Sources, bioaccumulation, and toxicity mechanisms of cadmium in Chlamys farreri.

The Potentially toxic elements (PTEs) cadmium (Cd) is one of the most serious stressors polluting the marine environment. Marine bivalves have specific high enrichment capacity for Cd. Previous studies have investigated the tissue distribution changes and toxic effects of Cd in bivalves, but the sources of Cd enrichment, migration regulation during growth, and toxicity mechanisms in bivalves have not been fully explained. Here, we used stable-isotope labeling to investigate the contributions of Cd from different sources to scallop tissues. We sampled the entire growth cycle of Chlamys farreri, which is widely cultured in northern China, from juveniles to adult scallops. We found tissue variability in the bioconcentration-metabolism pattern of Cd in different bound states, with Cd in the aqueous accounting for a significant contribution. The accumulation pattern of Cd in all tissues during growth was more significant in the viscera and gills. Additionally, we combined a multi-omics approach to reveal a network of oxidative stress-induced toxicity mechanisms of Cd in scallops, identifying differentially expressed genes and proteins involved in metal ion binding, oxidative stress, energy metabolism, and apoptosis. Our findings have important implications for both ecotoxicology and aquaculture. They also provide new insights into marine environmental assessment and mariculture development.

Neonicotinoids in draining micro-watersheds dominated by rice-vegetable rotations in tropical China: Multimedia occurrence, influencing factors, transport, and associated ecological risks.

Multimedia contamination by neonicotinoid (NEO) residues has attracted global attention. However, data regarding the multimedia polluted status under certain typical cropping scenarios and the associated risks are scarce. Here, the multimedia occurrence, spatiotemporal distribution, driving factors, transport, and ecological risks of NEOs from tropical rice-vegetable rotation fields were characterized. The heavy NEOs resided in multiple media, and imidacloprid and acetamiprid were the prevailing NEOs, with concentration contributions of 65-80%. The pollution levels of the NEOs, rather than their compositions, exhibited significant spatiotemporal heterogeneity and were highly correlated with the collective (agricultural practices and climate conditions) and differential (e.g., media properties) factors identified using an auto linear regression model. Furthermore, the multimedia transport of NEOs was largely similar but non-negligibly different during the rainy and dry seasons. A new multimedia ecological risk assessment revealed that 50.6% sites were at high risk, and the risk hotspots occurred in the central areas and the winter planting period. The risks were largely contributed by imidacloprid and thiamethoxam, indicating that there were non-ignorable ecological risks. Our results highlight the differential pollution patterns (distribution, transport, and driving factors) of the prevailing NEOs under tropical agricultural scenarios, and the fact that special attention should be paid to the risks posed by NEOs.

Occurrence, distribution, and driving factors of current-use pesticides in commonly cultivated crops and their potential risks to non-target organisms: A case study in Hainan, China.

Multiple pesticides are heavily applied in crops grown in China's tropics due to the prevalence of diseases and pests, thus posing potential risks to nontarget organisms (e.g., honeybees, lacewings, ladybugs, and humans). However, there is little information on this topic. This study is the first assessment of the occurrence, driving factors, and ecological/human health risks of 32 current-use pesticides (CUPs) in 10 frequently-planted crops collected from practicing rice-vegetable rotation systems in Hainan, China. Of the 132 whole crop samples, 44 (33.3 %) residues from ≥8 pesticides were detected in 9.09 % of crop samples with concentrations ≥0.5 mg kg-1. Six pesticide residues, namely carbendazim, pyraclostrobin, acetamiprid, thiophanate methyl, phoxim, and imidacloprid, were detected in 72.7 % of samples, with concentrations ranging from 0.0021 to 13.5 (median = 0.032) mg kg-1. Among them, carbendazim, pyraclostrobin, and acetamiprid were the most common, contributions from 10.2 to 25.5 % and a detection frequency ranging from 25.6 to 56.1 %. The order of total concentration of 32 CUPs (∑32 CUP) concentrations during the year was January > May > November > August and vegetables > rice, being highly related with pesticides usage pattern, crop type, plant accumulation/dissipation and plant lipid contents. The ecological risk quotients (RQs) to four beneficial terrestrial organisms showed that 9.6-39.1 % of samples posed a potential medium or high ecological risk, with 13.6-65.9 % of samples at ∑RQ > 1 being highly affected by the residues of neonicotinoids and emamectin benzoate. Emamectin benzoate (8.9 %) and acetamiprid (5.6 %) exceeded the individual Maximum Residue Levels based on Chinese legislation (GB2763-2021). Moreover, cumulative dietary exposure presented a higher risk to humans in 11.0 and 22.0 % of the cases for acute and chronic, mainly originating from the higher concentration contributors of systemic pesticides in edible crops. Therefore, the regulation and monitoring of CUP residues is imperative for rice-vegetable rotation systems in tropical China to avoid negative effects on nontarget organisms.

