Hepatocellular carcinoma (HCC) is a common and challenging malignancy of the digestive tract. Unfortunately, patients with advanced HCC frequently experience limited long-term benefits from current treatments, highlighting the critical need for innovative therapeutic agents. The discovery and development of new small-molecule compounds that target tumours have become crucial aspects of cancer research. In this study, we report on L-741626, a compound that has significant inhibitory effects on HCC. Both in vivo and in vitro experiments confirmed that L-741626 inhibited the growth of HCC by suppressing the MAPK/ERK signalling pathway. Molecular docking simulations and drug affinity responsive target stability assays further identified redox Factor 1 (Ref-1) as a target of L-741626. Ref-1 is overexpressed in HCC and is correlated with poor prognosis and high stage. Further studies demonstrated that Ref-1 interacts with CRAF, a crucial component of the MAPK/ERK signalling pathway. Knockdown of Ref-1 in HCC cells led to inhibition of the MAPK/ERK pathway. Sorafenib is a well-established targeted therapy for the treatment of HCC, with its primary antitumor mechanism being the inhibition of the MAPK/ERK signalling pathway. However, the presence of tumor stem cells is a key factor contributing to resistance to sorafenib. Our study demonstrates that L-741626 can suppress tumor stemness in HCC. The combination of L-741626 and sorafenib significantly enhances the sensitivity of HCC, resulting in increased tumoricidal effects. Our findings reveal a novel pharmacological effect of L-741626, which inhibits MAPK/ERK signalling activity in HCC by targeting Ref-1. Furthermore, L-741626 exhibits a synergistic effect when combined with sorafenib, suggesting a new potential approach for HCC treatment.

The tumor microenvironment (TME) is a highly complex and continuous evolving ecosystem, consisting of a diverse array of cellular and non-cellular components. Among these, benign non-immune cells, including cancer-associated fibroblasts (CAFs), adipocytes, endothelial cells (ECs), pericytes (PCs), Schwann cells (SCs) and others, are crucial factors for tumor development. Benign non-immune cells within the TME interact with both tumor cells and immune cells. These interactions contribute to tumor progression through both direct contact and indirect communication. Numerous studies have highlighted the role that benign non-immune cells exert on tumor progression and potential tumor-promoting mechanisms via multiple signaling pathways and factors. However, these benign non-immune cells may play different roles across cancer types. Therefore, it is important to understand the potential roles of benign non-immune cells within the TME based on tumor heterogeneity. A deep understanding allows us to develop novel cancer therapies by targeting these cells. In this review, we will introduce several types of benign non-immune cells that exert on different cancer types according to tumor heterogeneity and their roles in the TME.

Trypanosomatids are parasites of health importance that cause neglected diseases in humans and animals. Chagas' disease, caused by Trypanosoma cruzi, affects 6-7 millions of people worldwide, mostly in Latin America, most of whom do not have access to diagnosis or treatment. Currently, there are no available vaccines, and the antiparasitic drugs used for treatment are often toxic and ineffective for the chronic stage of infection. Therefore, exploration of new therapeutic targets is necessary and highlights the importance of identifying new therapeutic options for the treatment of this disease. Trypanosomatid genes are organized and expressed in a species-specific fashion and many of their regulatory factors remain to be explored, so proteins involved in the regulation of gene expression are interesting candidates as drug targets. Previously, we demonstrated that the TbRRM1 protein from T. brucei is an essential nuclear factor involved in Pol-II transcriptional regulation. TcSR62 is a TbRRM1 orthologous protein in T. cruzi, but little is known about its function. In this study, we used molecular modeling of the RNA-binding domains of the TcSR62 protein and computational molecular docking to identify TcSR62-specific drug candidates. We identified sorafenib tosylate (ST) as a compound with trypanocidal activity. Sorafenib tosylate showed promising half-maximal inhibitory concentration (IC50) for all parasite stages in vitro. Furthermore, overexpression of TcSR62 protein led to ST-resistant parasites, suggesting that the trypanocidal effect might be due to the inhibition of TcSR62 function. These results demonstrate that ST could be repurposed as a novel drug to treat Chagas' disease.

The ASGR-mediated endocytosis has been successfully applied to the hepatocyte-targeted delivery of therapeutic oligonucleotides via glycoconjugates. However, few studies have explored the conjugated small molecules due to the challenge of cleaving suitable linkers for the release of active small molecules, which is especially different from GalNAc-ONs cleaved by the deoxyribonuclease II in the lysosome. In this study, GalNAc-MMAE conjugates linked by CTSB-cleavable linkers were designed and synthesized. A comprehensive approach revealed that the conjugates were endocytosed by ASGR and subsequently hydrolyzed by CTSB, releasing MMAE. The optimized conjugate with a succinic acid monoamide as the fragment of the linker demonstrated favorable plasma stability, excellent biodistribution, and significant antitumor activities in vivo with weight gain at the effective dose in an orthotopic hepatocellular carcinoma mouse model. This research provides a strategy for developing anti-HCC therapeutic agents using GalNAc drug conjugates with CTSB-cleavable linkers to release active small molecules.

In the 21st century, thanks to advances in biotechnology and developing pharmaceutical technology, significant progress is being made in effective drug design. Drug targeting aims to ensure that the drug acts only in the pathological area; it is defined as the ability to accumulate selectively and quantitatively in the target tissue or organ, regardless of the chemical structure of the active drug substance and the method of administration. With drug targeting, conventional, biotechnological and gene-derived drugs target the body's organs, tissues, and cells that can be selectively transported to specific regions. These systems serve as drug carriers and regulate the timing of release. Despite having many advantageous features, these systems have limitations in thoroughly treating complex diseases such as cancer. Therefore, combining these systems with nanoparticle technologies is imperative to treat cancer at both local and systemic levels effectively. The nanocarrier-based drug delivery method involves encapsulating target-specific drug molecules into polymeric or vesicular systems. Various drug delivery systems (DDS) were investigated and discussed in this review article. The first part discussed active and passive delivery systems, hydrogels, thermoplastics, microdevices and transdermal-based drug delivery systems. The second part discussed drug carrier systems in nanobiotechnology (carbon nanotubes, nanoparticles, coated, pegylated, solid lipid nanoparticles and smart polymeric nanogels). In the third part, drug targeting advantages were discussed, and finally, market research of commercial drugs used in cancer nanotechnological approaches was included.

