Promising natural products targeting protein tyrosine phosphatase SHP2 for cancer therapy.

The development of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors is a hot spot in the research and development of antitumor drugs, which may induce immunomodulatory effects in the tumor microenvironment and participate in anti-tumor immune responses. To date, several SHP2 inhibitors have made remarkable progress and entered clinical trials for the treatment of patients with advanced solid tumors. Multiple compounds derived from natural products have been proved to influence tumor cell proliferation, apoptosis, migration and other cellular functions, modulate cell cycle and immune cell activation by regulating the function of SHP2 and its mutants. However, there is a paucity of information about their diversity, biochemistry, and therapeutic potential of targeting SHP2 in tumors. This review will provide the structure, classification, inhibitory activities, experimental models, and antitumor effects of the natural products. Notably, this review summarizes recent advance in the efficacy and pharmacological mechanism of natural products targeting SHP2 in inhibiting the various signaling pathways that regulate different cancers and thus pave the way for further development of anticancer drugs targeting SHP2.

Methyl rosmarinate is an allosteric inhibitor of SARS-CoV-2 3 CL protease as a potential candidate against SARS-cov-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been ongoing for more than three years and urgently needs to be addressed. Traditional Chinese medicine (TCM) prescriptions have played an important role in the clinical treatment of patients with COVID-19 in China. However, it is difficult to uncover the potential molecular mechanisms of the active ingredients in these TCM prescriptions. In this paper, we developed a new approach by integrating the experimental assay, virtual screening, and the experimental verification, exploring the rapid discovery of active ingredients from TCM prescriptions. To achieve this goal, 4 TCM prescriptions in clinical use for different indications were selected to find the antiviral active ingredients in TCMs. The 3-chymotrypsin-like protease (3CLpro), an important target for fighting COVID-19, was utilized to determine the inhibitory activity of the TCM prescriptions and single herb. It was found that 10 single herbs had better inhibitory activity than other herbs by using a fluorescence resonance energy transfer (FRET) - based enzymatic assay of SARS-CoV-2 3CLpro. The ingredients contained in 10 herbs were thus virtually screened and the predicted active ingredients were experimentally validated. Thus, such a research strategy firstly removed many single herbs with no inhibitory activity against SARS-CoV-2 3CLpro at the very beginning by FRET-based assay, making our subsequent virtual screening more effective. Finally, 4 active components were found to have stronger inhibitory effects on SARS-CoV-2 3CLpro, and their inhibitory mechanism was subsequently investigated. Among of them, methyl rosmarinate as an allosteric inhibitor of SARS-CoV-2 3CLpro was confirmed and its ability to inhibit viral replication was demonstrated by the SARS-CoV-2 replicon system. To validate the binding mode via docking, the mutation experiment, circular dichroism (CD), enzymatic inhibition and surface plasmon resonance (SPR) assay were performed, demonstrating that methyl rosmarinate bound to the allosteric site of SARS-CoV-2 3CLpro. In conclusion, this paper provides the new ideas for the rapid discovery of active ingredients in TCM prescriptions based on a specific target, and methyl rosmarinate has the potential to be developed as an antiviral therapeutic candidate against SARS-CoV-2 infection.

Fungal polyketides produced by an endophytic fungus Phoma sp. associated with Gastrodia elata.

Two novel fungal polyketides, phometides A (1) and B (2), together with four known compounds (3-6), were isolated from the endophytic fungus Phoma sp. YUD17001 obtained from Gastrodia elata Blume. The structures were elucidated based on spectroscopic analyses, X-ray crystal diffraction, and time-dependent density functional theory/electronic circular dichroism (TDDFT/ECD) calculations. Structurally, phometide A (1) represented the first example of C12 polyketide characterized by an unusual tetrahydrobenzofuran-3(2H)-one core with an α,ß-unsaturated ketone functionality, while phometide B (2) was an unprecedented molecule containing a 2-pentylcycloheptan-1-one scaffold. In an antimicrobial activity assay, phometide A (1) exhibited significant inhibitory activity against Staphylococcus aureus with MIC value of 4 µg/mL. Phometide B (2) showed moderate antifungal activity against Candida albicans with an MIC value of 16 µg/mL. Furthermore, compounds 1 and 2 were evaluated for their acetylcholinesterase inhibitory and cytotoxic activities.