Analyzing toxicological effects of AsIII and AsV to Chlamys farreri by integrating transcriptomic and metabolomic approaches.

Inorganic arsenic (iAs) is a widespread contaminant in marine environments, which is present in two different oxidation states (arsenate (AsV) and arsenite (AsIII)) that have complex toxic effects on marine organisms. The scallop Chlamys farreri (C. farreri) accumulates high levels of As and is a suitable bioindicator of As. In this report, we integrated transcriptomics and metabolomics to investigate genetic and metabolite changes and functional physiological disturbances in C. farreri exposured to inorganic arsenic. Physiological indicators antioxidant factors and cell apoptosis analysis macroscopically corroborated the toxic effects of inorganic arsenic revealed by omics results. Toxic effects of inorganic arsenic on C. farreri were signaling-mediated, causing interference with a variety of cell growth and small molecule metabolism. The results provide evidence that inorganic arsenic disrupts the physiological functions of bivalves, highlighting the correlations between different metabolic pathways and providing new insights into the toxic effects of environmental pollutants on marine organisms.

CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis.

Radiation enteritis (RE) is a prevalent complication of radiotherapy for pelvic malignant tumors, characterized by severe intestinal epithelial destruction and progressive submucosal fibrosis. However, little is known about the pathogenesis of this disease, and so far, there is no specific targeted therapy. Here, we report that CXCL16 is upregulated in the injured intestinal tissues of RE patients and in a mouse model. Genetic deletion of Cxcl16 mitigates fibrosis and promotes intestinal stem cell-mediated epithelial regeneration after radiation injury in mice. Mechanistically, CXCL16 functions on myofibroblasts through its receptor CXCR6 and activates JAK3/STAT3 signaling to promote fibrosis and, at the same time, to transcriptionally modulate the levels of BMP4 and hepatocyte growth factor (HGF) in myofibroblasts. Moreover, we find that CXCL16 and CXCR6 auto- and cross-regulate themselves in positive feedback loops. Treatment with CXCL16 neutralizing monoclonal antibody attenuates fibrosis and improves the epithelial repair in RE mouse model. Our findings emphasize the important role of CXCL16 in the progression of RE and suggest that CXCL16 signaling could be a potential therapeutic target for RE. © 2022 The Pathological Society of Great Britain and Ireland.

Mitochondrial ferritin alleviates apoptosis by enhancing mitochondrial bioenergetics and stimulating glucose metabolism in cerebral ischemia reperfusion.

