Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma.

BACKGROUND & AIMS: Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation shows decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression. METHODS: Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and the HCC clinical characteristics as well as anti-PD-1 response. Subcutaneous xenograft, orthotopic xenograft, Trp53Δhep/Δhep; MYC- as well as Ctnnboe; METoe- driven mouse models were adopted to validate GCDH effects on HCC suppression. RESULTS: GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDHhigh cells. These cells induced the infiltration of immune cells by the senescence-associated secretory cell phenotype (SASP) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDHlow population was sensitized to anti-programmed cell death protein 1 (PD-1) therapy. CONCLUSION: GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment by SASP. The GCDHlow population is vulnerable to anti-PD-1 therapy because more PD-1+CD8+ T cells are exhibited in GCDHlow population. IMPACT AND IMPLICATIONS: GCDH is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most of GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Therefore, studies on the correlation between GCDH and liver cancer would contribute to discovering the initiation and progression of hepatocellular carcinoma, of which over 70% of patients occupied >2-fold GCDH downregulation. Given that the GCDHlow and GCDHhigh HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH.

High-Precision and Real-Time Measurement of Water Isotope Ratios Based on a Mid-Infrared Optical Sensor.

A compact spectrometer based on a mid-infrared optical sensor has been developed for high-precision and real-time measurement of water isotope ratios. The instrument uses laser absorption spectroscopy and applies the weighted Kalman filtering method to determine water isotope ratios with high precision and fast time response. The precision of the measurements is 0.41‰ for δ18O and 0.29‰ for δ17O with a 1 s time. This is much faster than the standard running average technique, which takes over 90 s to achieve the same level of precision. The successful development of this compact mid-infrared optical sensor opens up new possibilities for its future applications in atmospheric and breath gas research.

Topological Photonic Alloy.

We present the new concept of photonic alloy as a nonperiodic topological material. By mixing nonmagnetized and magnetized rods in a nonperiodic 2D photonic crystal configuration, we realized photonic alloys in the microwave regime. Our experimental findings reveal that the photonic alloy sustains nonreciprocal chiral edge states even at very low concentration of magnetized rods. The nontrivial topology and the associated edge states of these nonperiodic systems can be characterized by the winding of the reflection phase. Our results indicate that the threshold concentrations for the investigated system within the first nontrivial band gap to exhibit topological behavior approach zero in the thermodynamic limit for substitutional alloys, while the threshold remains nonzero for interstitial alloys. At low concentration, the system exhibits an inhomogeneous structure characterized by isolated patches of nonpercolating magnetic domains that are spaced far apart within a topologically trivial photonic crystal. Surprisingly, the system manifests chiral edge states despite a local breakdown of time-reversal symmetry rather than a global one. Photonic alloys represent a new category of disordered topological materials, offering exciting opportunities for exploring topological materials with adjustable gaps.

Constrained tandem neural network assisted inverse design of metasurfaces for microwave absorption.

Designing microwave absorbers with customized spectrums is an attractive topic in both scientific and engineering communities. However, due to the massive number of design parameters involved, the design process is typically time-consuming and computationally expensive. To address this challenge, machine learning has emerged as a powerful tool for optimizing design parameters. In this work, we present an analytical model for an absorber composed of a multi-layered metasurface and propose a novel inverse design method based on a constrained tandem neural network. The network can provide structural and material parameters optimized for a given absorption spectrum, without requiring professional knowledge. Furthermore, additional physical attributes, such as absorber thickness, can be optimized when soft constraints are applied. As an illustrative example, we use the neural network to design broadband microwave absorbers with a thickness close to the causality limit imposed by the Kramers-Kronig relation. Our approach provides new insights into the reverse engineering of physical devices.

Experimental Realization of Stable Exceptional Chains Protected by Non-Hermitian Latent Symmetries Unique to Mechanical Systems.