Mechanism of Liuwei Dihuang Pills in treating osteoporosis based on network pharmacology.

Osteoporosis is a prevalent age-related disease that poses a significant public health concern as the population continues to age. While current treatments have shown some therapeutic benefits, their long-term clinical efficacy is limited by a lack of stable curative effects and significant adverse effects. Traditional Chinese Medicine has gained attention due to its positive curative effects and fewer side effects. Liuwei Dihuang Pill has been found to enhance bone mineral density in patients with osteoporosis and rats, but the underlying mechanism is not yet clear. To shed more light on this problem, this study aims to explore the pharmacological mechanism of Liuwei Dihuang Pill in treating osteoporosis using network pharmacology and molecular docking. The findings indicate that Liuwei Dihuang Pills treat osteoporosis through various targets and channels. Specifically, it mainly involves TNF, IL17, and HIF-1 signaling pathways and helps regulate biological processes such as angiogenesis, apoptosis, hypoxia, and gene expression. Furthermore, molecular docking demonstrates excellent binding properties between the drug components and key targets. Therefore, this study offers a theoretical foundation for understanding the pharmacological mechanism and clinical application of Liuwei Dihuang Pills in treating osteoporosis more comprehensively.

TCMFP: a novel herbal formula prediction method based on network target's score integrated with semi-supervised learning genetic algorithms.

Traditional Chinese medicine (TCM) has accumulated thousands years of knowledge in herbal therapy, but the use of herbal formulas is still characterized by reliance on personal experience. Due to the complex mechanism of herbal actions, it is challenging to discover effective herbal formulas for diseases by integrating the traditional experiences and modern pharmacological mechanisms of multi-target interactions. In this study, we propose a herbal formula prediction approach (TCMFP) combined therapy experience of TCM, artificial intelligence and network science algorithms to screen optimal herbal formula for diseases efficiently, which integrates a herb score (Hscore) based on the importance of network targets, a pair score (Pscore) based on empirical learning and herbal formula predictive score (FmapScore) based on intelligent optimization and genetic algorithm. The validity of Hscore, Pscore and FmapScore was verified by functional similarity and network topological evaluation. Moreover, TCMFP was used successfully to generate herbal formulae for three diseases, i.e. the Alzheimer's disease, asthma and atherosclerosis. Functional enrichment and network analysis indicates the efficacy of targets for the predicted optimal herbal formula. The proposed TCMFP may provides a new strategy for the optimization of herbal formula, TCM herbs therapy and drug development.

Bioactive sorbicillinoids from a rhizospheric soil-derived Paecilomyces sp. KMU21009.

A new hybrid sorbicillinoid named paeciureallin (1) and a new monomeric sorbicillinoid named paecillyketide (2), along with six known analogues (3-8), were isolated from the rhizospheric soil-derived fungus Paecilomyces sp. KMU21009 associated with Delphinium yunnanense. Their structures were elucidated by extensive spectroscopic analysis and comparison with literature values. Paeciureallin (1) is the first example of hybrid sorbicillinoids possessing a rare sorbicillinoid urea unit and containing a ß-D-ribofuranose functionality. In pharmacological studies, compounds 1 and 2 were evaluated for in vitro anti-inflammatory and cytotoxic activities. Paeciureallin (1) exhibited moderate cytotoxicity against SW480 and A549 cell lines, and the IC50 values were 32.0 ± 0.1 and 34.4 ± 2.0 µM, respectively.

Deep Fusion of Intelligent Meridian Sensing Technology and Huoluo Xiaoling Pills in the Treatment of Knee Osteoarthritis.

Based on the deep fusion of intelligent meridian sensing technology and Huoluo Xiaoling Pill (HXP) in the treatment of knee osteoarthritis (KOA), firstly, the effective components and targets of Salvia miltiorrhiza, Angelica sinensis, frankincense, and myrrh were obtained by using TCMSP, SwissADME, and Swisstarget databases. Similarly, relevant targets of KOA were collected through GeneCards, OMIM, TTD, PharmGKB, and DrugBank databases. Next, the potential targets of ZXP in the treatment of KOA were obtained by intersection of drug and disease targets. Finally, Cytoscape 3.7.1 software was used to construct a "disease-drug-component-target" network, and Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Gnomes (KEGG) signaling pathway enrichment analysis were performed on the core targets through Metascape website. A total of 99 active components and 203 corresponding potential therapeutic targets were obtained from the components of HXP. And KOA has 2543 potential therapeutic targets, of which 120 cross targets correspond to 120 active compounds in HXP. Then, topology analysis displayed that the six targets form the core PPI network. In addition, GO and KEGG enrichment analyses showed that these core targets were mainly enriched in inflammatory response, apoptosis, oxidation reaction, and other related pathways.