Oxidative stress and deficient bioenergetics are key players in the pathological process of cerebral ischemia reperfusion injury (I/R). As a mitochondrial iron storage protein, mitochondrial ferritin (FtMt) plays a pivotal role in protecting neuronal cells from oxidative damage under stress conditions. However, the effects of FtMt in mitochondrial function and activation of apoptosis under cerebral I/R are barely understood. In the present study, we found that FtMt deficiency exacerbates neuronal apoptosis via classical mitochondria-depedent pathway and the endoplasmic reticulum (ER) stress pathway in brains exposed to I/R. Conversely, FtMt overexpression significantly inhibited oxygen and glucose deprivation and reperfusion (OGD/R)-induced apoptosis and the activation of ER stress response. Meanwhile, FtMt overexpression rescued OGD/R-induced mitochondrial iron overload, mitochondrial dysfunction, the generation of reactive oxygen species (ROS) and increased neuronal GSH content. Using the Seahorse and O2K cellular respiration analyser, we demonstrated that FtMt remarkably improved the ATP content and the spare respiratory capacity under I/R conditions. Importantly, we found that glucose consumption was augmented in FtMt overexpressing cells after OGD/R insult; overexpression of FtMt facilitated the activation of glucose 6-phosphate dehydrogenase and the production of NADPH in cells after OGD/R, indicating that the pentose-phosphate pathway is enhanced in FtMt overexpressing cells, thus strengthening the antioxidant capacity of neuronal cells. In summary, our results reveal that FtMt protects against I/R-induced apoptosis through enhancing mitochondrial bioenergetics and regulating glucose metabolism via the pentose-phosphate pathway, thus preventing ROS overproduction, and preserving energy metabolism.

Polycyclic aromatic hydrocarbons (PAHs) in surface soils of tropical reef islands in China under external plant and soil introduction: Occurrence, sources, risks, and relationships with soil properties, vegetation cover, and soil source.

This study explored the levels, sources, and risks of PAHs in soils from Yongle Atoll (YLA) and Xuande Atoll (XDA) of the Xisha Islands (XSIs) in the South China Sea, China, under different vegetation cover types and soil sources. The results clearly showed that the levels of 16 US EPA priority PAHs (Σ16PAHs) are relatively low in XDA and YLA, with concentrations ranging from not detected (ND) to 151 ng/g (average 15.7 ng/g) and ND to 5.8 ng/g (average 2.1 ng/g), respectively. Three- and four-ring PAHs (62.3% and 53.8%) were widely distributed in YLA and XDA. The average concentration of Σ16PAHs in soils with shrub cover was 1.4, 1.8, 4.8, and 5.0 times higher than that in soils with herbaceous cover, vegetable cover, arbor cover, and no plant cover, respectively. Source analysis using binary diagnostic ratios and the positive matrix factorization (PMF) model suggested that PAHs have similar sources (gasoline/coal combustion, coke production, and biomass combustion), but different contributions in native soil and introduced soil. Moreover, diesel-related vehicular emission was identified to be an additional source of PAHs in native soil. Pearson's correlations revealed strong relationships between PAHs and organic matter or total organic carbon. The cancer risk of PAHs varied among different vegetation cover types and soil sources, following the orders herbaceous cover > vegetable cover > shrub cover > arbor cover > no plant cover and introduced soil > mixed soil > native soil. Nevertheless, the risk remained lower than the risk threshold (10-6), suggesting low carcinogenesis risk in the two atolls. Our findings provide new evidence for the introduction of external vegetation/soil acting as a driver of changes in the characteristics of PAHs in islands, and also underline the negligibility of the PAH increase in soils in the South China Sea, China, from the perspective of health hazards.

The dynamic cellular and molecular features during the development of radiation proctitis revealed by transcriptomic profiling in mice.

BACKGROUND: Radiation proctitis (RP) is the most common complication of radiotherapy for pelvic tumor. Currently there is a lack of effective clinical treatment and its underlying mechanism is poorly understood. In this study, we aimed to dynamically reveal the mechanism of RP progression from the perspective of RNomics using a mouse model, so as to help develop reasonable therapeutic strategies for RP. RESULTS: Mice were delivered a single dose of 25 Gy rectal irradiation, and the rectal tissues were removed at 4 h, 1 day, 3 days, 2 weeks and 8 weeks post-irradiation (PI) for both histopathological assessment and RNA-seq analysis. According to the histopathological characteristics, we divided the development process of our RP animal model into three stages: acute (4 h, 1 day and 3 days PI), subacute (2 weeks PI) and chronic (8 weeks PI), which could recapitulate the features of different stages of human RP. Bioinformatics analysis of the RNA-seq data showed that in the acute injury period after radiation, the altered genes were mainly enriched in DNA damage response, p53 signaling pathway and metabolic changes; while in the subacute and chronic stages of tissue reconstruction, genes involved in the biological processes of vessel development, extracellular matrix organization, inflammatory and immune responses were dysregulated. We further identified the hub genes in the most significant biological process at each time point using protein-protein interaction analysis and verified the differential expression of these genes by quantitative real-time-PCR analysis. CONCLUSIONS: Our study reveals the molecular events sequentially occurred during the course of RP development and might provide molecular basis for designing drugs targeting different stages of RP development.

