cAMP binding to closed pacemaker ion channels is non-cooperative.

Electrical activity in the brain and heart depends on rhythmic generation of action potentials by pacemaker ion channels (HCN) whose activity is regulated by cAMP binding1. Previous work has uncovered evidence for both positive and negative cooperativity in cAMP binding2,3, but such bulk measurements suffer from limited parameter resolution. Efforts to eliminate this ambiguity using single-molecule techniques have been hampered by the inability to directly monitor binding of individual ligand molecules to membrane receptors at physiological concentrations. Here we overcome these challenges using nanophotonic zero-mode waveguides4 to directly resolve binding dynamics of individual ligands to multimeric HCN1 and HCN2 ion channels. We show that cAMP binds independently to all four subunits when the pore is closed, despite a subsequent conformational isomerization to a flip state at each site. The different dynamics in binding and isomerization are likely to underlie physiologically distinct responses of each isoform to cAMP5 and provide direct validation of the ligand-induced flip-state model6-9. This approach for observing stepwise binding in multimeric proteins at physiologically relevant concentrations can directly probe binding allostery at single-molecule resolution in other intact membrane proteins and receptors.

Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack of a detailed understanding of oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. The role of protein lactylation, a newly unraveled post-translational modification that orchestrates gene expression, remains largely elusive in the pathogenesis of iCCA. METHODS: Proteomics analysis of clinical iCCA specimens and adjacent tissues was performed to screen for proteins aberrantly lactylated in iCCA. Mass spectrometry, macromolecule interaction and cell behavioral studies were employed to identify the specific lactylation sites on the candidate protein(s) and to decipher the downstream mechanisms responsible for iCCA development, which were subsequently validated using a xenograft tumor model and clinical samples. RESULTS: Nucleolin (NCL), the most abundant RNA-binding protein in the nucleolus, was identified as a functional lactylation target that correlates with iCCA occurrence and progression. NCL was lactylated predominantly at lysine 477 by the acyltransferase P300 in response to a hyperactivity of glycolysis, and promoted the proliferation and invasion of iCCA cells. Mechanistically, lactylated NCL bound to the primary transcript of MAP kinase-activating death domain protein (MADD) and led to efficient translation of MADD by circumventing alternative splicing that generates a premature termination codon. NCL lactylation, MADD translation and subsequent ERK activation promoted xenograft tumor growth and were associated with overall survival in patients with iCCA. CONCLUSION: NCL is lactylated to upregulate MADD through an RNA splicing-dependent mechanism, which potentiates iCCA pathogenesis via the MAPK pathway. Our findings reveal a novel link between metabolic reprogramming and canonical tumor-initiating events, and uncover biomarkers that can potentially be used for prognostic evaluation or targeted treatment of iCCA. IMPACT AND IMPLICATIONS: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy with largely uncharacterized pathogenetic mechanisms. Herein, we demonstrated that glycolysis promotes P300-catalyzed lactylation of nucleolin, which upregulates MAP kinase-activating death domain protein (MADD) through precise mRNA splicing and activates ERK signaling to drive iCCA development. These findings unravel a novel link between metabolic rewiring and canonical oncogenic pathways, and reveal new biomarkers for prognostic assessment and targeting of clinical iCCA.

Targeting metabolic sensing switch GPR84 on macrophages for cancer immunotherapy.

INTRODUCTION: As one of the major components of the tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate tumor escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward the anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity against cancer. However, a plethora of mechanisms have been described for pro-tumorigenic differentiation in cancer, metabolic switches to program the anti-tumorigenic property of TAMs are elusive. MATERIALS AND METHODS: From an unbiased analysis of single-cell transcriptome data from multiple tumor models, we discovered that anti-tumorigenic TAMs uniquely express elevated levels of a specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy. CONCLUSION: Overall, we report a previously unappreciated fatty acid receptor, GPR84, that serves as an important metabolic sensing switch for orchestrating anti-tumorigenic macrophage polarization. Pharmacological agonists of GPR84 hold promise to reshape and reverse the immunosuppressive TME, and thereby restore responsiveness of cancer to overcome resistance to immune checkpoint blockade.

