: Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear. METHODS: In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo. RESULTS: Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo. CONCLUSIONS: Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.

The pan-cancer landscape of glutamate and glutamine metabolism: A comprehensive bioinformatic analysis across 32 solid cancer types.

Glutamine metabolism is a hallmark of cancer metabolism, which matters in the progression of the tumor. This synthetic study conducted a large-scale systematic analysis at the pan-cancer level on the glutamate and glutamine metabolism (GGM) across 32 solid tumors from the TCGA database. The glutamine metabolism activity was quantified through a scoring system. This study revealed that the GGM score in tumor tissues was up-regulated in 13 cancer types (BCLA, BRCA, COAD, KICH, KIRP, LUAD, LUSC, PAAD, PRAD, READ, STAD, THYM, UCEC) and down-regulated in 4 cancer types (CHOL, GBM, LIHC, THCA), exhibiting tissue specificity. The mRNA expression levels of glutamine metabolism-related genes were relatively high, and GLUL exhibited the highest expression level. The expression levels were up-regulated with copy number amplification. ALDH18A1, PYCR1, and PYCR2 show a significant upregulation in protein levels in cancer tissues compared to normal tissues, making them potential pan-cancer therapeutic targets. For the TME related to glutamine metabolism, the GGM score exhibited significant immune and stromal environment inhibitory effects in all involved tumors. Up-regulated GGM score indicated the widespread promotion of drug resistance at the pan-cancer level. GGM score and glutamine metabolism-related genes signature tended to be risk factors for the overall survival of cancer patients.

The role of N6-methyladenosine methylation in PAHs-induced cancers.

Polycyclic aromatic hydrocarbons (PAHs), which are a wide range of environmental toxicants, may act on humans through inhalation, ingestion, and skin contact, resulting in a range of toxic reactions. Epidemiological studies showed that long-term exposure to PAHs in the occupational and living environment results in a substantial rise in the incidence rate of many cancers in the population, so the prevention and treatment of these diseases have become a major worldwide public health problem. N6-methyladenosine (m6A) modification greatly affects the metabolism of RNA and is implicated in the etiopathogenesis of many kinds of diseases. In addition, m6A-binding proteins have an important role in disease development. The abnormal expression of these can cause the malignant proliferation, migration, invasion, and metastasis of cancers. Furthermore, a growing number of studies revealed that environmental toxicants are one of the cancer risk factors and are related to m6A modifications. Exposure to environmental toxicants can alter the methylation level of m6A and the expression of the m6A-binding protein, thus promoting the occurrence and development of cancers through diverse mechanisms. m6A may serve as a biomarker for early environmental exposure. Through the study of m6A, we can find the health injury early, thus providing a new sight for preventing and curing environmental health-related diseases.

Lipid metabolism as a target for cancer drug resistance: progress and prospects.

Cancer is the world's leading cause of human death today, and the treatment process of cancer is highly complex. Chemotherapy and targeted therapy are commonly used in cancer treatment, and the emergence of drug resistance is a significant problem in cancer treatment. Therefore, the mechanism of drug resistance during cancer treatment has become a hot issue in current research. A series of studies have found that lipid metabolism is closely related to cancer drug resistance. This paper details the changes of lipid metabolism in drug resistance and how lipid metabolism affects drug resistance. More importantly, most studies have reported that combination therapy may lead to changes in lipid-related metabolic pathways, which may reverse the development of cancer drug resistance and enhance or rescue the sensitivity to therapeutic drugs. This paper summarizes the progress of drug design targeting lipid metabolism in improving drug resistance, and providing new ideas and strategies for future tumor treatment. Therefore, this paper reviews the issues of combining medications with lipid metabolism and drug resistance.

Vacancy-mediated anomalous phononic and electronic transport in defective half-Heusler ZrNiBi.

