Glycolytic reprogramming is closely associated with the occurrence and progression of gastric cancer. Specifically, the energy derived from glucose metabolism and the cellular proteins by its intermediate products influence gastric cancer development. However, as an important branch of glucose metabolism, sialic acid metabolism and its mediated sialylation modifications remain insufficiently studied in gastric cancer, and their specific relationship with malignant tumor progression requires further exploration. This study employed a multi‑omics approach, integrating metabolomics, single‑cell RNA sequencing, and bulk RNA sequencing analyses, to investigate the metabolic landscape of gastric cancer and its associated alterations. The results indicated that sialic acid is a characteristic metabolite in malignant gastric cancer tissues. It modulates biological functions such as immune response, proliferative activity, and metabolic remodeling within gastric cancer tissues by influencing sialylation modifications. Furthermore, we identified the drug WZ35, which can inhibit the malignant proliferation of gastric cancer by targeting both sialic acid metabolism and sialylated protein modifications. We put forward a conjecture that the metabolism and modification of sialic acid promote the malignant development of gastric cancer, and we discovered that the drug WZ35 has an inhibitory effect on the sialic acid metabolism of gastric cancer.

Gastric cancer (GC), a highly aggressive tumor with significant mortality, exhibits metabolic reprogramming involving glucose, lipid, and amino acid metabolism. This study employed non-targeted metabolomics and transcriptomics to analyze metabolic alterations in patients with GC, complemented by single-cell RNA-seq to dissect lactate shuttle dynamics and metabolic alterations between tumor epithelial and endothelial cells. The impact of niclosamide and YTHDF2, an m6A methylation regulator, on gastric cancer cell proliferation was investigated both in vitro and in vivo. Niclosamide disrupted metabolic reprogramming and lactate dynamics within the tumor microenvironment. YTHDF2 emerged as a critical modulator of GC metabolism, with niclosamide suppressing tumors through the YTHDF2-mediated regulation of metabolic genes. Our research revealed comprehensive metabolic alterations in gastric cancer, including upregulated lactate metabolism that promotes tumorigenesis via the lactate shuttle. Niclosamide targets the m6A methylation regulatory protein YTHDF2, which influences genes related to metabolism, indicating its potential as a prospective treatment for GC.

The dysregulation of mitochondrial homeostasis in tumor cells plays a significant role in tumorigenesis and progression. Mitochondria within tumor cells exhibit extensive mutations, proliferation, and fragmentation to accommodate heightened metabolic and energy requirements. This disruption of mitochondrial homeostasis is intricately linked to tumor cell proliferation, invasion, metastasis, energy metabolism, and redox balance. Disrupting the homeostasis of mitochondria in tumor cells has emerged as a novel approach in the clinical management of tumors, with mitochondria-targeted pharmaceuticals showing promise as a potential breakthrough in tumor therapy. This review outlines recent advancements in the understanding of mitochondrial homeostatic dysregulation in oncology and discusses the potential of targeting oncogenic mitochondria as a novel therapeutic avenue for the treatment of tumors.

The aim of this study was to investigate the underlying molecular mechanism behind the promotion of cell survival under conditions of glucose deprivation by l-lactate. To accomplish this, we performed tissue microarray and immunohistochemistry staining to analyze the correlation between the abundance of pan-Lysine lactylation and prognosis. In vivo evaluations of tumor growth were conducted using the KPC and nude mice xenograft tumor model. For mechanistic studies, multi-omics analysis, RNA interference, and site-directed mutagenesis techniques were utilized. Our findings robustly confirmed that l-lactate promotes cell survival under glucose deprivation conditions, primarily by relying on GLS1-mediated glutaminolysis to support mitochondrial respiration. Mechanistically, we discovered that l-lactate enhances the NMNAT1-mediated NAD+ salvage pathway while concurrently inactivating p-38 MAPK signaling and suppressing DDIT3 transcription. Notably, Pan-Kla abundance was significantly upregulated in patients with Pancreatic adenocarcinoma (PAAD) and associated with poor prognosis. We identified the 128th Lysine residue of NMNAT1 as a critical site for lactylation and revealed EP300 as a key lactyltransferase responsible for catalyzing lactylation. Importantly, we elucidated that lactylation of NMNAT1 enhances its nuclear localization and maintains enzymatic activity, thereby supporting the nuclear NAD+ salvage pathway and facilitating cancer growth. Finally, we demonstrated that the NMNAT1-dependent NAD+ salvage pathway promotes cell survival under glucose deprivation conditions and is reliant on the activity of Sirt1. Collectively, our study has unraveled a novel molecular mechanism by which l-lactate promotes cell survival under glucose deprivation conditions, presenting a promising strategy for targeting lactate and NAD+ metabolism in the treatment of PAAD.