Exploring the Diagnostic Potential of EPB41L3 Methylation in Cervical Cancer and Precancerous Lesions: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis aimed to comprehensively evaluate the diagnostic use of erythrocyte membrane protein band 4.1like3 (EPB41L3) methylation detection in cervical cancer (CC) and its precancerous lesions. METHODS: CNKI, Wanfang, Cochrane Library, PubMed, and Ovid databases were searched using a combination of subject headings and free words. Pertinent data were retrieved after screening for inclusion and exclusion criteria, and the quality of the included studies was evaluated using QUADAS-2 criteria. The appropriate software was used for heterogeneity analysis and combined effect size calculation. Additionally, sensitivity analysis was used to evaluate the robustness of the combined results, and meta-regression and subgroup analysis were conducted to investigate the origins of heterogeneity. RESULTS: This meta-analysis included six studies, including 525 healthy individuals, 182 cervical intraepithelial neoplasia 1 (CIN1) samples, 182 CIN2 samples, 281 CIN3 samples, and 226 CC samples. EPB41L3 methylation detection for CIN2 and above lesions demonstrated combined sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio (DOR), and the area under the curve of the comprehensive receiver operating characteristic curve of 0.67, 0.76, 3.19, 0.41, 7.60, and 0.80, respectively; CIN3 and above lesions demonstrated these evaluations at 0.73, 0.84, 4.35, 0.33, 23.94, and 0.90, respectively. Meta-regression analysis revealed that the population, time, sample type, detection method, literature quality, and sample size were not significant sources of heterogeneity affecting the combined diagnostic efficacy of CIN2 and above lesions (p > 0.05). Subgroup analysis revealed higher combined diagnostic values of CIN2 and above lesions in retrospective studies, tissue samples, and Chinese populations, with DORs of 41.03, 14.59, and 13.70, respectively. CONCLUSION: EPB41L3 methylation demonstrated a relatively low diagnostic performance in CC and precancerous lesions. However, it merits further investigation as a potential biomarker. Integrating it with multiple gene detection, human papillomavirus testing, and ThinPrep liquid-based cytology test examination is recommended to explore improved diagnostic strategies for CC and its precancerous lesions.

Prognostic value of the pretreatment systemic immune-inflammation index in patients with prostate cancer: a systematic review and meta-analysis.

BACKGROUND: The systemic immune-inflammation index (SII) is a novel biomarker to predict the prognosis of some malignant tumors based on neutrophil, platelet, and lymphocyte counts. Evidence is scarce about the prognostic value of SII for prostate cancer patients. This systematic review and meta-analysis was conducted to explore the prognostic value of the SII in prostate cancer. METHODS: The PubMed, Embase, Web of Science, and Cochrane Library (CENTRAL) databases were searched to determine eligible studies from inception to August 15, 2022. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to pool the results. Statistical analyses were conducted by using Stata 17.0 software. RESULTS: A total of 12 studies with 8083 patients were included. The quantitative synthesis showed that a high SII was related to poor overall survival (OS) (HR = 1.44, 95% CI 1.23-1.69, p < 0.001). Furthermore, a subgroup analysis showed that a high SII was associated with poor OS in the groups of any ethnicity, tumor type, and cutoff value. An increased SII was also associated with inferior progression-free survival (PFS) (HR = 1.80, 95% CI 1.27-2.56, p = 0.001). In the subgroup analysis, a high SII value was related to poor PFS in Asian patients (HR = 4.03, 95% CI 1.07-15.17, p = 0.04) and a cutoff value > 580 (HR = 1.19, 95% CI 1.04-1.36, p = 0.01). CONCLUSION: Based on the current evidence, a high pretreatment SII may be associated with poor OS and PFS. The SII may serve as an important prognostic indicator in patients with prostate cancer. More rigorously designed studies are needed to explore the SII and the prognosis of prostate cancer.

Risk factors analysis of surgical complications of hepatic hemangioma: a modified Clavien-Dindo classification-based study.