Serum Raman spectroscopy combined with multiple classification models for rapid diagnosis of breast cancer.

Breast cancer is a malignant tumor with the highest incidence rate in women. Current diagnostic methods are time-consuming, costly, and dependent on physician experience. In this study, we used serum Raman spectroscopy combined with multiple classification algorithms to implement an auxiliary diagnosis method for breast cancer, which will help in the early diagnosis of breast cancer patients. We analyzed the serum Raman spectra of 171 invasive ductal carcinoma (IDC) and 100 healthy volunteers; The analysis showed differences in nucleic acids, carotenoids, amino acids, and lipid concentrations in their blood. These differences provide a theoretical basis for this experiment. First, we used adaptive iteratively reweighted penalized least squares (airPLS) and Savitzky-Golay (SG) for baseline correction and smoothing denoising to remove the effect of noise on the experiment. Then, the Principal component analysis (PCA) algorithm was used to extract features. Finally, we built four classification models: support vector machine (SVM), decision tree (DT), linear discriminant analysis (LDA), and Neural Network Language Model (NNLM). The LDA, SVM, and NNLM achieve 100% accuracy. As supplementary, we added the classification experiment of the raw data. By comparing the experimental results of the two groups, We concluded that the NNLM was the best model. The results show the reliability of the combination of serum Raman spectroscopy and classification models under large sample conditions.

[Exploration of the development direction of contemporary acupuncture-moxibustion school: acupuncture-moxibustion treatment for periarthritis of shoulder].

Taking acupuncture-moxibustion for periarthritis of shoulder as an example, the characteristics of contemporary acupuncture-moxibustion school are analyzed in terms of the theories of syndrome treatment, acupoint selection, needle devices and acupuncture techniques, as well as the encountered questions during its development; and the exploratory suggestions are proposed. The contemporary acupuncture-moxibustion school should be developed in three aspects, i.e. constructing data platform, expanding inheritance model and formulating acupuncture-moxibustion standard.

Analysis of Medication Rule of Primary Epilepsy Based on Xiaocheng Yan's Clinical Experience Collection of Epilepsy.

Objective: To explore and analyze the medication rule of Professor Xiaocheng Yan in the treatment of primary epilepsy, hoping to provide reference for the clinical treatment of primary epilepsy. Methods: Mining and analysis of Professor Xiaocheng Yan sorted out the medical cases of primary epilepsy in Xiaocheng Yan's clinical experience collection of epilepsy, extracted the traditional Chinese medicine (TCM) prescription data in the medical cases, standardized the obtained TCM prescription data, and used the data mining function integrated by the ancient and modern medical case cloud platform V2.3.5 to carry out frequency statistics, cluster analysis, association analysis, and complex network analysis on the TCM data, and the common herbs used by Professor Xiaocheng Yan in the treatment of primary epilepsy, properties and classifications of commonly used herbs, pairs of commonly used herbs, and core prescriptions were obtained. Results: A total of 39 cases, 228 medical records, and 230 prescriptions data of TCM were included. A total of 96 Chinese medicinal herbs were involved, and the total frequency of medication was 3,828. High-frequency herbs include Rhizoma Gastrodiae (Tianma) (222 times), Ramulus Uncariae cum Uncis (Gouteng) (220 times), Rhizoma Acori Tatarinowii (Shichangpu) (216 times), Rhizoma Pinelliae Praeparatum (Fabanxia) (207 times), Bombyx Batryticatus (Jiangcan) (206 times), and Periostracum Cicadae (Chantui) (181 times). The main properties and flavors of commonly used Chinese medicinal herbs were sweet, bitter, and pungent, which were mainly attributed to the four meridians of liver, lung, heart, and spleen. Commonly used couplet herbs were {Periostracum Cicadae (Chantui)} ≥ {Bombyx Batryticatus (Jiangcan)}, {Rhizoma Acori Tatarinowii (Shichangpu)} ≥{ Bombyx Batryticatus (Jiangcan)}, {Radix Bupleuri (Chaihu)} ≥ {Radix Scutellariae (Huangqin)}, {Rhizoma Gastrodiae (Tianma)} ≥ {Ramulus Uncariae cum Uncis (Gouteng)}, {Rhizoma Acori Tatarinowii (Shichangpu)} ≥ {Periostracum Cicadae (Chantui)}, {Ramulus Uncariae cum Uncis (Gouteng)} ≥ {Bombyx Batryticatus (Jiangcan)}, {Bombyx Batryticatus (Jiangcan)} ≥ {Rhizoma Gastrodiae (Tianma)}, {Rhizoma Acori Tatarinowii (Shichangpu)} ≥ {Ramulus Uncariae cum Uncis (Gouteng)}, etc. The core prescription composition was based on the addition and subtraction of Tianma Gouteng decoction and Erchen decoction. The main pharmacological mechanisms of core prescriptions are mainly reflected in antioxidation, enhancing GABA efficacy, and regulating NMDA channel and sodium channel, neuroprotection, and so on. Conclusion: Professor Xiaocheng Yan's medication for the treatment of primary epilepsy was based on the principle of relieving wind and spasm, drying dampness and resolving phlegm, giving consideration to both Qi and blood, and harmonizing liver, lung, heart, and spleen.