Background Post-pandemic era has provided an opportunity for new educational theory as long as the new way to make use of technology. This paper puts forward the architecture of the multimodal teaching interaction model and the prospect of application situations combining the research foundations of technological phenomenology and multimodal theory. Objective This paper aims to clarify a multimodal teaching interaction model perspective, we hope the interactive feedback between medical education subjects can be improved, meet the teaching and learning needs in the post-epidemic era, and promote the development of medical education reform. The focal point is the characteristics, structure, and application of MTIM. Method Using the behavioral education model, situational learning, and human-computer interaction theory as the theoretical framework, we take the medical teaching model as the background, combined with cutting-edge virtual reality, haptic feedback, gesture interaction, and other technologies, rely on the multi-level application architecture such as physical layer and perceptual feedback layer, to successfully build a teaching method of multimodal virtual experience and the overall conceptual framework of learning scenarios. Results This is an innovative conceptual model that focuses on the fundamentals of the overall framework. The characteristics of the model have obvious application advantages in three types of virtual medical education scenarios: "Theoretical knowledge learning", "Operational skill learning" and "Practical experiential learning". And through the characteristics of model immersion, collaboration, dynamic feedback, and other characteristics, the cross-spatial connection between virtual and real is established, which greatly breaks through the limitations of space scenes. Conclusion The multimodal teaching interaction model(MTIM) broadens the application scenarios of teaching, effectively enhances the sense of reality and experience of situational teaching, has great application prospects for promoting the development of medical education reform, and provides some feasible ideas and suggestions for the future development of artificial intelligence in medical education.

Gastric cancer (GC) is highly heterogeneous and GC patients have low overall survival rates. It is also challenging to predict the prognosis of GC patients. This is partly because little is known about the prognosis-related metabolic pathways in this disease. Hence, our objective was to identify GC subtypes and genes related to prognosis, based on changes in the activity of core metabolic pathways in GC tumor samples. Differences in the activity of metabolic pathways in GC patients were analyzed using Gene Set Variation Analysis (GSVA), leading to the identification of three clinical subtypes by non-negative matrix factorization (NMF). Based on our analysis, subtype 1 showed the best prognosis while subtype 3 exhibited the worst prognosis. Interestingly, we observed marked differences in gene expression between the three subtypes, through which we identified a new evolutionary driver gene, CNBD1. Furthermore, we used 11 metabolism-associated genes identified by LASSO and random forest algorithms to construct a prognostic model and verified our results using qRT-PCR (five matched clinical tissues of GC patients). This model was found to be both effective and robust in the GSE84437 and GSE26253 cohorts, and the results from multivariate Cox regression analyses confirmed that the 11-gene signature was an independent prognostic predictor (p < 0.0001, HR = 2.8, 95% CI 2.1–3.7). The signature was found to be relevant to the infiltration of tumor-associated immune cells. In conclusion, our work identified significant GC prognosis-related metabolic pathways in different GC subtypes and provided new insights into GC-subtype prognostic assessment.

Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis. In particular, the mitochondria-endoplasmic reticulum (ER) membrane contact site (MAM) is known to regulate ion and lipid transfer, as well as signaling and organelle dynamics. However, the regulatory mechanisms of MAM formation and their function are still elusive. Here, we identify mitochondrial Lon protease (LonP1), a highly conserved mitochondrial matrix protease, as a new MAM tethering protein. The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation. Furthermore, deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER (UPRER). Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling. These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity, mitochondrial dynamics, and UPRER, offering exciting new insights into the potential therapeutic strategy for heart failure.

Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: (1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. (2) Even with possible access for 'local refrigeration', cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4 °C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas.