Lines of exceptional points are robust in the three-dimensional non-Hermitian parameter space without requiring any symmetry. However, when more elaborate exceptional structures are considered, the role of symmetry becomes critical. One such case is the exceptional chain (EC), which is formed by the intersection or osculation of multiple exceptional lines (ELs). In this Letter, we investigate a non-Hermitian classical mechanical system and reveal that a symmetry intrinsic to second-order dynamical equations, in combination with the source-free principle of ELs, guarantees the emergence of ECs. This symmetry can be understood as a non-Hermitian generalized latent symmetry, which is absent in prevailing formalisms rooted in first-order Schrödinger-like equations and has largely been overlooked so far. We experimentally confirm and characterize the ECs using an active mechanical oscillator system. Moreover, by measuring eigenvalue braiding around the ELs meeting at a chain point, we demonstrate the source-free principle of directed ELs that underlies the mechanism for EC formation. Our Letter not only enriches the diversity of non-Hermitian exceptional point configurations, but also highlights the new potential for non-Hermitian physics in second-order dynamical systems.

Photonic Z_{2} Topological Anderson Insulators.

That disorder can induce nontrivial topology is a surprising discovery in topological physics. As a typical example, Chern topological Anderson insulators (TAIs) have been realized in photonic systems, where the topological phases exist without symmetry protection. In this Letter, by taking transverse magnetic and transverse electric polarizations as pseudospin degrees of freedom, we theoretically propose a scheme to realize disorder-induced symmetry-protected topological phase transitions in two-dimensional photonic crystals with a combined time-reversal, mirror, and duality symmetry T_{f}=TM_{z}D. In particular, we demonstrate that the disorder-induced symmetry-protected topological phase persists even without pseudospin conservation, thereby realizing a photonic Z_{2} TAI, in contrast to a Z-classified quantum spin Hall (QSH) TAI with decoupled spins. By formulating a new scattering approach, we show that the topology of both the QSH and Z_{2} TAIs can be manifested by the accumulated spin rotations of the reflected waves from the photonic crystals. Using a transmission structure, we also illustrate the trivialization of a disordered QSH phase with an even integer topological index caused by spin coupling.

Cell division cycle associated 8: A novel diagnostic and prognostic biomarker for hepatocellular carcinoma.

The cell division cycle associated 8 (CDCA8) is a crucial component of the chromosome passenger complex (CPC). It has been implicated in the regulation of cell dynamic localization during mitosis. However, its role in hepatocellular carcinoma (HCC) is not clearly known. In this study, data of 374 patients with HCC were retrieved from the Cancer Genome Atlas (TCGA) database. Pan analysis of Gene Expression Profiling Interactive Analysis (GEPIA) database was performed to profile the mRNA expression of CDCA8 in HCC. Then, the Kaplan-Meier plotter database was analysed to determine the prognostic value of CDCA8 in HCC. In addition, samples of tumour and adjacent normal tissues were collected from 88 HCC patients to perform immunohistochemistry (IHC), reverse transcription-quantitative polymerase chain reaction (qRT-PCR) and Western blotting. The results obtained from bioinformatic analyses were validated through CCK-8 assay, EdU assay, colony formation assay, cell cycle assays and Western blotting experiments. Analysis of the Kaplan-Meier plotter database showed that high expression of CDCA8 may lead to poor overall survival (OS, p = 4.06e-05) in patients with HCC. For the 88 patients with HCC, we found that stages and grades appeared to be strongly linked with CDCA8 expression. Furthermore, the high expression of CDCA8 was found to be correlated with poor OS (p = 0.0054) and progression-free survival (PFS, p = 0.0009). In vitro experiments revealed that inhibition of CDCA8 slowed cell proliferation and blocked the cell cycle at the G0/G1 phase. In vivo experiments demonstrated that inhibition of CDCA8 inhibited tumour growth. Finally, blockade of CDCA8 reduced the expression levels of cyclin A2, cyclin D1, CDK4, CDK6, Ki67 and PCNA. And, there is an interaction between CDCA8 and E2F1. In conclusion, this research demonstrates that CDCA8 may serve as a biomarker for early diagnosis and prognosis prediction of HCC patients. In addition, CDCA8 could be an effective therapeutic target in HCC.

Circ_0075829 facilitates the progression of pancreatic carcinoma by sponging miR-1287-5p and activating LAMTOR3 signalling.