Studies of vacancy-mediated anomalous transport properties have flourished in diverse fields since these properties endow solid materials with fascinating photoelectric, ferroelectric, and spin-electric behaviors. Although phononic and electronic transport underpin the physical origin of thermoelectrics, vacancy has only played a stereotyped role as a scattering center. Here we reveal the multifunctionality of vacancy in tailoring the transport properties of an emerging thermoelectric material, defective n-type ZrNiBi. The phonon kinetic process is mediated in both propagating velocity and relaxation time: vacancy-induced local soft bonds lower the phonon velocity while acoustic-optical phonon coupling, anisotropic vibrations, and point-defect scattering induced by vacancy shorten the relaxation time. Consequently, defective ZrNiBi exhibits the lowest lattice thermal conductivity among the half-Heusler family. In addition, a vacancy-induced flat band features prominently in its electronic band structure, which is not only desirable for electron-sufficient thermoelectric materials but also interesting for driving other novel physical phenomena. Finally, better thermoelectric performance is established in a ZrNiBi-based compound. Our findings not only demonstrate a promising thermoelectric material but also promote the fascinating vacancy-mediated anomalous transport properties for multidisciplinary explorations.

NSUN2 stimulates tumor progression via enhancing TIAM2 mRNA stability in pancreatic cancer.

NSUN2 is a nuclear RNA methyltransferase which catalyzes 5-methylcytosine (m5C), a posttranscriptional RNA modification. Aberrant m5C modification has been implicated in the development of multiple malignancies. However, its function in pancreatic cancer (PC) needs to be elucidated. Herein, we determined that NSUN2 was overexpressed in PC tissues and related to aggressive clinical features. Silence of NSUN2 by lentivirus weakened the capability of proliferation, migration and invasion of PC cells in vitro and inhibited the growth and metastasis of xenograft tumors in vivo. Contrarily, overexpression of NSUN2 stimulated PC growth and metastasis. Mechanistically, m5C-sequencing (m5C-seq) and RNA-sequencing (RNA-seq) were carried out to identify downstream targets of NSUN2 and results showed that loss of NSUN2 led to decreased m5C modification level concomitant with reduced TIAM2 mRNA expression. Further validation experiments proved that NSUN2 silence accelerated the decay of TIAM2 mRNA in a YBX1-dependent manner. Additionally, NSUN2 exerted its oncogenic function partially through enhancing TIAM2 transcription. More importantly, disruption of the NSUN2/TIAM2 axis repressed the malignant phenotype of PC cells through blocking epithelial-mesenchymal transition (EMT). Collectively, our study highlighted the critical function of NSUN2 in PC and provided novel mechanistic insights into NSUN2/TIAM2 axis as promising therapeutic targets against PC.

Photocatalytic Cascade Reaction Driven by Directed Charge Transfer over VS -Zn0.5 Cd0.5 S/GO for Controllable Benzyl Oxidation.

Photocatalysis is an important technique for synthetic transformations. However, little attention has been paid to light-driven synergistic redox reactions for directed synthesis. Herein, the authors report tunable oxidation of benzyl to phenylcarbinol with the modest yield (47%) in 5 h via singlet oxygen (1 O2 ) and proton-coupled electron transfer (PCET) over the photocatalyst Zn0.5 Cd0.5 S (ZCS)/graphene oxide (GO) under exceptionally mild conditions. Theoretical calculations indicate that the presence of S vacancies on the surface of ZCS/GO photocatalyst is crucial for the adsorption and activation of O2 , successively generating the superoxide radical (• O2 - ) and 1 O2 , attributing to the regulation of local electron density on the surface of ZCS/GO and photogenerated holes (h+ ). Meanwhile, accelerated transfer of photogenerated electrons (e- ) to GO caused by the π-π stacking effect is conducive to the subsequent aldehyde hydrogenation to benzyl alcohol rather than non-selective oxidation of aldehyde to carboxylic acid. Anisotropic charge transport driven by the built-in electric field can further promote the separation of e- and h+ for multistep reactions. Promisingly, one-pot photocatalytic conversion of p-xylene to 4-methylbenzyl alcohol is beneficial for reducing the harmful effects of aromatics on human health. Furthermore, this study provides novel insights into the design of photocatalysts for cascade reactions.

Insight into the intrinsic microstructures of polycrystalline SnSe based compounds.