Abstract Background Aberrant splice variants play different roles in the formation of tumors. We observed the splice isoform of Protein arginine methyltransferase 5 (PRMT5-ISO5) increases in HCC patients undergoing stereotactic body radiotherapy, which is associated with improvement of poor prognosis. However, the mechanism of alternative splicing of PRMT5-ISO5 induced by ionizing radiation (IR) is still unclear. Methods The transcriptional changes of PRMT5-ISO5 induced by IR were validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay. Bioinformatic analyses were performed to identify potential splicing factors involved in regulating PRMT5 splicing. Small interferring RNA and overexpressing plasmids for SRSF3 and HNRNPH1 were introduced into HCC cell lines, followed by in vitro functional experiments in regulating PRMT5 splicing by RT-qPCR, western blot and RNA-immunoprecipitation assay in vitro. The roles of IR-induced PRMT5-ISO5 and hepatocyte-specific Prmt5 knockout on HCC progression were evaluated in vivo. Results we indicated IR could induce PRMT5-ISO5 transcript in HCC cells by virtue of splicing factors SRSF3 and HNRNPH1. Mechanistically, HNRNPH1 silencing resulted in the decrease of PRMT5-ISO5 while SRSF3 silencing led to the increase of PRMT5-ISO5. In addition, both SRSF3 and HNRNPH1 bound to PRMT5 precursor mRNA on the region around 3' splicing site of intron 2 and alternative 3’ splicing site on exon 4, leading to their opposite functions on regulating PRMT5 splicing. In vivo, the increase of PRMT5-ISO5 induced by IR led to tumor regression, and liver-specific Prmt5 depletion decelerated the progression of Akt/N-Ras-derived spontaneous HCC. Conclusion Our study not only provides mechanistic views that IR-induced SRSF3 downregulation leads to the imbalance of SRSF3 and HNRNPH1 in regulating PRMT5-ISO5 transcript, but also indicates a potential radiotherapeutic of PRMT5-ISO5 in HCC formation since liver-specific Prmt5 knockout inhibits spontaneous HCC tumorigenesis.

BACKGROUND:Liver cancer is the fifth leading cause of cancer death worldwide, but early diagnosis and treatment of liver cancer remains a clinical challenge. How to screen and diagnose liver cancer early and prolong the survival rate is still the focus of researchers.METHODS:Cell experiments were used to detect the effect of WZ35 on the colony formation ability and proliferation activity of hepatoma cells, nude mouse experiment to observe the in vivo anticancer activity and toxic side effects of WZ35; metabolomics analysis, glucose metabolism experiment and Seahorse analysis of liver cancer cells treated with WZ35; cell experiments combined with bioinformatics analysis to explore the mechanism of WZ35-mediated metabolic reprogramming to exert anticancer activity; tissue microarray and case analysis to evaluate the clinical significance of biomarkers for early diagnosis, treatment and prognosis evaluation of liver cancer.RESULTS:WZ35 inhibited the proliferation activity of various cell lines of liver cancer, and showed good therapeutic effect in nude mice model of hepatocellular carcinoma without obvious toxic and side effects; WZ35 inhibited the absorption of glucose in hepatoma cells, and the drug effect glycolysis, phosphorylation and purine metabolism are relatively seriously damaged; WZ35 mainly inhibits YAP from entering the nucleus as a transcription factor activator by activating oxidative stress in liver cancer cells, reducing the transcription of GLUT1, and finally reducing its GLUT1. Tissue microarray and case analysis showed that GLUT1 and YAP were highly expressed and correlated in liver cancer patients, and were associated with poor patient prognosis. The GLUT1-YAP risk model had a high score in predicting prognosis.CONCLUSION:The study confirms that WZ35 is a small molecule glycolysis inhibitor, and through its properties, it mediates metabolic reprogramming dominated by impaired glycolysis, oxidative phosphorylation and purine metabolism to inhibit the proliferation activity of liver cancer cells. Our findings present novel insights into the pathology of liver cancer and potential targets for new therapeutic strategies. GLUT1-YAP has important reference significance for predicting the stages of disease progression in liver cancer patients and have the potential to serve as novel biomarkers for the diagnosis and treatment of liver cancer.