Pancreatic cancer (PC) is a leading cause of cancer-related mortality globally. Though increasing evidence has demonstrated that circular RNAs (circRNAs) are linked to the development and progression of cancers, the biological functions of circRNAs in PC remain largely unexplored so far. Based on previous studies, Hsc_circ_0075829 (circ_0075829) was screened out and then further identified in PC clinical specimens and cell lines by real-time PCR. After the stability tests, a series of in vitro and in vivo functional experiments were performed to investigate the role of circ_0075829 in PC development. Furthermore, fluorescent in situ hybridization (FISH), bioinformatics tools, dual-luciferase assays and rescue experiments were conducted to clarify the regulatory mechanisms of circ_0075829 in SW1990 and BxPC-3 cells. Compared with paracancerous tissues, the expression of circ_0075829 was increased in PC tissues, which was positively correlated with the clinical features of PC. Knockdown of circ_0075829 significantly suppressed the proliferative, migratory and invasive rates of SW1990 and BxPC-3 cells both in vitro and in vivo. Bioinformatics analysis and dual-luciferase reporter gene assay indicated that circ_0075829 could bind to miR-1287-5p. Mechanism research and rescue experiments demonstrated that circ_0075829 could regulate the LAMTOR3/p-ERK signalling pathway via sponging miR-1287-5p in PC cell lines. Our data reveal that the circ_0075829 could facilitate the proliferation and metastasis of PC through circ_0075829/miR-1287-5p/LAMTOR3 axis.

Expression and prognostic analyses of the insulin-like growth factor 2 mRNA binding protein family in human pancreatic cancer.

BACKGROUND: Despite advances in early diagnosis and treatment, cancer remains the leading cause of mortality worldwide. The insulin-like growth factor 2 mRNA binding protein (IGF2BP) family has been reported to be involved in a variety of human malignant tumours. However, little is known about their expression and prognostic value in human pancreatic cancer. Therefore, we performed a detailed cancer versus normal differential analysis. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to analyse the mRNA expression levels of the IGF2BP family in various cancers, including pancreatic cancer. Then, the LinkedOmics and GEPIA databases were used to assess the relation between the expression levels of IGF2BPs and overall survival (OS). Then, univariate and multivariate Cox regression analyses were performed, and subgroups based on grade and stage were analysed. The signalling pathways associated with IGF2BP2 and IGF2BP3 were then investigated via gene set enrichment analysis (GSEA). RESULTS: IGF2BP2 and IGF2BP3 were associated with each subset of OS based on grade and stage. Further clinical correlation analysis of IGF2BP2 and IGF2BP3 confirmed that IGF2BP2 and IGF2BP3 are fundamental factors in promoting pancreatic cancer progression. CONCLUSION: IGF2BP2 and IGF2BP3 are key factors in promoting the progression of pancreatic cancer and are closely related to overall survival.

Superlens induced loss-insensitive optical force.

A slab with relative permittivity ɛ = -1+iδ and permeability µ = ­1+iδ has a critical distance away from the slab where a small particle will either be cloaked or imaged depending on whether it is located inside or outside that critical distance. We find that the optical force acting on a small cylinder under plane wave illumination reaches a maximum value at this critical distance. Contrary to the usual observation that superlens systems should be highly loss-sensitive, this maximum optical force remains a constant when loss is changed within a certain range. For a fixed particle-slab distance, increasing loss can even amplify the optical force acting on the small cylinder, contrary to the usual belief that loss compromises the response of supenlens.

Hyperbolic metamaterial based on anisotropic Mie-type resonance.

A hyperbolic metamaterial (MM) based on anisotropic Mie-type resonance is theoretically and experimentally demonstrated in microwave range. Based on the shape-dependent Mie-type resonance, metamaterials with indefinite permeability or permittivity parameters are designed by tailoring the isotropic particle into an anisotropic one. The flat lens consisting of anisotropic dielectric resonators has been designed, fabricated and tested. The experimental observation of refocusing and a plane wave with ominidirectional radiation directly verify the predicted properties, which confirm the potential application in negative index material and superlens. This work will also help to develop all-dielectric anisotropic MM devices such as 3D spatial power combination, cloak, and electromagnetic wave converter, etc.