PURPOSE: There are few studies on the risk factors of postoperative complications after surgical treatment of hepatic hemangioma (HH). This study aims to provide a more scientific reference for clinical treatment. METHODS: The clinical characteristics and operation data of HH patients undergoing surgical treatment in the First Affiliated Hospital of Air Force Medical University from January 2011 to December 2020 were retrospectively collected. All enrolled patients were divided into two groups based on the modified Clavien-Dindo classification: Major group (Grade II/III/IV/V) and Minor group (Grade I and no complications). Univariate and multivariate regression analysis was used to explore the risk factors for massive intraoperative blood loss (IBL) and postoperative Grade II and above complications. RESULTS: A total of 596 patients were enrolled, with a median age of 46.0 years (range, 22-75 years). Patients with Grade II/III/IV/V complications were included in the Major group (n = 119, 20%), and patients with Grade I and no complications were included in the Minor group (n = 477, 80%). The results of multivariate analysis of Grade II/III/IV/V complications showed that operative duration, IBL, and tumor size increased the risk of Grade II/III/IV/V complications. Conversely, serum creatinine (sCRE) decreased the risk. The results of multivariate analysis of IBL showed that tumor size, surgical method, and operative duration increased the risk of IBL. CONCLUSIONS: Operative duration, IBL, tumor size, and surgical method are independent risk factors that should be paid attention to in HH surgery. In addition, as an independent protective factor for HH surgery, sCRE should attract more attention from scholars.

Familiarity of teaching skills among general practitioners transfer training trainers in China: a cross-sectional survey.

BACKGROUND: The insufficient number of general practitioners (GPs) is a major challenge facing China's healthcare system. The purpose of the GP transfer training programme was to provide training for experienced doctors to transition to general practice. However, research on the competencies of GP transfer training trainers in teaching skills in China is limited. This cross-sectional study aimed to examine the baseline familiarity with teaching skills among Chinese GP transfer training trainers. METHODS: An online survey was conducted among trainers who participated in the 2021 Sichuan Province General Practice Training Trainer Program. The survey collected data on participants' characteristics and familiarity with 20 skills in three essential teaching knowledge areas: the core functions of primary care (five questions), preparation for lesson plan (four questions), and teaching methods (11 questions). RESULTS: In total, 305 participants completed the survey. Familiarity rates were generally low across all three essential teaching knowledge areas. No significant differences were observed in familiarity rates between the tertiary and secondary hospitals. CONCLUSION: This study revealed gaps in the teaching skills of GP transfer training trainers in China. These results suggest the necessity for targeted training programs to enhance the teaching skills and competencies of trainers.

Quality of life and its influencing factors in patients with schizophrenia. / ç²¾ç¥žåˆ†è£‚ç—‡æ‚£è€ ç”Ÿæ´»è´¨é‡åŠå ¶å½±å“å› ç´ .

Schizophrenia is a chronic mental disease. With the change of medical model, quality of life has gradually become an important prognostic indicator for patients with schizophrenia. People with schizophrenia have a lower quality of life than the general population or people with other chronic diseases, Sociodemographic factors such as age, gender, employment, education level, income and living situation; clinical factors such as psychiatric symptoms, medication compliance and insight; and psychosocial factors such as social support, cognition, stigma, self-esteem and needs are the main influencing factors for schizophrenia patients. Medication and psychological interventions such as social skills training, family intervention, cognitive correction and cognitive behavioral therapy can be used to improve the quality of life of patients with schizophrenia. Understanding the factors affecting the quality of life of schizophrenia patients and the improvement measures helps to provide reference for improving their quality of life.

Multiplexed Analysis of Photochemical Oxidants Using a Nanoparticle-Based Optoelectronic Nose.