SnSe based compounds have attracted much attention due to the ultra-low lattice thermal conductivity and excellent thermoelectric properties. The origin of the low thermal conductivity has been ascribed to the strong phonon anharmonicity. Generally, the microstructures are also effective in scattering the phonons and further reducing the lattice thermal conductivity. In this work, the microstructures of undoped SnSe and Bi-doped Sn0.97SeBi0.03have been investigated by transmission electron microscopy. A characteristic microstructure of lath-like grains has been observed in SnSe based compounds from perpendicular to the pressure direction. In addition, there exist a large quantity of low-angle grain boundaries and a high concentration of edge dislocations and stacking faults in the grains. All these microstructures result in lattice mismatch and distortion and can act as the phonon scattering centers, which broaden the understanding of the low thermal conductivity of SnSe based compounds.

Norepinephrine inhibits CD8+ T-cell infiltration and function, inducing anti-PD-1 mAb resistance in lung adenocarcinoma.

BACKGROUND: Mental stress-induced neurotransmitters can affect the immune system in various ways. Therefore, a better understanding of the role of neurotransmitters in the tumour immune microenvironment is expected to promote the development of novel anti-tumour therapies. METHODS: In this study, we analysed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments and experiments in vitro were used to reveal the specific mechanism of norepinephrine's (NE) effect on immunotherapy. RESULTS: The plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of C-X-C Motif Chemokine Ligand 9 (CXCL9) and adenosine (ADO) in tumour cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/ß-catenin signalling pathway plays a crucial role in this progression. CONCLUSION: NE can affect the secretion of CXCL9 and ADO in tumour cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD).

The Role of Alternative Splicing Factors hnRNP G and Fox-2 in the Progression and Prognosis of Esophageal Cancer.

Aim: Alternative splicing (AS) has been widely demonstrated in the occurrence and progression of many cancers. Nevertheless, the involvement of cancer-associated splicing factors in the development of esophageal carcinoma (ESCA) remains to be explored. Method: RNA-Seq data and the corresponding clinical information of the ESCA cohort were downloaded from The Cancer Genome Atlas database. Bioinformatics methods were used to further analyzed the differently expressed AS (DEAS) events and their splicing network. Kaplan-Meier, Cox regression, and unsupervised cluster analyses were used to assess the association between AS events and clinical characteristics of ESCA patients. The splicing factors screened out were verified in vitro at the cellular level. Results: A total of 50,342 AS events were identified, of which 3,988 were DEAS events and 46 of these were associated with overall survival (OS) of ESCA patients, with a 5-year OS rate of 0.941. By constructing a network of AS events with survival-related splicing factors, the AS factors related to prognosis can be further identified. In vitro experiments and database analysis confirmed that the high expression of hnRNP G in ESCA is related to the high invasion ability of ESCA cells and the poor prognosis of ESCA patients. In contrast, the low expression of fox-2 in esophageal cancer is related to a better prognosis. Conclusion: ESCA-associated AS factors hnRNP G and Fox-2 are of great value in deciphering the underlying mechanisms of AS in ESCA and providing clues for therapeutic goals for further validation.

Revealing the Defect-Dominated Electron Scattering in Mg3Sb2-Based Thermoelectric Materials.

The thermoelectric parameters are essentially governed by electron and phonon transport. Since the carrier scattering mechanism plays a decisive role in electron transport, it is of great significance for the electrical properties of thermoelectric materials. As a typical example, the defect-dominated carrier scattering mechanism can significantly impact the room-temperature electron mobility of n-type Mg3Sb2-based materials. However, the origin of such a defect scattering mechanism is still controversial. Herein, the existence of the Mg vacancies and Mg interstitials has been identified by synchrotron powder X-ray diffraction. The relationship among the point defects, chemical compositions, and synthesis conditions in Mg3Sb2-based materials has been revealed. By further introducing the point defects without affecting the grain size via neutron irradiation, the thermally activated electrical conductivity can be reproduced. Our results demonstrate that the point defects scattering of electrons is important in the n-type Mg3Sb2-based materials.

Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC.

The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.