ASF1B, as an Independent Prognostic Biomarker, Correlates with Immune Infiltrates in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular Carcinoma (HCC) is one of the fastest-growing malignancies globally. The impact of surgical treatment is limited, and molecular targeted therapy has not yielded a consistent efficacy. This warrants for identification of novel molecular targets. The Anti- Silencing Function of 1B histone chaperone (ASF1B) was previously studied in numerous cancers. However, the understanding of its role in HCC is limited. METHODS: The TIMER database was used to analyze the ASF1B expression in pan-cancer and paracarcinoma tissues. ASF1B expression in HCC was confirmed using the HCCDB database, Quantitative real-time PCR (q-PCR), and Western Blot (WB) assays. The relationship between clinicopathological parameters and ASF1B expression was analyzed using UALCAN, whereas the prognostic value of ASF1B was evaluated using the GEPIA database. Linkedomics and cBioPortal databases were used to validate the ASF1B co-expression associated with immune infiltration by the TIMER database. Moreover, cell proliferation after ASF1B-knockdown was determined through CCK8 and clone formation assays. RESULTS: ASF1B was highly expressed in HCC tissues, and the expression levels were linked to tumor grade, race, and disease stage. Univariate and multivariate Cox models showed that ASF1B is an independent prognostic factor in HCC. CCK8 and clone formation assays demonstrated that ASF1B promotes cell proliferation. Gene co-expression analysis in Linkedomics demonstrated that HJURP, KIF2C, KIF4A, KIF18B, and KIFC1 expressions were closely associated with ASF1B and immune infiltrate cells. CONCLUSION: This study shows that ASF1B promotes the proliferation of HCC. Besides, ASF1B could be a potential prognostic biomarker for HCC patients.

Exploration on dynamics in a discrete predator-prey competitive model involving feedback controls.

In this work, we set up a new discrete predator-prey competitive model with time-varying delays and feedback controls. By virtue of the difference inequality knowledge, a sufficient condition which guarantees the permanence of the established discrete predator-prey competitive model with time-varying delays and feedback controls is derived. Under some appropriate parameter conditions, we have proved that the periodic solution of the system without delay exists and globally attractive. To verify the correctness of the derived theoretical fruits, we give two examples and execute computer simulations. Our obtained results are novel and complement previous known results.

Line positions and effective line strengths of trans-HONO near 1280 cm-1.

The measurement of the line positions and effective line strengths of the ν3 fundamental band of trans-nitrous acid (trans-HONO) near 1280 cm-1 (7.8 µm) by tunable laser absorption spectroscopy (TLAS) utilizing a room temperature continuous-wave quantum cascade laser (cw-QCL) was reported. The effective line strengths of 30 well-resolved trans-HONO absorption lines in the range of 1279.8-1282.2 cm-1 were determined using the HONO line strength at 1280.3841 cm-1 as a scale. The maximum measurement uncertainty of 7.64% in the line strengths is mainly determined by the uncertainty of the referenced line strength, while the measurement precision of the line positions is better than 5.56 * 10-3 cm-1. The line positions and strengths of the trans-HONO absorption lines obtained in this work provide a reference for continuous gas monitoring and analysis of the sources and sinks of atmospheric HONO.

HMGCL-induced ß-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility.

BACKGROUND: Metabolic disorder is an essential characteristic of tumor development. Ketogenesis is a heterogeneous factor in multiple cancers, but the effect of ketogenesis on hepatocellular carcinoma (HCC) is elusive. METHODS: We aimed to explain the role of ketogenesis-related hydroxy-methyl-glutaryl-CoA lyase (HMGCL) on HCC suppression. Expression pattern of HMGCL in HCC specimens was evaluated by immunohistochemistry (IHC). HMGCL was depleted or overexpressed in HCC cells to investigate the functions of HMGCL in vitro and in vivo. The anti-tumor function of HMGCL was studied in subcutaneous xenograft and Trp53Δhep/Δhep; c-Myc-driven HCC mouse models. The mechanism of HMGCL-mediated tumor suppression was studied by IHC, western blot (WB) and Cut & Tag. RESULTS: HMGCL depletion promoted HCC proliferation and metastasis, whereas its overexpression reversed this trend. As HMGCL catalyzes ß-hydroxy-butyric acid (ß-OHB) production, we discovered that HMGCL increased acetylation at histone H3K9, which further promoted the transcription of dipeptidyl peptidase 4 (DPP4), a key protein maintains intracellular lipid peroxidation and iron accumulation, leading to HCC cells vulnerability to erastin- and sorafenib-induced ferroptosis. CONCLUSION: Our study identified a critical role of HMGCL on HCC suppression, of which HMGCL regulated H3K9 acetylation through ß-OHB and modulating the expression of DPP4 in a dose-dependent manner, which led to ferroptosis in HCC cells.