Photochemical pollutants pose a substantial threat to human health in both outdoor and indoor environments. Herein, we prepare a class of gold nanoparticle-based colorimetric sensor arrays on optimized hydrophobic substrates using a simple pin-printing method for accurate identification and quantification of various gas-phase oxidants, as these microdetectors are low cost, sensitive, and easy to fabricate. For an array of AuNP sensors modified with various thiol-terminated ligands, a unique and distinguishable change in color (i.e., red, green, and blue response patterns) was obtained for each specific pollutant for molecular fingerprinting. Remarkable discrimination among 15 gases at a fairly low vapor concentration (i.e., 500 ppb) was illustrated using standard chemometric methods. Using digital imaging, the AuNP colorimetric sensor array offers ultrasensitive dosimetric identification of gas-phase oxidants relevant to outdoor and indoor air pollution, with limits of detection generally at sub-ppb levels for 2 h measurement. As a practical application, the sensor array is able to predict the overall air quality in indoor office environments over 24 h. Such sensor array based on chemically induced sintering of nanoparticles has significant implications for the development of nanosensors used in continuous monitoring of potential airborne pollutants at low concentrations from a large number of locations in a cost-effective manner.

Parallel Neural Multiprocessing with Gamma Frequency Latencies.

The Poisson variability in cortical neural responses has been typically modeled using spike averaging techniques, such as trial averaging and rate coding, since such methods can produce reliable correlates of behavior. However, mechanisms that rely on counting spikes could be slow and inefficient and thus might not be useful in the brain for computations at timescales in the 10 millisecond range. This issue has motivated a search for alternative spike codes that take advantage of spike timing and has resulted in many studies that use synchronized neural networks for communication. Here we focus on recent studies that suggest that the gamma frequency may provide a reference that allows local spike phase representations that could result in much faster information transmission. We have developed a unified model (gamma spike multiplexing) that takes advantage of a single cycle of a cell's somatic gamma frequency to modulate the generation of its action potentials. An important consequence of this coding mechanism is that it allows multiple independent neural processes to run in parallel, thereby greatly increasing the processing capability of the cortex. System-level simulations and preliminary analysis of mouse cortical cell data are presented as support for the proposed theoretical model.

Modeling sensory-motor decisions in natural behavior.

Although a standard reinforcement learning model can capture many aspects of reward-seeking behaviors, it may not be practical for modeling human natural behaviors because of the richness of dynamic environments and limitations in cognitive resources. We propose a modular reinforcement learning model that addresses these factors. Based on this model, a modular inverse reinforcement learning algorithm is developed to estimate both the rewards and discount factors from human behavioral data, which allows predictions of human navigation behaviors in virtual reality with high accuracy across different subjects and with different tasks. Complex human navigation trajectories in novel environments can be reproduced by an artificial agent that is based on the modular model. This model provides a strategy for estimating the subjective value of actions and how they influence sensory-motor decisions in natural behavior.

The electric dipole moments in the ground states of gold oxide, AuO, and gold sulfide, AuS.

The B2Σ- - X2Π3/2(0,0) bands of a cold molecular beam sample of gold monoxide, AuO, and gold monosulfide, AuS, have been recorded at high resolution both field free and in the presence of a static electric field. The observed electric field induced splittings and shifts were analyzed to produce permanent electric dipole moments, µâ†’el, of 2.94±0.06 D and 2.22±0.05 D for the X2Π3/2(v = 0) states of AuO and AuS, respectively. A molecular orbital correlation diagram is used to rationalize the trend in ground state µâ†’el values for AuX (X = F, Cl, O, and S) molecules. The experimentally determined µâ†’el are compared to those computed at the coupled-cluster singles and doubles (CCSD) level augmented with a perturbative inclusion of triple excitations (CCSD(T)) level of theory.

Au-S Bonding Revealed from the Characterization of Diatomic Gold Sulfide, AuS.

Gold monosulfide, AuS, has been detected and characterized in the gas phase using optical spectroscopy. The symmetries of the ground and low-lying electronic excited states have been determined by application of a synergy of hot and cold laser excitation techniques. The electronic spectra are assigned to progressions in four band systems associated with excitations from the X(2)Πi ((2σ)(2)(2π)(3)) ground state to the A(2)Σ(+) state arising from the (2σ)(1)(2π)(4) configuration and to the a(4)Σ(-), B(2)Σ(-), and C(2)Δi states arising from the (2σ)(2)(2π)(2)(3σ*)(1) configuration. The bond length and dissociation energy of the ground X(2)Πi state are determined to be 2.156(2) Å and 298 ± 2 kJ/mol, respectively. A molecular orbital correlation diagram is used to rationalize the energy ordering of the excited states and the associated harmonic frequencies.