生物节律是周期性的生命活动现象.肿瘤细胞内普遍存在代谢重编程,有研究表明生物节律与代谢调控密切相关.氯硝柳胺(Niclosamide)是一种传统抗蠕虫药,具有氧化磷酸化解偶联的特性,近年来已步入抗癌药物研究领域.为探究氯硝柳胺抑制胃癌发生发展的具体机制,该研究通过CCK-8增殖、ROS和凋亡等实验发现氯硝柳胺可抑制增殖促进凋亡.通过生物信息学筛选出胃癌与癌旁生物节律差异基因Clock、Per、Dbp等,Western blot实验检测发现它们所编码的蛋白在药物作用后表达均有明显变化,其中CLOCK变化最为显著,提示药物作用后胞内生物节律紊乱.通过海马能量代谢和代谢组学分析进一步探讨药物作用后细胞代谢特性及其与生物节律的相关性,结果提示细胞内氧化磷酸化整体趋势呈药物浓度依赖性下降,同时证实了三羧酸循环中间产物延胡索酸在氯硝柳胺抑癌机制中的重要度.通过Western blot实验发现药物作用后支链氨基酸相关蛋白下调,CLOCK敲低与加药联合作用可进一步抑制支链氨基酸转氨酶1(BCAT1)的表达.综上,该研究认为氯硝柳胺可通过紊乱胃癌细胞节律,诱导支链氨基酸代谢失调从而发挥抑癌效应,有望成为抗癌药物的新星.

Protein arginine methyltransferase 5 (PRMT5) is an epigenetic regulator which has been proven to be a potential target for cancer therapy. We observed that PRMT5 underwent alternative splicing (AS) and generated a spliced isoform PRMT5-ISO5 in hepatocellular carcinoma (HCC) patients after radiotherapy. However, the regulatory mechanism and the clinical implications of IR-induced PRMT5 AS are unclear. This work revealed that serine and arginine rich splicing factor 3 (SRSF3) silencing increased PRMT5-ISO5 level, whereas heterogeneous nuclear ribonucleoprotein H 1 (HNRNPH1) silencing reduced it. Then, we found that SRSF3 and HNRNPH1 competitively combined with PRMT5 pre-mRNA located at the region around the 3′- splicing site on intron 2 and the alternative 3′- splicing site on exon 4. IR-induced SRSF3 downregulation led to an elevated level of PRMT5-ISO5, and exogenous expression of PRMT5-ISO5 enhanced cell radiosensitivity. Finally, we confirmed in vivo that IR induced the increased level of PRMT5-ISO5 which in turn enhanced tumor killing and regression, and liver-specific Prmt5 depletion reduced hepatic steatosis and delayed tumor progression of spontaneous HCC. In conclusion, our data uncover the competitive antagonistic interaction of SRSF3 and HNRNPH1 in regulating PRMT5 splicing induced by IR, providing potentially effective radiotherapy by modulating PRMT5 splicing against HCC.

Background At present, immunotherapy has become an established treatment for cancer. Recently, we have realized that tumor metabolism has a huge impact on the shaping of immune reactivity in the tumor microenvironment (TME). Exploration of the tumor metabolic and immunocellular response reveals metabolic vulnerability as a therapeutic window for intervention to enhance immunotherapy. The clinical significance of glycolysis and its role in tumor-immune evolution have not been fully explored. Understanding the relationships between glycolysis, TME evolution and disease progression is of great significance for optimizing immunotherapy of liver cancer. Methods A glycolysis-related biomarker signature was initially identified in transcriptomic data within The Cancer Genome Atlas (TCGA, n=424). Predicted overall survival (OS) for the gene signature in the GSE54236 dataset (n=161) and our HCC cohort (n=132) was subsequently independently verified. The relative number of immune cells in the microenvironment was calculated using CIBERSORT. CCK-8, IHC, Transwell and Seahorse were used to assess the effects of a 3-gene signature on the malignant phenotype of liver cancer. Results A 3-gene signature of glycolysis significantly associated with poor OS was identified. Based on a multi-omics research strategy, we found the 3-gene signature was closely related to the evolution of liver cancer TME and disease progression, and was associated with liver cancer mutation load and immune evolution. High-risk patients have inhibition and depletion of the immune TME and immune escape through antigen presentation inhibition. Remarkably, the 3-gene signature can predict the clinical outcomes of HCC patients with different clinical subtypes. Conclusions Our investigation of the 3-gene signature provided evidence for tumor metabolism-immune co-evolution along HCC progression. The 3-gene signature for stratification of liver cancer risk has robust predictive power, both at the RNA and protein levels.