A series of semisynthetic noscapine-urea congeners (7a-7h) as potential tubulin-binding agents are being developed by integrating a urea pharmacophore at the C-9 position of the noscapine scaffold. Their binding affinity to tubulin was predicted through molecular docking, molecular dynamics (MD) simulations, and the MM-PBSA approach. These molecules were subsequently chemically synthesized and assessed using breast cancer cell lines (MCF-7 and MDA-MB-231) and normal human embryonic kidney cells (HEK). Both the docking score and the predicted binding free energy (ΔGbind,pred) revealed that urea congeners had a stronger affinity towards tubulin than noscapine and effectively inhibited the proliferation of all cancer cell types without affecting normal healthy cells. The results indicated that compound 7g exhibited the most promise and was chosen for further studies. Moreover, MDA-MB-231 cells treated with 7g at its IC50 concentration showed morphological changes such as membrane blebbing, fragmented nuclei, and the presence of apoptotic bodies. Apoptosis induction was further confirmed by flow cytometry. Moreover, the tubulin binding assay revealed a greater binding affinity with an equilibrium dissociation constant (KD) of 42 ± 2.4 μM for compound 7g. The number of MCF-7 cells engrafted as breast tumors in nude mice was found to be reduced significantly without any adverse effects. Noscapine is already in clinical trials, but the urea noscapine congener offers an advantage because of its increased potency without impacting the nontoxic profile of noscapine.

Platinum-based anticancer chemotherapy (PAC) represents a cornerstone in cancer treatment, retaining its status as the gold standard therapy. However, PAC's efficacy is countered by significant toxicities, such as nephrotoxicity, ototoxicity, and neurotoxicity. Recent studies have linked these toxicities to ferroptosis, characterized by iron accumulation, reactive oxygen species generation, and lipid peroxidation. This review explores the mechanisms underlying PAC-induced toxicities, focusing on the involvement of ferroptosis with three major PAC drugs-cisplatin, carboplatin, and oxaliplatin. Further, we provide a comprehensive analysis of the natural product mitigation of PAC-induced ferroptotic toxicity.

The mechanistic role of ferroptosis in cisplatin- and oxaliplatin-induced toxicities has been investigated, while studies on carboplatin-induced ferroptotic toxicities are lacking. Natural compounds targeting molecular pathways of ferroptosis have been explored to mitigate PAC-induced ferroptotic toxicity.

While ferroptosis in cisplatin- and oxaliplatin-induced toxicities has been investigated, there remains a notable dearth of studies examining its involvement in carboplatin-induced toxicities. Hence, further exploration is warranted to define the role of ferroptosis in carboplatin-induced toxicities, and its further mitigation. Moreover, in-depth mechanistic evaluation is necessary to establish natural products evaluated against PAC-induced ferroptosis, as PAC adjuvants.

Liver and Breast cancer are ranked as the most prevailing cancers that cause high cancer-related mortality. As cancer is a life-threatening disease that affects the human population globally, there is a need to develop novel therapies. Among the available treatment options include radiotherapy, chemotherapy, surgery, and immunotherapy. The most superlative modern method is the use of plant-derived anticancer drugs that target the cancerous cells and inhibit their proliferation. Plant-derived compounds are generally considered safer than synthetic drugs/traditional therapies and could serve as potential novel targets to treat liver and breast cancer to revolutionize cancer treatment. Alkaloids and Polyphenols have been shown to act as anticancer agents through molecular approaches. They disrupt various cellular mechanisms, inhibit the production of cyclins and CDKs to arrest the cell cycle, and activate the DNA repairing mechanism by upregulating p53, p21, and p38 expression. In severe cases, when no repair is possible, they induce apoptosis in liver and breast cancer cells by activating caspase-3, 8, and 9 and increasing the Bax/Bcl-2 ratio. They also deactivate several signaling pathways, such as PI3K/AKT/mTOR, STAT3, NF-κB, Shh, MAPK/ERK, and Wnt/β-catenin pathways, to control cancer cell progression and metastasis. The highlights of this review are the regulation of specific protein expressions that are crucial in cancer, such as in HER2 over-expressing breast cancer cells; alkaloids and polyphenols have been reported to reduce HER2 as well as MMP expression. This study reviewed more than 40 of the plant-based alkaloids and polyphenols with specific molecular targets against liver and breast cancer. Among them, Oxymatrine, Hirsutine, Piperine, Solamargine, and Brucine are currently under clinical trials by qualifying as potent anticancer agents due to lesser side effects. As a lot of research is there on anticancer compounds, there is a desideratum to compile data to move towards clinical trials phase 4 and control the prevalence of liver and breast cancer.

We aimed to determine the effects of piperine on cell viability, cellular stresses, and apoptosis first, then the relationship of piperine's effects with the c-Jun N-terminal kinase (JNK) signaling pathway, and also the interaction of piperine with sorafenib in hepatocellular carcinoma. Hepatocellular carcinoma (HepG2 and Hep3B) and non-cancerous hepatocyte (AML12) cell lines were used. The cell viability was determined by using MTT assay. Cellular stresses, apoptosis, and JNK signaling markers were measured by Western blotting. Cells were pre-treated with SP600125 as a JNK inhibitor. The inhibitory concentration 50% (IC50) values and interaction of piperine with sorafenib were calculated by using CompuSyn software. IC50 values of piperine were 97 µM for HepG2, 58 µM for Hep3B, and 184 µM for AML12 with incubation for 48 h. Piperine caused a significant concentration-dependent increase in cellular stresses, apoptosis, and activated JNK signaling in hepatocellular carcinoma cells. Pre-treatment with a JNK inhibitor significantly reduced piperine-induced cellular stresses, apoptosis, and cytotoxicity. Piperine had concentration-dependent additive or synergistic effects when combined with sorafenib in both HepG2 and Hep3B cells. We found that piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma.