POU5F1 promotes the proliferation, migration, and invasion of gastric cancer cells by reducing the ubiquitination level of TRAF6.

POU5F1 plays an important role in maintaining the cancer stem cell (CSC) -like properties of gastric cancer (GC) cells. The impact of POU5F1 on the proliferation and metastasis of GC was examined, along with the potential of ATRA as a specific therapeutic agent for GC. The dysregulation of POU5F1 expression in GC tissues was analyzed using public databases and bioinformatics techniques, and the disparity in POU5F1 expression between normal gastric tissues and GC tissues was further assessed through western blot, RT-qPCR, and immunohistochemistry. The present study aimed to investigate the impact of POU5F1 on the proliferation, migration, and invasion of GC cells through both in vivo and in vitro experiments. Additionally, the effects of ATRA on the proliferation, migration, and invasion of GC cells were examined using in vivo and in vitro approaches. Our findings revealed a significant upregulation of POU5F1 in GC tissues, which was found to be associated with a poorer prognosis in patients with GC. Moreover, POU5F1 was observed to enhance the proliferation, migration, and invasion of GC cells in vitro, as well as promote subcutaneous tumor growth and lung metastasis of GC cells in vivo. The overexpression of POU5F1 mechanistically triggers the process of Epithelial-mesenchymal transition (EMT) by down-regulating E-Cadherin and up-regulating N-Cadherin and VIM. POU5F1 hinders the ubiquitination of TRAF6 through negative regulation of TRIM59, thereby facilitating the activation of the NF-κB pathway. Furthermore, the administration of ATRA effectively impedes the proliferation, migration, and invasion of GC cells by suppressing the expression of POU5F1. The upregulation of POU5F1 elicits EMT, fosters the initiation of the NF-κB signaling pathway in GC cells, and stimulates the proliferation, invasion, and metastasis of GC cells. All-trans retinoic acid (ATRA) can impede these POU5F1-induced effects, thereby potentially serving as an adjunctive therapeutic approach for GC.

Meta-analysis reveals variations in microbial communities from diverse stony coral taxa at different geographical distances.

Coral-associated microbial communities play a vital role in underpinning the health and resilience of reef ecosystems. Previous studies have demonstrated that the microbial communities of corals are affected by multiple factors, mainly focusing on host species and geolocation. However, up-to-date, insight into how the coral microbiota is structured by vast geographic distance with rich taxa is deficient. In the present study, the coral microbiota in six stony coral species collected from the coastal area of three countries, including United States of America (USA), Australia and Fiji, was used for analysis. It was found that the geographic influence on the coral microbiota was stronger than the coral host influence, even though both were significant. Interestingly, the contribution of the deterministic process to bacterial community composition increased as geographical distance grew. A total of 65 differentially abundant features of functions in coral microbial communities were identified to be associated with three geolocations. While in the same coastal area of USA, the similar relationship of coral microbiota was consistent with the phylogenetic relationship of coral hosts. In contrast to the phylum Proteobacteria, which was most abundant in other coral species in USA, Cyanobacteria was the most abundant phylum in Orbicella faveolata. The above findings may help to better understand the multiple natural driving forces shaping the coral microbial community to contribute to defining the healthy baseline of the coral microbiome.

Effects of 60 days of 6° head-down bed rest on the composition and function of the human gut microbiota.