Application of the Delphi Method in the Construction of an Evaluating and Grading Scale for Evidence of Disease Prevention and Treatment in Ancient Books of Traditional Chinese Medicine.

Objective: This study aimed to develop a scale for evaluating and grading the evidence of prevention and treatment in ancient books of traditional Chinese medicine (TCM), in view of providing a reference for TCM clinicians, supporting the compilation or revision of evidence-based practice guidelines for TCM, improving the level of evidence-based research on ancient TCM books, and supplementing the development of evidence-based ancient TCM books. Methods: The Delphi method was used for consultation among 40 experts in relevant fields. Excel 2016 and SPSS 21.0 were used to analyze the positive coefficient, authority coefficient, degree of concentration, degree of coordination, and degree of expert consensus. Results: In the first round of the questionnaire, a total of 17 evaluation indexes were formulated in three aspects: 5 were deleted, 1 was modified according to the expert opinions, and no additional index was added. In addition, quantitative standards, weight assignment, and grading standards were developed according to the findings of the expert consultation. The positive coefficients of experts in the first and second rounds of questionnaires were 87.5% and 82.9%, respectively. The authority coefficient was 0.835 (>0.7). The coefficient of variation of the first and second rounds were 0.14∼0.29 and 0.09∼0.27, respectively. Kendall's coefficient of concordance of the first and second rounds were 0.135 (p < 0.05) and 0.081 (p < 0.05), respectively. Conclusion: The evaluation indexes and quantitative reference values of the developed scale conform to the characteristics of prevention and treatment evidence in ancient TCM books. It can provide a useful exploration tool for the evaluation and grading of evidences in TCM ancient books.

Discussion on the Rehabilitation of Stroke Hemiplegia Based on Interdisciplinary Combination of Medicine and Engineering.

Interdisciplinary combinations of medicine and engineering are part of the strategic plan of many universities aiming to be world-class institutions. One area in which these interactions have been prominent is rehabilitation of stroke hemiplegia. This article reviews advances in the last five years of stroke hemiplegia rehabilitation via interdisciplinary combination of medicine and engineering. Examples of these technologies include VR, RT, mHealth, BCI, tDCS, rTMS, and TCM rehabilitation. In this article, we will summarize the latest research in these areas and discuss the advantages and disadvantages of each to examine the frontiers of interdisciplinary medicine and engineering advances.

Acupuncture protects against cerebral ischemia-reperfusion injury via suppressing endoplasmic reticulum stress-mediated autophagy and apoptosis.