Apigenin (C15H10O5, API) is a natural flavonoid widely found in vegetables, fruits, and plants such as celery, oranges, and chamomile. In recent years, API has attracted considerable attention as a dietary supplement due to its low toxicity, non-mutagenic properties and remarkable therapeutic efficacy in various diseases. In particular, evidence from a large number of preclinical studies suggests that API has promising effects in the prevention and treatment of a variety of liver diseases, including multifactorial liver injury, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, liver fibrosis and liver cancer. This paper provides a comprehensive review of the progress of research into the therapeutic applications of API in liver diseases as of August 2024, based on literature retrieved from databases such as Web of Science, PubMed, CNKI, Google Scholar and ScienceDirect. The hepatoprotective effects of API involve multiple molecular mechanisms, including inhibition of inflammation, alleviation of hepatic oxidative stress, amelioration of insulin resistance, promotion of fatty acid oxidation, inhibition of liver cancer cell proliferation and differentiation, and induction of tumour cell apoptosis. More importantly, signaling pathways such as Nrf2, NF-κB, PI3K/Akt/mTOR, NLRP3, Wnt/β-catenin, TGF-β1/Smad3, AMPK/SREBP, PPARα/γ, MAPKs, and Caspases are identified as key targets through which API exerts its beneficial effects in various liver diseases. Studies on its toxicity and pharmacokinetics indicate that API has low toxicity, is slowly metabolized and excreted in vivo, and has low oral bioavailability. In addition, the paper summarises and discusses the sources, physicochemical properties, new dosage forms, and current challenges and opportunities of API, with the aim of providing direction and rationale for the further development and clinical application of API in the food, pharmaceutical and nutraceutical fields.

Hepatocellular carcinoma is the predominant histologic variant of hepatic malignancy and has become a major challenge to global health. The increasing incidence and mortality of hepatocellular carcinoma has created an urgent need for effective prevention, diagnosis, and treatment strategies. This is despite the impressive results of multiple treatments in the clinic. However, the unique tumor immunosuppressive microenvironment of hepatocellular carcinoma increases the difficulty of treatment and immune tolerance. In recent years, the application of nanoparticles in the treatment of hepatocellular carcinoma has brought new hope for tumor patients. Nano agents target tumor-associated fibroblasts, regulatory T cells, myeloid suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, and immature dendritic cells, reversed the immunosuppressive microenvironment of hepatocellular carcinoma. In addition, he purpose of this review is to summarize the advantages of nanotechnology in guiding surgical excision, local ablation, TACE, standard chemotherapy, and immunotherapy, application of nano-vaccines has also continuously enriched the treatment of liver cancer. This study aims to investigate the potential applications of nanotechnology in the management of hepatocellular carcinoma, with the ultimate goal of enhancing therapeutic outcomes and improving the prognosis for patients affected by this malignancy.

The progression of liver cancer is a complicated process that involves genetic and epigenetic changes. Paired box 6 (PAX6) is a critical transcription factor for embryonic development. PAX6 is abnormally methylated in human cancer. The role of the PAX6 gene in the pathogenesis of hepatocellular carcinoma (HCC) is still unclear.

Transcriptional silencing of PAX6 mediated by promoter methylation was confirmed using quantitative methylation-specific polymerase chain reaction (PCR) and reverse-transcription (RT)-PCR. Then we conducted gain-and-loss of function approaches to evaluate the function of PAX6 in HCC progression in vitro. Moreover, we designed xenograft mouse models to assess the effect of PAX6 on tumor growth and metastasis. Finally, we used RNA sequencing (RNA-seq) strategy and phenotypic rescue experiments to identify potential targets of PAX6 performing tumor-suppressive function.

Constitutive expression of PAX6 suppressed anchorage-independent growth and cell invasion in vitro as well as tumor growth and metastasis in xenograft mouse models. In contrast, the inhibition of PAX6 using knockout and knockdown strategies increased tumor growth both in vitro and in vivo. Downregulation of PAX6 by doxycycline depletion partially reversed the malignant phenotypes of HCC cells induced by PAX6. Moreover, we identified E-cadherin (CDH1) and thrombospondin-1 (THBS1) as targets of PAX6. Ultimately, we demonstrated that the knockdown of CDH1 and overexpression of THBS1 in PAX6-expressing HCC cells partly reversed the tumor-suppressive effect.

PAX6 functions as a tumor suppressor partly through upregulation of CDH1 and downregulation of THBS1. Promoter hypermethylation-mediated suppression of PAX6 reduces the tumor suppressor function in the progression of liver cancer.

Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with premalignancy1,2. Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS dose-escalation models in vitro and in vivo, revealing a RAS dose-driven non-linear continuum of downstream phenotypes. In a hepatocyte OIS model in vivo, ectopic expression of NRAS(G12V) does not induce tumours, in part owing to OIS-driven immune clearance3. Single-cell RNA sequencing analyses reveal distinct hepatocyte clusters with typical OIS or progenitor-like features, corresponding to high and intermediate levels of NRAS(G12V), respectively. When titred down, NRAS(G12V)-expressing hepatocytes become immune resistant and develop tumours. Time-series monitoring at single-cell resolution identifies two distinct tumour types: early-onset aggressive undifferentiated and late-onset differentiated hepatocellular carcinoma. The molecular signature of each mouse tumour type is associated with different progenitor features and enriched in distinct human hepatocellular carcinoma subclasses. Our results define the oncogenic dosage-driven OIS spectrum, reconciling the senescence and tumour initiation phenotypes in early tumorigenesis.

The selection of appropriate second-line therapy for liver cancer after first-line treatment failure poses a significant clinical challenge due to the lack of direct comparative studies and standard treatment protocols. A network meta-analysis (NMA) provides a robust method to systematically evaluate the clinical outcomes and adverse effects of various second-line treatments for hepatocellular carcinoma (HCC).

We systematically searched PubMed, Embase, Web of Science and the Cochrane Library to identify phase III/IV randomized controlled trials (RCTs) published up to March 11, 2024. The outcomes extracted were median overall survival (OS), median progression-free survival (PFS), time to disease progression (TTP), disease control rate (DCR), objective response rate (ORR), and adverse reactions. This study was registered in the Prospective Register of Systematic Reviews (CRD42023427843) to ensure transparency, novelty, and reliability.