The electric dipole moment of magnesium deuteride, MgD.

The (0,0) A(2)Π-X (2)Σ(+) band of a cold molecular beam sample of magnesium monodeuteride, MgD, has been recorded field-free and in the presence of a static electric field of up to 11 kV/cm. The lines associated with the lowest rotational levels are detected for the first time. The field-free spectrum was analyzed to produce an improved set of fine structure parameters for the A(2)Π (v = 0) state. The observed electric field induced splittings and shifts were analyzed to produce permanent electric dipole moments, µ(el) of 2.567(10)D and 1.31(8)D for A(2)Π (v = 0) and X(2)Σ(+)(v = 0) states, respectively. The recommended value for µ(el)(X(2)Σ(+) (v = 0)) for MgH, based upon the measured value for MgD, is 1.32(8)D.

The Insular Cortex: An Interface Between Sensation, Emotion and Cognition.

The insula is a complex brain region central to the orchestration of taste perception, interoception, emotion, and decision-making. Recent research has shed light on the intricate connections between the insula and other brain regions, revealing the crucial role of this area in integrating sensory, emotional, and cognitive information. The unique anatomical position and extensive connectivity allow the insula to serve as a critical hub in the functional network of the brain. We summarize its role in interoceptive and exteroceptive sensory processing, illustrating insular function as a bridge connecting internal and external experiences. Drawing on recent research, we delineate the insular involvement in emotional processes, highlighting its implications in psychiatric conditions, such as anxiety, depression, and addiction. We further discuss the insular contributions to cognition, focusing on its significant roles in time perception and decision-making. Collectively, the evidence underscores the insular function as a dynamic interface that synthesizes diverse inputs into coherent subjective experiences and decision-making processes. Through this review, we hope to highlight the importance of the insula as an interface between sensation, emotion, and cognition, and to inspire further research into this fascinating brain region.

Different cortical connectivities in human females and males relate to differences in strength and body composition, reward and emotional systems, and memory.

Sex differences in human brain structure and function are important, partly because they are likely to be relevant to the male-female differences in behavior and in mental health. To analyse sex differences in cortical function, functional connectivity was measured in 36,531 participants (53% female) in the UK Biobank (mean age 69) using the Human Connectome Project multimodal parcellation atlas with 360 well-specified cortical regions. Most of the functional connectivities were lower in females (Bonferroni corrected), with the mean Cohen's d = - 0.18. Removing these as covariates reduced the difference of functional connectivities for females-males from d = - 0.18 to - 0.06. The lower functional connectivities in females were especially of somatosensory/premotor regions including the insula, opercular cortex, paracentral lobule and mid-cingulate cortex, and were correlated with lower maximum workload (r = 0.17), and with higher whole body fat mass (r = - 0.17). But some functional connectivities were higher in females, involving especially the ventromedial prefrontal cortex and posterior cingulate cortex, and these were correlated with higher liking for some rewards such as sweet foods, higher happiness/subjective well-being, and with better memory-related functions. The main findings were replicated in 1000 individuals (532 females, mean age 29) from the Human Connectome Project. This investigation shows the cortical systems with different functional connectivity between females and males, and also provides for the first time a foundation for understanding the implications for behavior of these differences between females and males.

Selective activations and functional connectivities to the sight of faces, scenes, body parts and tools in visual and non-visual cortical regions leading to the human hippocampus.

Connectivity maps are now available for the 360 cortical regions in the Human Connectome Project Multimodal Parcellation atlas. Here we add function to these maps by measuring selective fMRI activations and functional connectivity increases to stationary visual stimuli of faces, scenes, body parts and tools from 956 HCP participants. Faces activate regions in the ventrolateral visual cortical stream (FFC), in the superior temporal sulcus (STS) visual stream for face and head motion; and inferior parietal visual (PGi) and somatosensory (PF) regions. Scenes activate ventromedial visual stream VMV and PHA regions in the parahippocampal scene area; medial (7m) and lateral parietal (PGp) regions; and the reward-related medial orbitofrontal cortex. Body parts activate the inferior temporal cortex object regions (TE1p, TE2p); but also visual motion regions (MT, MST, FST); and the inferior parietal visual (PGi, PGs) and somatosensory (PF) regions; and the unpleasant-related lateral orbitofrontal cortex. Tools activate an intermediate ventral stream area (VMV3, VVC, PHA3); visual motion regions (FST); somatosensory (1, 2); and auditory (A4, A5) cortical regions. The findings add function to cortical connectivity maps; and show how stationary visual stimuli activate other cortical regions related to their associations, including visual motion, somatosensory, auditory, semantic, and orbitofrontal cortex value-related, regions.