BACKGROUND: Acupuncture treatment possesses the neuroprotection potential to attenuate cerebral ischemia-reperfusion (I/R) injury. Endoplasmic reticulum (ER) stress has been suggested to be involved in the pathogenic mechanism of cerebral I/R injury. Whether acupuncture protects against cerebral I/R injury via regulating ER stress remains unclear. This study aimed to evaluate the role of ER stress in the neuroprotection of acupuncture against cerebral I/R injury and its underlying mechanisms. METHODS: Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO) in rats. Acupuncture was carried out at Baihui (GV 20), and Qubin (GB7) acupoints in rats immediately after reperfusion. The infarct volumes, neurological score, ER stress, autophagy and apoptosis were determined. RESULTS: Acupuncture treatment decreased infarct volume, neurological score and suppressed ER stress via inactivation of ATF-6, PERK, and IRE1 pathways in MCAO rats. Attributing to ER stress suppression, 4-PBA (ER stress inhibitor) promoted the beneficial effect of acupuncture against cerebral I/R injury. Whereas, ER stress activator tunicamycin significantly counteracted the neuroprotective effects of acupuncture. In addition, acupuncture restrained autophagy via regulating ER stress in MCAO rats. Finally, ER stress took part in the neuroprotective effect of acupuncture against apoptosis in cerebral I/R injury. CONCLUSIONS: Our findings suggest that acupuncture offers neuroprotection against cerebral I/R injury, which is attributed to repressing ER stress-mediated autophagy and apoptosis.

Penctrimertone, a bioactive citrinin dimer from the endophytic fungus Penicillium sp. T2-11.

Penctrimertone (1), a novel citrinin dimer bearing a 6/6/6/6 tetracyclic ring scaffold, along with two known compounds xerucitrinic acid A (2) and citrinin (3) were isolated from the endophytic fungus Penicillium sp. T2-11. Their structures were unequivocally established by a comprehensive interpretation of the spectroscopic data, with the stereochemistry for 1 was defined by a combination of TDDFT-ECD calculations and the DP4+ probability analysis based on NMR chemical shift calculations. Bioassays revealed that compound 1 exhibited noticeable antimicrobial activities and moderate cytotoxicity. A plausible biosynthetic pathway of 1 was also proposed.

Neuroprotective racemic germacranolides from the roots of Chloranthus henryi.

Three pairs of new germacranolides, (+)/(-)-chlogermacrones A-C, along with two known analogues were obtained from the roots of Chloranthus henryi. Spectroscopic techniques and single-crystal X-ray crystallographic analyses were used for the structure elucidation of the compounds. All of the isolated compounds were tested for their neuroprotective effects on H2O2 damaged PC12 cells, compounds 3 and 5 increased cell viability from 43.4 ± 1.3% to 99.6 ± 8.7 and 68.1 ± 4.8% at 10 µM, respectively.

Peniterester, a carotane-type antibacterial sesquiterpene from an artificial mutant Penicillium sp. T2-M20.

Peniterester (1), a new tricyclic sesquiterpene, together with 6 known compounds (2-7) were isolated from the secondary metabolites of an artificial mutant Penicillium sp. T2-M20 which was obtained from the parental strain Penicillium sp. T2-8 via UV irradiation as well as nitrosoguanidine (NTG) induction. Peniterester was only produced by the mutant T2-M20 on the basis of LC-MS analysis. Meanwhile, the results of in vitro bioactivities screening indicated that peniterester owned obvious antibacterial activities against Bacillus subtilis, Escherichia coli and Staphylococcus aureus with MICs of 8.0, 8.0 and 4.0 µg/mL, respectively.

Single-molecule detection of biomarker and localized cellular photothermal therapy using an optical microfiber with nanointerface.

For early-stage diagnostics, there is a strong demand for sensors that can rapidly detect biomarkers at ultralow concentration or even at the single-molecule level. Compared with other types of sensors, optical microfibers are more convenient for use as point-of-care devices in early-stage diagnostics. However, the relatively low sensitivity strongly hinders their use. To this end, an optical microfiber is functionalized with a plasmonic nanointerface consisting of black phosphorus-supported Au nanohybrids. The microfiber is able to detect epidermal growth factor receptor (ErbB2) at concentrations ranging from 10 zM to 100 nM, with a detection limit of 6.72 zM, enabling detection at the single-molecule level. The nanointerface-sensitized microfiber is capable of differentiating cancer cells from normal cells and treating cancer cells through cellular photothermal therapy. This work opens up a possible approach for the integration of cellular diagnosis and treatment.