We included 16 RCTs involving 7,005 patients and 10 second-line treatments. For advanced HCC patients, regorafenib (HR = 0.62, 95%CI: 0.53-0.73) and cabozantinib (HR = 0.74, 95%CI: 0.63-0.85) provided the best OS benefits compared to placebo. Cabozantinib (HR = 0.42, 95%CI: 0.32-0.55) and regorafenib (HR = 0.46, 95% CI: 0.31-0.68) also offered the most significant PFS benefits. For TTP, apatinib (HR = 0.43, 95% CI: 0.33-0.57), ramucirumab (HR = 0.44, 95% CI: 0.34-0.57), and regorafenib (HR = 0.44, 95% CI: 0.38-0.51) showed significant benefits over placebo. Regarding ORR, ramucirumab (OR = 9.90, 95% CI: 3.40-42.98) and S-1 (OR = 8.68, 95% CI: 1.4-154.68) showed the most significant increases over placebo. Apatinib (OR = 3.88, 95% CI: 2.48-6.10) and cabozantinib (OR = 3.53, 95% CI: 2.54-4.90) provided the best DCR benefits compared to placebo. Tivantinib showed the most significant advantages in terms of three different safety outcome measures.

Our findings suggest that, in terms of overall efficacy and safety, regorafenib and cabozantinib are the optimal second-line treatment options for patients with advanced HCC.

Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety. Therefore, they were further examined to demonstrate their ability to induce apoptosis and alter cell cycle progression in hepatocellular carcinoma cells. The most potent compounds were tested against a panel of kinases that indicated their selectivity against FMS kinase. Compounds 8g and 8h showed the most potent activities against FMS kinase with IC50 values of 21.5 and 73.9 nM, respectively. The two compounds were also tested in NanoBRET assay to investigate their ability to inhibit FMS kinase in cells (IC50 = 563 nM (8g) and 1347 nM (8h) vs. IC50 = 1654 nM for sorafenib). Furthermore, compounds 8g and 8h possess potent inhibitory activities against macrophages when investigated in bone marrow-derived macrophages (BMDM) assay (IC50 = 56 nM and 167 nM, respectively, 164 nM for sorafenib). The safety and selectivity of these compounds were confirmed when tested against normal cell lines. Their safety profile was further confirmed using hERG assay. In silico studies were carried out to investigate their binding modes in the active site of FMS kinase, and to develop a QSAR model for these new motifs.

Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.

Hepatocellular carcinoma (HCC) is a global public health problem with increased morbidity and mortality. Agrimol B, a natural polyphenol, has been proved to be a potential anticancer drug. Our recent report showed a favorable anticancer effect of agrimol B in HCC, however, the mechanism of action remains unclear. Here, we found agrimol B inhibits the growth and proliferation of HCC cells in vitro as well as in an HCC patient-derived xenograft (PDX) model. Notably, agrimol B drives autophagy initiation and blocks autophagosome-lysosome fusion, resulting in autophagosome accumulation and autophagy arrest in HCC cells. Mechanistically, agrimol B downregulates the protein level of NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1) through caspase 3-mediated degradation, leading to mitochondrial reactive oxygen species (mROS) accumulation and autophagy arrest. NDUFS1 overexpression partially restores mROS overproduction, autophagosome accumulation, and growth inhibition induced by agrimol B, suggesting a cytotoxic role of agrimol B-induced autophagy arrest in HCC cells. Notably, agrimol B significantly enhances the sensitivity of HCC cells to sorafenib in vitro and in vivo. In conclusion, our study uncovers the anticancer mechanism of agrimol B in HCC involving the regulation of oxidative stress and autophagy, and suggests agrimol B as a potential therapeutic drug for HCC treatment.

More than 800,000 people worldwide are diagnosed with HCC (hepatocellular carcinoma) each year, with approximately 700,000 deaths alone occurring in that same year. Treatment of HCC presents complex therapeutic challenges, particularly in intermediate and advanced stages. LRTs such as transarterial chemoembolization (TACE) and ablations have been the mainstay treatment for early to intermediate-stage HCC, and systemic therapies are used to treat intermediate-late-stage HCC. However, novel literature describing combining LRT with systemic therapies has shown promising results. This review explores recent advances in both liver-directed techniques for hepatocellular carcinoma, including bland transarterial embolization, chemoembolization, radioembolization, and ablative therapies in conjunction as well as with systemic therapies, with a focus on combination therapies, patient selection, procedural technique, periprocedural management, and outcomes. Our findings suggest that LRT combined with systemic therapies is a viable strategy for improving progression-free survival and time to progression for patients with intermediate-to-late-stage HCC. However, further investigation is required to refine treatment protocols and define patient cohorts that would benefit the most.

Background: The effectiveness and safety of using Brucea javanica oil (BJO) in combination with Transarterial Chemoembolization (TACE) for liver cancer treatment are subjects of debate. This study aims to assess the comparative effectiveness and safety of BJO-assisted TACE versus TACE alone and quantifies the differences between these two treatment methods. Methods: A systematic search was conducted in multiple databases including PubMed, Cochrane, CNKI, and Wanfang, until 1 July 2023. Meta-analysis was conducted, and the results were presented as mean difference (MD), risk ratio (RR), and 95% confidence intervals (CI). Results: The search yielded 11 RCTs, with a combined sample size of 1054 patients. Meta-analysis revealed that BJO-assisted TACE exhibited superior outcomes compared to standalone TACE. Specific data revealed that BJO-assisted TACE improves clinical benefit rate by 22% [RR = 1.22, 95% CI (1.15, 1.30)], increases the number of people with improved quality of life by 32%, resulting in an average score improvement of 9.53 points [RR = 1.32, 95% CI (1.22, 1.43); MD = 9.53, 95% CI (6.95, 12.10)]. Furthermore, AFP improvement rate improved significantly by approximately 134% [RR = 2.34, 95% CI (1.58, 3.46)], accompanied by notable improvements in liver function indicators, with an average reduction of 27.19 U/L in AST [MD = -27.19, 95% CI (-40.36, -14.02)], 20.77 U/L in ALT [MD = -20.77, 95% CI (-39.46, -2.08)], 12.17 μmol/L in TBIL [MD = -12.17, 95% CI (-19.38, -4.97)], and a decrease of 43.72 pg/mL in VEGF [MD = -43.72, 95% CI (-63.29, -24.15)]. Most importantly, there was a 29% reduction in the occurrence of adverse reactions [RR = 0.71, 95% CI (0.60, 0.84)]. Conclusion: These findings indicate that BJO-assisted TACE may be considered as a potentially beneficial treatment option for liver cancer patients when compared to standalone TACE. It appears to contribute to improved treatment outcomes, enhanced quality of life, and potentially reduced adverse reactions, suggesting it warrants further investigation as a promising approach for liver cancer treatment. Systematic Review Registration: identifier CRD42023428948.