Ectopic expression of GmRNF1a encoding a soybean E3 ubiquitin ligase affects Arabidopsis silique development and dehiscence.

MAIN CONCLUSION: A soybean E3 ubiquitin ligase, GmRNF1a, may affect pod dehiscence and seed development through MADS family genes. These results would be useful for the study of soybean pod and seed development. Pod dehiscence is one of the critical causes of yield loss in cultivated soybeans, and it is of great significance to understand the molecular mechanisms underlying pod dehiscence in soybeans. In this study, we identified a new RING family member of the E3 ubiquitin ligase, GmRNF1a, which was observed to interact with the MADS-box protein GmAGL1 to regulate siliques dehiscence. Tissue-specific gene expression analysis revealed that GmRNF1a was mainly expressed in flowers and pods in soybean. The subcellular localization assay showed the nuclear and cytoplasmic localization of GmRNF1a. In addition, it was found that GmRNF1a exhibits higher promoter activity in soybean hairy roots as well as in Arabidopsis leaves, flowers, and siliques. Heterologous expression of GmRNF1a in Arabidopsis showed that the transgenic Arabidopsis siliques had a faster maturation rate and cracked earlier than the wild-type plants. The functional and nucleotide diversity analysis suggests that GmRNF1a might play an important role in pod maturation and dehiscence and has been strongly selected for during soybean domestication.

Metabolomic Alterations in the Digestive System of the Mantis Shrimp Oratosquilla oratoria Following Short-Term Exposure to Cadmium.

Mantis shrimp Oratosquilla oratoria is an economically critical aquatic species along the coast of China but strongly accumulates marine pollutant cadmium (Cd) in its digestive system. It is necessary to characterize the toxicity of Cd in the digestive system of mantis shrimp. The metabolic process is an essential target of Cd toxicity response. In this work, we used ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-TOF-MS) for untargeted metabolomics to characterize the metabolic changes in the digestive system of O. oratoria, exposed to 0.05 mg/L for 96 h. The aim of this study was to further investigate the effect of O. oratoria on Cd response to toxicity and develop biomarkers. Metabolomics analysis showed the alteration of metabolism in the digestive system of mantis shrimp under Cd stress. A total of 91 metabolites were differentially expressed and their main functions were classified into amino acids, phospholipids, and fatty acid esters. The enrichment results of differential metabolite functional pathways showed that biological processes such as amino acid metabolism, transmembrane transport, energy metabolism, and signal transduction are significantly affected. Based on the above results, the Cd-induced oxidative stress and energy metabolism disorders were characterized by the differential expression of amino acids and ADP in mantis shrimp, while the interference of transmembrane transport and signal transduction was due to the differential expression of phospholipids. Overall, this work initially discussed the toxicological response of Cd stress to O. oratoria from the metabolic level and provided new insights into the mechanism.

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A method for geographical discrimination of Portunus trituberculatus was explored to provide technical support for the protection of geographical indication products and for tracing the origin of seafood. P. trituberculatus were collected from three major production areas, including the Yellow Sea, the Bohai Sea, and the East China Sea. The variations of carbon and nitrogen stable isotope values of origins and the correlation of stable isotope ratios in different tissues were analyzed. The results showed that there were significant differences in carbon and nitrogen stable isotope ratio among different origins. Significant isotope fractionation effects were observed among different tissues. The discriminant model was developed and the origin discriminant analysis was performed by the stable isotope ratios of different tissues in P. trituberculatus. The correct rate of origin diffe-rentiationf using carbon and nitrogen stable isotopes in muscle and gills (>95%) was significantly higher than that of hepatopancreas and gonad, indicating that stable isotope ratios of muscle and gills could effectively differentiate P. trituberculatus in different sea areas. This study filled the gap of stable isotope tracing technology for P. trituberculatus.

Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis.

Ischaemic stroke is becoming the most common cerebral disease in aging populations, but the underlying molecular mechanism of the disease has not yet been fully elucidated. Increasing evidence has indicated that an excess of iron contributes to brain damage in cerebral ischaemia/reperfusion (I/R) injury. Although mitochondrial ferritin (FtMt) plays a critical role in iron homeostasis, the molecular function of FtMt in I/R remains unknown. We herein report that FtMt levels are upregulated in the ischaemic brains of mice. Mice lacking FtMt experience more severe brain damage and neurological deficits, accompanied by typical molecular features of ferroptosis, including increased lipid peroxidation and disturbed glutathione (GSH) after cerebral I/R. Conversely, FtMt overexpression reverses these changes. Further investigation shows that Ftmt ablation promotes I/R-induced inflammation and hepcidin-mediated decreases in ferroportin1, thus markedly increasing total and chelatable iron. The elevated iron consequently facilitates ferroptosis in the brain of I/R. In brief, our results provide evidence that FtMt plays a critical role in protecting against cerebral I/R-induced ferroptosis and subsequent brain damage, thus providing a new potential target for the treatment/prevention of ischaemic stroke.

Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis.

Most cancer-related deaths result from the progressive growth of metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate-limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT-qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non-PM primary tumors. Here, we showed that cancer-associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture-induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFsCPT1A-OE in vitro and impaired the survival and growth of organoids derived from CRC-PM. Finally, we found that directly blocking FAO in CAFsCPT1A-OE with etomoxir inhibits migration and invasion in vitro and decreases tumor growth and intraperitoneal dissemination in vivo, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF-induced colorectal cancer with peritoneal dissemination/metastases.

Analysis of amantadine in Laminaria Japonica and seawater of Daqin Island by ultra high performance liquid chromatography with positive electrospray ionization tandem mass spectrometry.

A sensitive and validated method for determination of amantadine in Laminaria Japonica and seawater was established using ultra high performance liquid chromatography with positive electrospray ionization tandem spectrometry (UHPLC-ESI-MS/MS). Laminaria Japonica was extracted with acetonitrile containing formic acid (1%), then purified with 10.0 g anhydrous sodium sulfate, 0.50 g C18 and 0.50 g PSA powder. Seawater added 10.0 mL 0.20 mol/L hydrochloric acid was purified with MCX solid phase extraction (SPE) cartridge. After extraction and purification, the supernatant of Laminaria Japonica and eluate of seawater were evaporated to nearly dry under a gentle stream of nitrogen at 40 °C. Acetonitrile-0.1% formic acid in water (3/7, v/v) was adjusted to 1.00 mL final volume. An aliquot (10 µL) was injected into the C18 column for separation with the mobile phase of acetonitrile and 0.1% formic acid in water at 0.25 mL·min-1. Calibration curves were linear ranged from 1.00 ng/mL to 20.0 ng/mL. Mean recoveries were 73.5% to 95.8%, and limit of detection (LOD) and quantification (LOQ) were 0.50 µg/kg and 1.00 µg/kg for Laminaria Japonica. Mean recoveries were 75.8% to 93.4%, and LOD and LOQ were 0.50 ng/L and 1.00 ng/L for seawater. Based on the method above, Laminaria Japonica and seawater in Daqin Island were analyzed in February to June continuously, lgBAF3.71 (bioaccumulation factor), indicating a bioenrichment effect.

Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation.

Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and a critical regulator of a variety of cellular processes as well as tumor progression. Therefore, more substrates must be identified in the physiology or disease context. Here, we found that TRIM65 is upregulated and associated with poor survival in colorectal cancer (CRC). More specifically, high expression of TRIM65 is associated with CRC metastasis and recurrence. Ectopic overexpression of TRIM65 in CRC cell lines enhanced proliferation, invasion, and migration, while knockdown of TRIM65 expression had the opposite effects. Furthermore, we identified a new substrate of TRIM65, namely ARHGAP35, a Rho GTPase-activating protein (GAP) that is involved in polarized cell migration. Phenotypically, forced expression of TRIM65 induces increased production of migration-related structures, focal adhesions, and/or filopodia and enhances CRC metastasis to the liver or the lung in a mouse model. Mechanistic studies revealed that TRIM65 mediates ubiquitination of ARHGAP35, whose degradation leads to elevated Rho GTPase activity. In addition, we identified several phosphorylation sites on TRIM65. In sum, we reveal a novel TRIM65-GAP-Rho regulatory axis that modulates the actin cytoskeleton and the migration behavior of CRC cells, and the TRIM65-ARHGAP35 interaction might be a valuable therapeutic target in CRC.

Overexpression of a soybean YABBY gene, GmFILa, causes leaf curling in Arabidopsis thaliana.

BACKGROUND: YABBY genes play important roles in the growth and polar establishment of lateral organs such as leaves and floral organs in angiosperms. However, the functions of YABBY homologous genes are largely unknown in soybean. RESULTS: In this study, we identified GmFILa encoding a YABBY transcription factor belonging to FIL subfamily. In situ mRNA hybridization analysis indicated that GmFILa had specific expression patterns in leaf as well as in flower bud primordia. Ectopic expression of GmFILa in Arabidopsis thaliana altered the partial abaxialization of the adaxial epidermises of leaves. Besides, GmFILa transgenic plants also exhibited longer flowering period and inhibition of shoot apical meristem (SAM) development compared to the wild type plants. Digital expression data and quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that the expression of GmFILa was induced by biotic and abiotic stresses and hormone treatments. Transcriptome analysis suggested that overexpressing GmFILa yielded 82 significant differentially expressed genes (DEGs) in Arabidopsis leaves, which can be classified into transcription factors, transporters, and genes involved in growth and development, metabolism, signal transduction, redox reaction and stress response. CONCLUSIONS: These results not only demonstrate the roles of GmFILa involved in leaf adaxial-abaxial polarity in Arabidopsis, but also help to reveal the molecular regulatory mechanism of GmFILa based on the transcriptomic data.

AKIP1 promotes early recurrence of hepatocellular carcinoma through activating the Wnt/ß-catenin/CBP signaling pathway.

The early recurrence of hepatocellular carcinoma (HCC) is the main obstacle for long-term survival of patients. Wnt/ß-catenin signaling has been involved in the development and progression of HCC. However, the molecular changes that link Wnt/ß-catenin activation and HCC early recurrence remain poorly understood. Here we identified AKIP1 as a binding partner of ß-catenin. AKIP1 interacted with and sustained ß-catenin in the nuclear by blocking its interaction with adenomatous polyposis coli protein (APC). Moreover, AKIP1 enhanced the protein kinase A catalytic subunit (PKAc)-mediated phosphorylation of ß-catenin, leading to recruitment of cyclic AMP response element-binding protein (CBP) and activation of ß-catenin downstream transcription. Increased AKIP1 expression was observed in HCC clinical samples and correlated with early recurrence and poor prognosis of HCC. AKIP1 promoted invasion and colony outgrowth in vitro and increased intrahepatic and lung metastasis in vivo. Treatment with a CBP inhibitor ICG-001 effectively inhibited the metastatic progression of HCC tumors that had elevated AKIP1 in both cell line and patient-derived xenograft mouse models. Our findings not only establish AKIP1 as a novel regulator of Wnt/ß-catenin signaling as well as HCC early recurrence but also highlight targeting the AKIP1/ß-catenin/CBP axis as attractive therapies for combating HCC metastatic relapse.