Lutein Suppresses Oxidative Stress and Inflammation by Nrf2 Activation in an Osteoporosis Rat Model.

BACKGROUND Osteoporosis is a major health risk for women worldwide. Osteoporosis is caused by an imbalance between bone resorption and formation. Hormonal imbalance and increased redox signaling cause bone deterioration. MATERIAL AND METHODS Oxidative stress was determined through assessment of ROS, lipid peroxide levels, and antioxidant activity. Inflammatory protein markers and Nrf2-related protein expressions were determined through Western blot analysis. Interleukin expressions were determined using ELSA. RESULTS In the present study, we showed that supplementation of lutein protects the ovariectomized (OVX) rats against oxidative stress through its antioxidant protection. OVX rats showed an increase in oxidative stress markers. Lutein treatment significantly decreased the lipid peroxidation levels and ROS in the OVX rats. OVX rats showed inflammatory responses through NF-κB activation and increased inflammatory cytokines (TNF-α, IL-6, IL-8). Further, there was significant upregulation in osteoclast-specific marker NFATc1 in OVX rats compared to sham rats. Lutein supplementation activated Nrf2 driven antioxidant gene expression (HO-1, NQO1) and protected OVX rats against inflammatory responses. CONCLUSIONS We showed the critical role of Lutein in protection against osteoporosis in OVX rats by downregulation of inflammation and osteoclast-specific marker (NFATc1) expression through Nrf2 activation.

A Novel Mutation of SLC19A2 in a Chinese Zhuang Ethnic Family with Thiamine-Responsive Megaloblastic Anemia.

BACKGROUND/AIMS: Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder resulting from mutations in SLC19A2, and is mainly characterized by megaloblastic anemia, diabetes, and progressive sensorineural hearing loss. METHODS: We study a Chinese Zhuang ethnicity family with thiamine-responsive megaloblastic anemia. The proband of the study presented with anemia and diabetes, similar to his late brother, as well as visual impairment. All clinical manifestations were corrected with thiamine (30 mg/d) supplementation for 1-3 months, except for visual impairment, which was irreversible. The presence of mutations in all exons and the flanking sequences of the SLC19A2 gene were analyzed in this family based on the proband's and his brother's clinical data. Computer analysis and prediction of the protein conformation of mutant THTR-1. The relative concentration of thiamine pyrophosphate in the proband's whole blood before and after initiation of thiamine supplement was measured by high performance liquid chromatography (HPLC). RESULTS: Gene sequencing showed a homozygous mutation in exon 6 of the SLC19A2 gene (c.1409insT) in the proband. His parents and sister were diagnosed as heterozygous carriers of the c.1409insT mutation. Computer simulation showed that the mutations caused a change in protein conformation. HPLC results suggested that the relative concentration of thiamine pyrophosphate in the proband's whole blood after thiamine supplement was significantly different (P=0.016) from that at baseline. CONCLUSIONS: This novel homozygous mutation (c.1409insT) caused the onset of thiamine-responsive megaloblastic anemia in the proband.

Integrative Epigenetic Analysis Reveals Therapeutic Targets to the DNA Methyltransferase Inhibitor Guadecitabine (SGI-110) in Hepatocellular Carcinoma.

There is an urgent need to develop more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi), which is currently in clinical trials for HCC and shows greater stability and performance over first-generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2, and SNU475) were used to evaluate the effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles, and its clinical relevance by comparison to The Cancer Genome Atlas (TCGA) HCC clinical data. Each HCC cell line represents a different DNA methylation subtype of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged antiproliferation effects. Expression of up-regulated genes, including tumor suppressors, was positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation. Alternatively, expression of down-regulated genes, such as oncogenes, was negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. SGI-110 can also act as a dual inhibitor to down-regulate polycomb repressive complex 2 (PRC2) genes by demethylating their gene bodies, resulting in reactivation of PRC2 repressed genes without involvement of DNA methylation. Furthermore, it can up-regulate endogenous retroviruses to reactivate immune pathways. Finally, about 48% of frequently altered genes in primary HCC tumors can be reversed by SGI-110 treatment. CONCLUSION: Our integrative analysis has successfully linked the antitumor effects of SGI-110 to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets, and provided a rationale for combination treatments of SGI-110 with immune checkpoint therapies.