Impacts of alcohol consumption on farmers' mental health: Insights from rural China.

The global mental health crisis presents a significant challenge to sustainable development, and this crisis is more pronounced in China's rural areas versus urban areas. Alcohol consumption has increased in rural areas with China's economic growth, but the number of studies on the relationship between farmers' alcohol consumption and their mental health is limited. Based on data from the China Labor Force Dynamics Survey (CLDS), this study uses the endogenous switching regression model (ESR) to analyze the influence of alcohol consumption on farmers' mental health. On this basis, the study further conducts a counterfactual analysis to estimate the average treatment effect of alcohol consumption on farmers' mental health. The results show that: (1) There is a significant positive relationship between alcohol consumption and farmers' mental health. Specifically, the mental health index of drinking farmers increases by 19.7 % compared to non-drinking farmers. (2) Heterogeneity analysis shows that alcohol consumption is more beneficial for improving the mental health of male farmers, elderly farmers, and employed farmers. Furthermore, drinking alcohol almost every day, consuming Baijiu, and each drinking consumption ranging from 0 to 100 mL per occasion are more conducive to improving farmers' mental health. These findings have implications for relieving depressive symptomology and improving farmers' mental health in developing countries. The results of this study also provide guidance for addressing the global mental health crisis.

Unveiling aging dynamics in the hematopoietic system insights from single-cell technologies.

As the demographic structure shifts towards an aging society, strategies aimed at slowing down or reversing the aging process become increasingly essential. Aging is a major predisposing factor for many chronic diseases in humans. The hematopoietic system, comprising blood cells and their associated bone marrow microenvironment, intricately participates in hematopoiesis, coagulation, immune regulation and other physiological phenomena. The aging process triggers various alterations within the hematopoietic system, serving as a spectrum of risk factors for hematopoietic disorders, including clonal hematopoiesis, immune senescence, myeloproliferative neoplasms and leukemia. The emerging single-cell technologies provide novel insights into age-related changes in the hematopoietic system. In this review, we summarize recent studies dissecting hematopoietic system aging using single-cell technologies. We discuss cellular changes occurring during aging in the hematopoietic system at the levels of the genomics, transcriptomics, epigenomics, proteomics, metabolomics and spatial multi-omics. Finally, we contemplate the future prospects of single-cell technologies, emphasizing the impact they may bring to the field of hematopoietic system aging research.

New Cytotoxic γ-Lactam Alkaloids from the Mangrove-Derived Fungus Talaromyces hainanensis sp. nov. Guided by Molecular Networking Strategy.

The fungus Talaromyces hainanensis, isolated from the mangrove soil, was characterized as a novel species by morphology observation and phylogenetic analyses. Four new γ-lactam alkaloids talaroilactams A-D (1-4) and two reported compounds harzianic acid (5) and isoharzianic acid (6) were identified from the fungus T. hainanensis WHUF0341, assisted by OSMAC along with molecular networking approaches. Their structures were determined through ECD calculations and spectroscopic analyses. Moreover, the biosynthetic route of 1-4 was also proposed. Compound 1 displayed potent cytotoxicity against HepG2 cell lines, with an IC50 value of 10.75 ± 1.11 µM. In addition, network pharmacology was employed to dissect the probable mechanisms contributing to the antihepatocellular carcinoma effects of compound 1, revealing that cytotoxicity was mainly associated with proteolysis, negative regulation of autophagy, inflammatory response, and the renin-angiotensin system. These results not only expanded the chemical space of natural products from the mangrove associated fungi but also afforded promising lead compounds for developing the antihepatocellular carcinoma agents.