This study aimed at elucidating the crosstalk between redox reaction and metabolic remodeling through uncovering the mechanism underlying WZ35-mediated reactive oxygen species (ROS) production and regulation of amino acid metabolism to inhibit gastric cancer (GC) cell metastasis. The activity and biosafety of curcumin analog, WZ35, were verified in vitro and in vivo. The potential molecular mechanism underlying WZ35-mediated enhanced radiotherapeutic sensitivity by reduced Glutathione (GSH) depletion was elucidated by RNA sequencing, single-cell sequencing (scRNA-seq), metabolic mass spectrometry, and other molecular experiments. Compared to curcumin, WZ35 proved more potent anti-proliferative and anti-metastasis properties. Importantly, we demonstrated that WZ35 could consume GSH in multiple ways, including by reduction of raw materials and consumption reserves, inhibition of reformation, and enhanced decomposition. Mechanistically, we identify that WZ35 maintains the GSH depletion phenotype through the ROS-YAP-AXL-ALKBH5-GLS2 loop, further backing the relevance of metabolic remodeling in the tumor microenvironment with tumor metastasis and the role of m6A in tumor metastasis. Collectively, our study identified WZ35 as a novel GSH depletion agent and a previously undiscovered GSH depletion loop mechanism in GC cell metastasis.

Protein quality control is pivotal to cellular homeostasis and integrity of cardiomyocytes for maintenance of normal heart function. The unfolded protein response (UPR) is an adaptive process to modulate protein quality control in the endoplasmic reticulum (ER) and mitochondria, and is accordingly termed UPRER and UPRmt, respectively. Lon protease (LonP1) is a highly conserved mitochondrial protease to modulate UPRmt, which is involved in regulating metabolism, mitophagy, and stress response. However, whether LonP1 regulates UPRER remains elusive. To investigate the regulation of protein quality control in cardiomyocytes, we generated cardiac-specific LonP1 deletion mice. Our findings show that LonP1 deficiency caused impaired mitochondrial respiratory function and fragmentation. Surprisingly, both UPRER and UPRmt is substantially induced in LonP1-deletion heart suggesting of LonP1 as a novel regulator of UPRER; however, the activation of UPRER occurs earlier than UPRmt in response to LonP1 deletion. Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming of cardiomyocytes, pathological heart remodeling, as well as impeded heart function. We uncovered the novel function of LonP1 as an UPRmt mediator, and reciprocal orchestration of UPRmt and UPRER and mitochondrial dynamics regulated by LonP1 in the cardiomyocytes that is critical to maintain heart function, which offers exciting new insights into the potential therapeutic strategy for heart failure.

Abstract Background: The significant changes in a series of biochemical activities during the process of tumorigenesis and development, including those in glucose, lipid, and amino acid metabolism can contribute to the ability of the cancer cells to proliferate indefinitely. WZ35 is a new small molecule YAP inhibitor, which can mediate YAP activity to inhibit the growth of gastric cancer, breast cancer and hepatocellular carcinoma. In this article, we explored how WZ35 can modulate YAP activity to influence the metabolism of hepatocellular carcinoma (HCC) cells to inhibit their proliferation activity. Methods: The Gene Expression Omnibus (GEO) data, the Cancer Genome Atlas (TCGA) data, immunohistochemistry (IHC) and preclinical mouse model was utilized to detect the differential expression and vital role of YAP in HCC cells. A series of in vitro and in vivo experiments were performed to explore the antitumor activity of WZ35 and how it can target YAP activity to inhibit the tumor progression. UCSC combined JASPAR public databases were used to predicted possible binding sites of TEAD on GLUT1 promoter. Additionally, seahorse energy metabolism experiments and metabolomics analysis were utilized to explore the possible metabolic changes induced by WZ35. The clinical use of YAP and GLUT1 was verified by bioformatics and tissue microarrays of immunocytochemistry. Results: WZ35 can significantly attenuate the proliferation and growth of HCC. In terms of mechanism(s), it was demonstrated that the suppressive effects of WZ35 on YAP were achieved by promoting ROS production and the drug can exert its significant YAP inhibitory capacity to decrease the level of GLUT1, a glucose transporter located on the surface of cytomembrane, thereby resulting in a significant decrease in the ability of cells to take up glucose and thus perturb the metabolism. Moreover, through bioinformatics mining, it was proposed that YAP/GLUT1 has the potential to serve as promising target for HCC therapy. Conclusions: Our findings indicate that potential inhibitory effects of WZ35 were achieved by affecting the ROS-YAP-GLUT1 signal axis to induce the metabolic reprogramming of hepatocellular carcinoma cells. YAP/GLUT1 could serve as an important molecular target for both the diagnosis and treatment of HCC.