Although sorafenib has been consistently used as a first-line treatment for advanced hepatocellular carcinoma (HCC), most patients will develop resistance, and the mechanism of resistance to sorafenib needs further study.

Using KAS-seq technology, we obtained the ssDNA profiles within the whole genome range of SMMC-7721 cells treated with sorafenib for differential analysis. We then intersected the differential genes obtained from the analysis of hepatocellular carcinoma patients in GSE109211 who were ineffective and effective with sorafenib treatment, constructed a PPI network, and obtained hub genes. We then analyzed the relationship between the expression of these genes and the prognosis of hepatocellular carcinoma patients.

In this study, we identified 7 hub ERGs (ACTB, CFL1, ACTG1, ACTN1, WDR1, TAGLN2, HSPA8) related to drug resistance, and these genes are associated with the cytoskeleton.

The cytoskeleton is associated with sorafenib resistance in hepatocellular carcinoma. Using KAS-seq to analyze the early changes in tumor cells treated with drugs is feasible for studying the drug resistance of tumors, which provides reference significance for future research.

Over the past few decades, extensive research has explored the development of supportive scaffold materials for in vitro hepatic cell culture, to effectively mimic in vivo microenvironments. It is crucial for hepatic disease modeling, drug screening, and therapeutic evaluations, considering the ethical concerns and practical challenges associated with in vivo experiments. This review offers a comprehensive perspective on hepatic cell culture using bioscaffolds by encompassing all stages of hepatic diseases-from a healthy liver to fibrosis and hepatocellular carcinoma (HCC)-with a specific focus on matrix stiffness. This review begins by providing physiological and functional overviews of the liver. Subsequently, it explores hepatic cellular behaviors dependent on matrix stiffness from previous reports. For hepatic cell activities, softer matrices showed significant advantages over stiffer ones in terms of cell proliferation, migration, and hepatic functions. Conversely, stiffer matrices induced myofibroblastic activation of hepatic stellate cells, contributing to the further progression of fibrosis. Elevated matrix stiffness also correlates with HCC by increasing proliferation, epithelial-mesenchymal transition, metastasis, and drug resistance of HCC cells. In addition, we provide quantitative information on available data to offer valuable perspectives for refining the preparation and development of matrices for hepatic tissue engineering. We also suggest directions for further research on this topic.

Hepatic carcinoma is one of the leading causes of morbidity and mortality among all cancers, but no effective treatment measures have been developed. Herein, polystyrene polysaccharide (PSP) extracted from Polygonatum was used to synthesize gold nanoparticles (PSP-AuNPs) by heating and reduction methods, and the characteristics of the PSP-AuNPs were detected after successful synthesis. In vitro, the immunoregulatory effects of PSP-AuNPs were studied by testing the concentrations of NO, TNF-α, and IL-12p70 in the culture media of PSP-AuNPs-treated RAW264.7 macrophages, and the effect of biocompatibility on the viability of RAW264.7 macrophages and L02 cells was studied via a CCK-8 assay. In vivo, tumor-bearing mice were established and treated with PSP-AuNPs, and the anticancer effects were studied by detecting trends in tumor volume, tumor inhibition rate, and tumor cell proliferation index. Immunoregulation was assessed by evaluating the serum levels of TNF-α and IL-10, the CD4+/CD8+ lymphocyte ratio in peripheral blood and the spleen and thymus indices; toxicity was investigated by measuring body weight, liver and renal function indices. The results showed that PSP-AuNPs could regulate immune function both in vitro and in vivo with almost no toxicity. PSP-AuNPs exhibited excellent anticancer effects on hepatic carcinoma in vivo. The anticancer effect could be strengthened, and the toxicity could be reduced by the combined use of PSP-AuNPs and ADM. In conclusion, PSP-AuNPs could be effective as a therapy and adjuvant therapy for treating hepatic carcinoma, providing potential treatment strategies for this disease.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide and no pharmacological treatment is available that can achieve complete remission of HCC. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a recently identified HCC tumor suppressor gene which plays an important role in the development of HCC and its inactivation and reactivation has been shown to result in respectively HCC tumorigenesis and suppression. Small activating RNAs (saRNAs) have been used to achieve targeted activation of therapeutic genes for the restoration of their encoded protein through the RNAa mechanism. Here we designed and validated saRNAs that could activate LHPP expression at both the mRNA and protein levels in HCC cells. Activation of LHPP by its saRNAs led to the suppression of HCC proliferation, migration and the inhibition of Akt phosphorylation. When combined with targeted anticancer drugs (e.g., regorafenib), LHPP saRNA exhibited synergistic effect in inhibiting in vitro HCC proliferation and in vivo antitumor growth in a xenograft HCC model. Findings from this study provides further evidence for a tumor suppressor role of LHPP and potential therapeutic value of restoring the expression of LHPP by saRNA for the treatment of HCC.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. PANoptosis is a recently unveiled programmed cell death pathway, Nonetheless, the precise implications of PANoptosis within the context of HCC remain incompletely elucidated.

We conducted a comprehensive bioinformatics analysis to evaluate both the expression and mutation patterns of PANoptosis-related genes (PRGs). We categorized HCC into two clusters and identified differentially expressed PANoptosis-related genes (DEPRGs). Next, a PANoptosis risk model was constructed using LASSO and multivariate Cox regression analyses. The relationship between PRGs, risk genes, the risk model, and the immune microenvironment was studies. In addition, drug sensitivity between high- and low-risk groups was examined. The expression profiles of these four risk genes were elucidate by qRT-PCR or immunohistochemical (IHC). Furthermore, the effect of CTSC knock down on HCC cell behavior was verified using in vitro experiments.