Spaceflight is rigorous and dangerous environment which can negatively affect astronauts' health and the entire mission. The 60 days of 6° head-down bed rest (HDBR) experiment provided us with an opportunity to trace the change of gut microbiota under simulated microgravity. The gut microbiota of volunteers was analyzed and characterized by 16S rRNA gene sequencing and metagenomic sequencing. Our results showed that the composition and function of the volunteers' gut microbiota were markedly was affected by 60 days of 6° HDBR. We further confirmed the species and diversity fluctuations. Resistance and virulence genes in the gut microbiota were also affected by 60 days of 6° HDBR, but the species attributions remained stable. The human gut microbiota affected by 60 days of 6° HDBR which was partially consistent with the effect of spaceflight, this implied that HDBR was a simulation of how spaceflight affects the human gut microbiota.

The biological behavior of tRNA-derived fragment tRF-Leu-AAG in pancreatic cancer cells.

Pancreatic cancer (PC) is a life-threatening cancer with increasing incidence in developed countries. Reports indicate that tRNA-derived fragments (tRFs) are possible therapeutic targets and biomarkers for cancer treatment. Nonetheless, the effect of tRF-Leu-AAG on PC is unclear. This study aims to explore the role of tRF-Leu-AAG and upstream frameshift mutant 1 (UPF1) in the development of PC and its potential underlying mechanisms. High-throughput second-generation sequencing techniques were used to detect the expression of tRFs in cancerous and adjacent normal tissues from PC patients. The role of tRF-Leu-AAG proliferation in PC cells was investigated via the Cell Counting Kit-8 (CCK8) assay. The effect of tRF-Leu-AAG on the invasion and migration ability of PC cells was also determined by the transwell assay. Thereafter, the downstream target genes of tRF-Leu-AAG were comprehensively predicted using bioinformatics analysis databases. We also used the Dual-Luciferase Reporter assay to assess the nexus between tRF-Leu-AAG and UPF1. Eventually, Western Blot was used to validate the expression of UPF1 in PC cells. A total of 33 tRF expressions significantly varied from PC patients. RT-qPCR confirmed that the expression of tRF-Leu-AAG was observably up-regulated in PC cells as compared to the control cells. Importantly, knockdown of tRF-Leu-AAG observably inhibited cell proliferation, migration, and invasion. Furthermore, according to the predicted frameshift database results, the UPF1 acted as downstream target genes for tRF-Leu-AAG and significantly down-regulated UPF1 expression.

Circular RNA circRASSF5 Functions as an Anti-Oncogenic Factor in Hepatocellular Carcinoma by Acting as a Competitive Endogenous RNA Through Sponging miR-331-3p.

Objective: Recently, emerging studies have validated that circular RNAs participate in multiple biological progresses in various human malignant tumors, including hepatocellular carcinoma (HCC). However, until now, the elucidated mechanism of circular RNAs is only the tip of the iceberg. In this study, we firstly identify a novel circular RNA circRASSF5 (the only circular RNA derived from the RASSF5 gene), and attempt to investigate its biological function and underlying mechanism in HCC. Methods: qRT-PCR, Western blotting and IHC were applied to detect the expression of related genes. CCK-8 assay, EdU staining, wound healing and transwell assays were used to investigate HCC proliferation, migration and invasion abilities. Animal model studies were included to investigate the function of circRASSF5 in HCC tumorigenesis and metastasis. RNA pull-down assay, luciferase reporter assay and FISH (fluorescence in situ hybridization) assay were performed to explore the potential biological mechanism underlying circRASSF5 function in HCC. Results: CircRASSF5 is obviously downregulated in both HCC tissues and cell lines. Low level of circRASSF5 is negatively associated with larger tumor size, severe vascular invasion, more portal vein tumor embolus and unfavorable prognosis. Loss-of-function assay reveals that circRASSF5 remarkably impedes the growth and metastasis of HCC cells in vitro and in vivo. Mechanistically, circRASSF5 directly interacts with miR-331-3p as a sponge, and then enhances the expression of PH domain and leucine-rich repeat protein phosphatase (PHLPP), thus restraining the progression of HCC cells. Conclusion: Altogether, we validate that circRASSF5 is a tumor suppressor in HCC, which competitively sponges with miR-331-3p and then enhances the tumor inhibitory effect of PHLPP, indicating the potential application value of circRASSF5 for HCC diagnosis and clinical treatment.