To investigate the anti-tumor activities of WZ35 and its possible molecular mechanism, bioinformatics analysis and the hematoxylin-eosin (HE) staining were applied to evaluate the Yes-associated-protein (YAP) level in gastric cancer. Cell counting kit-8 (CCK-8) was used to examine cell viability. Apoptosis was determined by flow cytometry analysis. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. SiRNA transfection was applied to silence endogenous YAP. Western blot was performed to detect indicated proteins. We found that treatment of gastric cancer cells with WZ35 exerted stronger anti-tumor activities than curcumin. Mechanistically, our research showed that WZ35 inhibited glycolysis, and induced reactive oxygen species (ROS) generation, resulting in Jun N-terminal Kinase (JNK) activation through downregulation of YAP in gastric cancer cells. ROS mediated YAP downregulation and JNK activation was regulated by glycolysis. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP downregulation and JNK activation. Similarly, the JNK inhibitor significantly reversed WZ35 induced anti-tumor activities in gastric cancer cells. Our study reveals a novel anti-gastric cancer mechanism of WZ35 by inhibiting glycolysis through the ROS-YAP-JNK pathway. WZ35 might be a potential therapeutics for the treatment of gastric cancer.

Gastric cancer is the fourth most common cancer and the second most frequent cause of cancer death worldwide. Chemotherapy is an important treatment. However, traditional chemotherapy drugs have low bioavailability and targeting ability. Therefore, we developed curcumin-encapsulated micelles for the treatment of gastric cancer and investigated their antitumor efficacy and active mechanism. Gastric cancer cells were treated with different concentrations of curcumin micelles. MTS cell proliferation assays, flow cytometry (FCM), real time cellular analysis (RTCA) and nude mice xenografts were used to evaluate the effects of curcumin micelles on gastric cancer cell growth in vitro and in vivo. Western blotting was performed to analyze the protein levels of the indicated molecules. A Seahorse bioenergetics analyzer was used to investigate alterations in oxygen consumption and the aerobic glycolysis rate. Curcumin micelles significantly inhibited proliferation and colony formation and induced apoptosis in gastric tumor cells compared to the control groups. We further investigated the mechanism of curcumin micelles on gastric tumor cells and demonstrated that curcumin micelles acted on mitochondrial proteins, causing changes in mitochondrial function and affecting mitochondrial bioenergetics. Furthermore, curcumin micelles decreased mitochondrial membrane potential, increased reactive oxygen species (ROS) generation and disrupted redox equilibrium. The nude mouse model verified that curcumin micelle treatment significantly attenuated tumor growth in vivo. Curcumin micelles suppress gastric tumor cell growth in vitro and in vivo. The mechanism may be related to increasing ROS generation, disrupting redox equilibrium and affecting mitochondrial bioenergetics.

Hepatocellular carcinoma (HCC) is a common cancer type throughout the world. Due to the high occurrence rate and mortality, liver cancer is one of the leading causes of cancer associated death. With the development of monoclonal antibodies and immunotherapy, the mortality of HCC cancer patients has reduced. However, the recurrence and outcomes of patients remain poor. Therefore, there is an urgent need to develop more effective drugs for HCC therapy. WZ35, a novel curcumin derivative, exhibits potential anti-tumor activity in gastric cancer cells by regulating ROS dependent JNK activation and ER stress. Here, we evaluated the tumor suppressive activity of WZ35 in hepatocellular carcinoma in vitro and in vivo. CCK-8 was used to detect cell viability with or without curcumin or WZ35; cell apoptosis was determined by flow cytometry analysis; GFP-LC3 plasmids were used to investigate the level of autophagy-associated LC3; siRNA transfection was applied to silence endogenous YAP; and western blot was performed to detect the alteration of indicated molecules. Bioinformatics analysis and IHC assay were applied to evaluate the YAP level in normal and liver cancer tissues. In this study, we found that WZ35 effectively suppresses HCC cancer cell growth in vitro and in vivo by promoting cell apoptosis. Importantly, downregulation of YAP contributes to WZ35 caused autophagy inhibition which is different from that of curcumin. We also confirmed that WZ35 is more effective at suppressing HCC cell growth in vivo. Finally, we confirmed that YAP was significantly overexpressed in liver cancer tissues. Collectively, these data indicate that WZ35 could be considered as a promising compound for HCC therapy.