We constructed a prognostic signature of four DEPRGs (CTSC, CDCA8, G6PD, and CXCL9). Receiver operating characteristic curve analyses underscored the superior prognostic capacity of this signature in assessing the outcomes of HCC patients. Subsequently, patients were stratified based on their risk scores, which revealed that the low-risk group had better prognosis than those in the high-risk group. High-risk group displayed a lower Stromal Score, Immune Score, ESTIMATE score, and higher cancer stem cell content, tumor mutation burden (TMB) values. Furthermore, a correlation was noted between the risk model and the sensitivity to 56 chemotherapeutic agents, as well as immunotherapy efficacy, in patient with. These findings provide valuable guidance for personalized clinical treatment strategies. The qRT-PCR analysis revealed that upregulated expression of CTSC, CDCA8, and G6PD, whereas downregulated expression of CXCL9 in HCC compared with adjacent tumor tissue and normal liver cell lines. The knockdown of CTSC significantly reduced both HCC cell proliferation and migration.

Our study underscores the promise of PANoptosis-based molecular clustering and prognostic signatures in predicting patient survival and discerning the intricacies of the tumor microenvironment within the context of HCC. These insights hold the potential to advance our comprehension of the therapeutic contribution of PANoptosis plays in HCC and pave the way for generating more efficacious treatment strategies.

N6-methyladenosine (m6A) is important in regulating mRNA stability, splicing, and translation, and it also contributes to tumor development. However, there is still limited understanding of the comprehensive effects of m6A modification patterns on the tumor immune microenvironment, metabolism, and drug resistance in hepatocellular carcinoma (HCC). In this study, we utilized unsupervised clustering based on the expression of 23 m6A regulators to identify m6A clusters. We identified differential m6A modification patterns and characterized m6A-gene-cluster A, which exhibited poorer survival rates, a higher abundance of Treg cells, and increased expression of TGFβ in the tumor microenvironment (TME). Additionally, m6A-gene-cluster A demonstrated higher levels of glycolysis activity, cholesterol metabolism, and fatty acid biosynthesis. We also found that the m6A score was associated with prognosis and drug resistance. Patients with a low m6A score experienced worse prognoses, which were linked to an abundance of Treg cells, upregulation of TGFβ, and increased metabolic activity. HCC patients with a higher m6A score showed improved prognosis following sorafenib treatment and immunotherapy. In conclusion, we reveals the association between m6A modification patterns and the tumor immune microenvironment, metabolism, and drug resistance in HCC. Furthermore, the m6A score holds potential as a predictive factor for the efficacy of targeted therapy and immunotherapy in HCC.

Colorectal cancer (CRC) is a common and deadly malignancy, ranking second in terms of mortality and third in terms of incidence on a global scale. The survival rates for CRC patients are unsatisfactory primarily because of the absence of highly effective clinical strategies. The efficacy of existing CRC treatments, such as chemotherapy (CT), is constrained by issues such as drug resistance and damage to healthy tissues. Alternative approaches such as photothermal therapy (PTT), while offering advantages over traditional therapies, suffer instead from a low efficiency in killing tumor cells when used alone. In this context, nanostructures can efficiently contribute to a selective and targeted treatment. Here, we combined CT and PTT by developing a nanoplatform based on polydopamine nanoparticles (PDNPs), selected for their biocompatibility, drug-carrying capabilities, and ability to produce heat upon exposure to near-infrared (NIR) irradiation. As a chemotherapy drug, sorafenib has been selected, a multikinase inhibitor already approved for clinical use. By encapsulating sorafenib in polydopamine nanoparticles (Sor-PDNPs), we were able to successfully improve the drug stability in physiological media and the consequent uptake by CRC cells, thereby increasing its therapeutic effects. Upon NIR stimulus, Sor-PDNPs can induce a temperature increment of about 10 °C, encompassing both PTT and triggering a localized and massive drug release. Sor-PDNPs were tested on healthy colon cells, showing minimal adverse outcomes; conversely, they demonstrated excellent efficacy against CRC cells, with a strong capability to hinder cancer cell proliferation and induce apoptosis. Obtained findings pave the way to new synergistic chemo-photothermal approaches, maximizing the therapeutic outcomes against CRC while minimizing side effects on healthy cells.

Hepatocellular carcinoma (HCC) is a primary cancer that poorly responds to treatment. Molecular cancer studies led to the development of kinase inhibitors, among which sorafenib stands out as a multi-kinase inhibitor approved by FDA for first line use in HCC patients. However, the efficiency of sorafenib was shown to be counteracted by numerous subcellular pathways involving the effector kinase AKT, causing resistance and limiting its survival benefit. On the way of breaking such resistance mechanisms and increase the efficiency of sorafenib, deeper understanding of hepatocellular physiology is essential. Thyroid hormones were shown to be metabolized in liver and inevitably affect the molecular behaviour of hepatocytes. Interestingly, thyroid hormone T3 was also demonstrated to be potentially influential in liver regeneration and treatment with this hormone reportedly led to a decrease in HCC tumor growths. In this study, we aimed to uncover the impact of T3 hormone on the cytotoxic response to sorafenib in HCC in vitro.

We pre-treated the HCC cell line Huh-7 with T3 prior to sorafenib exposure both in 2D and 3D culture. We checked cell viability with MTT assay in 2D culture and measured the sizes of 3D spheroids with bright-field microscopy followed by a surface analysis with ImageJ. We also performed scratch assay to measure cell migration as well as western blot and qPCR to uncover affected pathways.

We observed an additive effect to sorafenib's cytotoxicity both in 2D and 3D culture. Cell migration assay also confirmed our finding and pointed out a benefit of T3 hormone in HCC cell migration. Western blot experiments showed that T3 exerts its additive effect by suppressing AKT expression upon sorafenib treatment both at protein and gene expression levels.

Our results open a promising new avenue in increasing sorafenib's cytotoxicity where thyroid hormone T3 is utilized to modulate AKT expression to combat resistance, and warrant further studies in the field.

Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond apoptosis, providing promise in cancer treatment. Oncosis, characterized by cellular swelling and increased membrane permeability, represents a non-apoptotic form of cell death. In our study, we discovered that Arnicolide D (AD), a natural sesquiterpene lactone compound, induces ER stress-mediated oncosis in hepatocellular carcinoma (HCC) cells, and this process is reactive oxygen species (ROS)-dependent. Furthermore, we identified the activation of the PERK-eIF2α-ATF4-CHOP pathway during ER stress as a pivotal factor in AD-induced oncosis. Notably, the protein synthesis inhibitor cycloheximide (CHX) was found to effectively reverse AD-induced oncosis, suggesting ATF4 and CHOP may hold crucial roles in the induction of oncosis by AD. These proteins play a vital part in promoting protein synthesis during ER stress, ultimately leading to cell death. Subsequent studies, in where we individually or simultaneously knocked down ATF4 and CHOP in HCC cells, provided further confirmation of their indispensable roles in AD-induced oncosis. Moreover, additional animal experiments not only substantiated AD's ability to inhibit HCC tumor growth but also solidified the essential role of ER stress-mediated and ROS-dependent oncosis in AD's therapeutic potential. In summary, our research findings strongly indicate that AD holds promise as a therapeutic agent for HCC by its ability to induce oncosis.

A novel series of 1-(5-((6-nitroquinazoline-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives 8 were designed and synthesized to evaluate their cytotoxic potencies. The structures of these obtained compounds were thoroughly characterized by IR, 1H, and 13C NMR, MASS spectroscopy and elemental analysis methods. Additionally, their in vitro anticancer activities were investigated using the MTT assay against A549 (human lung cancer), MDA-MB231 (human triple-negative breast cancer), and MCF7 (human hormone-dependent breast cancer). Etoposide was used as a reference marketed drug for comparison. Among the compounds tested, compounds 8b and 8c demonstrated acceptable antiproliferative activity, particularly against MCF7 cells. Considering the potential VEGFR-2 inhibitor potency of these compounds, a molecular docking study was performed for the most potent compound, 8c, to determine its probable interactions. Furthermore, computational investigations, including molecular dynamics, frontier molecular orbital analysis, Fukui reactivity descriptor, electrostatic potential surface, and in silico ADME evaluation for all compounds were performed to illustrate the structure-activity relationship (SAR).

Transarterial chemoembolization (TACE) is currently the standard of care in patients with unresectable hepatocellular carcinoma (HCC), and selective internal radionuclide therapy (SIRT) with 90Y microspheres is mainly used as an alternative modality in patients considered poor candidates for TACE. Treatment with sorafenib is the recommended option for patients with progressive disease after TACE. This study aims to evaluate the safety and efficacy of SIRT with glass microspheres in patients with progressive HCC after repeated TACE who are not eligible for treatment with sorafenib. Forty-seven patients with progressive HCC after a median of three TACE sessions (range 2-14) underwent SIRT (3.5 ± 1.5 GBq; liver target dose 110-120 Gy). Toxicity was recorded 4 and 12 weeks after treatment and reported according to the Common Terminology Criteria for Adverse Events Version 5.0. Treatment response was assessed three months after SIRT using multiphase computed tomography and modified criteria in solid tumors (mRECIST). Survival analyses were performed using Kaplan-Meier curves and a Cox proportional hazards model for uni- and multivariate analyses. Significant but reversible hepatotoxicity (≥grade 3) occurred in five patients (11%). No radioembolization-induced liver disease (REILD) was observed. The number of previous TACE sessions and cumulative administered activity did not predict the incidence of post-SIRT significant hepatotoxicity. Treatment responses consisted of partial responses in 26 (55%), stable disease in 12 (26%), and progressive disease in 9 (19%) patients. The median overall survival (OS) was 11 months (95% confidence interval (CI), 9-13), and objective responses to SIRT were associated with a longer OS (p = 0.008). Significant hepatotoxicity (≥grade 3) after SIRT was a contributor to impaired survival (median OS 6 months (95% CI, 4-8) vs. 12 months (95% CI, 10-14), p < 0.001). SIRT with glass microspheres is a safe and effective salvage treatment for patients with progressive HCC refractory to TACE who are considered poor candidates for sorafenib treatment.

Vascular endothelial growth factors (VEGF), Vascular endothelial growth factor receptors (VEGFR) and their downstream signaling pathways are promising targets in anti-angiogenic therapy. They constitute a crucial system to regulate physiological and pathological angiogenesis. In the last 20 years, many anti-angiogenic drugs have been developed based on VEGF/VEGFR system to treat diverse cancers and retinopathies, and new drugs with improved properties continue to emerge at a fast rate. They consist of different molecular structures and characteristics, which enable them to inhibit the interaction of VEGF/VEGFR, to inhibit the activity of VEGFR tyrosine kinase (TK), or to inhibit VEGFR downstream signaling. In this paper, we reviewed the development of marketed anti-angiogenic drugs involved in the VEGF/VEGFR axis, as well as some important drug candidates in clinical trials. We discuss their mode of action, their clinical benefits, and the current challenges that will need to be addressed by the next-generation of anti-angiogenic drugs. We focus on the molecular structures and characteristics of each drug, including those approved only in China.

Tyrosine kinases are implicated in a wide array of cellular physiological processes, including cell signaling. The discovery of the BCR-ABL tyrosine kinase inhibitor imatinib and its FDA approval in 2001 paved the way for the development of small molecule chemical entities of diverse structural backgrounds as tyrosine kinase inhibitors for the treatment of various ailments. Two of the most prominent tyrosine kinases as drug targets are the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), as evidenced by the clinical success of their many inhibitors in the drug market. Among several other physiological roles, EGFR regulates epithelial tissue development and homeostasis, while VEGFR regulates tumor-induced angiogenesis. The pyrrolo[2,3-d]pyrimidine nucleus represents a deaza-isostere of adenine, the nitrogenous base of ATP. The recent introduction of many pyrrolo[2,3-d]pyrimidines to the drug market as tyrosine kinase inhibitors makes them a hot topic in the medicinal chemistry research area at the present time. This review article comprehensively sheds light on the structure-activity relationship (SAR) of pyrrolo[2,3-d]pyrimidines as EGFR and VEGFR tyrosine kinase inhibitors, aiming to provide help medicinal chemists in the design of future pyrrolopyrimidine kinase inhibitors.

Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is considered as the first-line therapy for advanced HCC. However, the response to sorafenib varies among patients, and the development of drug resistance poses a prevalent obstacle. Ferroptosis, a newly characterized form of cell death featured by iron-dependent lipid peroxidation, has emerged as a critical player in the reaction to sorafenib therapy in HCC. The induction of ferroptosis has been shown to augment the anticancer benefits of sorafenib. However, it has also been observed to contribute to sorafenib resistance. This review presents a comprehensive and thorough analysis that elucidates the intricate relationship between ferroptosis and sorafenib over recent years, aiming to formulate effective therapeutic approaches for liver cancer. Based on this exploration, we propose innovative strategies intended to overcome sorafenib resistance via targeted modulation of ferroptosis.

The tumor immune response plays a vital role in cancer recurrence in patients with malignancies. We aim to clarify the risk factors for early recurrence and investigate the efficacy of blood-based biomarkers to predict the risk of early recurrence in early-stage hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) after hepatectomy.

A total of 101 cases of HCC with MVI who underwent liver resection were enrolled. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors of early recurrence. We calculated the area under the receiver operating characteristic curve to evaluate the performance of the four biomarkers identified as risk factors for early recurrence.

Multiple logistic regression analysis indicated that complement (C)4, cluster of differentiation (CD)4+, immunoglobulin A (IgA), and hepatitis B virus (HBV) DNA of greater than 500 IU/mL were correlated with early recurrence of HCC. The area under the curve was greater for the combination model than for the HBV DNA, CD4+, IgA, or C4 models alone.

Preoperative serum CD4+, C4, IgA, and HBV DNA levels were linked with early recurrence of early-stage HCC with MVI and the combination model was of considerable predictive value for the prognosis of HCC with MVI.

Sorafenib improves the overall survival in patients with advanced hepatocellular carcinoma (HCC). Dickkopf-1 (DKK1) is commonly overexpressed in HCC. In this study, we investigated whether the inhibition of DKK1 enhances the anti-tumor efficacy of sorafenib in HCC.

HCC cells were treated with sorafenib and WAY-262611, which is an inhibitor of DKK1. Transgenic mouse models were also developed using hydrodynamic tail vein injection. Mice were orally administered with sorafenib (32 mg/kg), WAY-262611 (16 mg/kg), or sorafenib + WAY-262611 for 10 days. Mechanisms of sorafenib and WAY-262611 were explored via western blotting, immunostaining, and RNA sequencing.

DKK1 was significantly overexpressed in patients with HCC than in the healthy controls and patients with liver diseases except HCC (all P < 0.05). Compared with sorafenib alone, sorafenib + WAY-262611 significantly inhibited the cell viability, invasion, migration, and colony formation by promoting apoptosis and altering the cell cycles in HCC cells (all P < 0.05). Moreover, sorafenib + WAY-262611 decreased the p110α, phospho-Akt (all P < 0.05), active β-catenin (all P < 0.05) and phospho-GSK-3β (Ser9) expression levels, while increasing the phospho-GSK-3β (Tyr216) expression levels compared with those in the sorafenib alone in vitro and in vivo. In addition, sorafenib + WAY-262611 inhibited tumor progression by regulating cell proliferation and apoptosis, significantly better than sorafenib alone in mouse models.

Our results indicate that DKK1 inhibition significantly enhances the anti-tumor efficacy of sorafenib by inhibiting the PI3K/Akt and Wnt/β-catenin pathways via regulation of GSK3β activity, suggesting a novel therapeutic strategy for HCC. Video Abstract.

To investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs: sorafenib and lenvatinib) plus PD-1 inhibitor (camrelizumab) versus TKIs alone in transarterial chemoembolization-refractory (TACE-refractory) hepatocellular carcinoma (HCC).

Data of TACE-refractory HCC patients treated with TACE+TKIs+PD-1 inhibitor (TACE+TKIs+PD-1group) (n=57) or TACE+TKIs (TACE+TKIs group) (n=50) from January 2019 to January 2022 were retrospectively collected and analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups. Potential factors affecting OS and PFS were evaluated by univariate and multivariate analyses.

Compared with the TKIs group, both PFS and OS were prolonged in the TACE+TKIs+PD-1 group (median PFS: 7 months vs. 5 months, P=0.007; median OS: 17 months vs. 11 months, P=0.002). In multivariate analysis, tumor size and treatment were independent prognostic factors for PFS and OS. The incidence and severity of AEs related to the treatment between the two groups showed no significant difference.

The treatment of TACE combined with TKIs plus camrelizumab demonstrated promising efficacy and safety in TACE-refractory HCC.

Qizhu Anti-Cancer Recipe (QACR) is a traditional Chinese medicine widely used in treating several liver diseases. However, its function and the relevant mechanism underlying its effect in treating hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to explore the effect of QACR in HCC, which are expected to be a potential therapeutic scheme for HCC.

The chemical compositions of QACR were determined by liquid chromatography/quadrupole time-of-fight mass spectrometry (LC-QTOF-MS). The anoikis-resistant HCC cell proliferation and angiopoiesis were detected using the cell counting kit 8 (CCK8) assay, trypan blue, calcein AM/EthD-1, flow cytometer, Western blot, and tube formation assays. An orthotopic xenograft mouse model was established to evaluate the in vivo effects of the QACR. The expression of proliferating cell nuclear antigen (PCNA), Bcl-2, CD31, caspase-3, caspase-8, caspase-9, PARP-1, DFF40, phospho-c-Jun NH2-terminal kinase (p-JNK), and JNK was assessed using Western blot and immunohistochemical analysis.

QACR reduced the growth and tube formation of anoikis-resistant HCC cells and enhanced cell apoptosis in vitro. In the orthotopic xenograft mouse models, QACR suppressed the tumorigenesis of HCC in vivo. Mechanistically, QACR modulated the JNK pathway. The JNK inhibitor (SP600125) reverses the inhibitory effects of QACR on anoikis-resistant HCC cell proliferation and angiopoiesis.

Our study suggests that QACR suppresses the proliferation and angiopoiesis of anoikis-resistant HCC cells by activating the JNK pathway. Therefore, QACR is a promising new therapeutic strategy for treating hepatocellular carcinoma.