MDSCs are immature neutrophils and monocytes with immunosuppressive potentials, involving mononuclear MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs).

They are significant components of the tumor microenvironment (TME). Besides, recent studies also verified that MDSCs also facilitated the progression of bone metastasis by regulating the network of cytokines and the function of immune cells.

It is necessary to summarize the mechanisms of MDSC recruitment and immunosuppression, and their impact on bone metastasis.

Recent advances in high-resolution mass spectrometry-based proteomics have improved our understanding of lysine acetylation in proteins, including histones and non-histone proteins. Lysine acetylation, a reversible post-translational modification, is catalyzed by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Proteins comprising evolutionarily conserved bromodomains (BRDs) recognize these acetylated lysine residues and consequently activate transcription. Lysine acetylation regulates almost all cellular processes, including transcription, cell cycle progression, and metabolic functions. Studies have reported the aberrant expression, translocation, and mutation of genes encoding lysine acetylation regulators in various cancers, including digestive tract cancers. These dysregulated lysine acetylation regulators contribute to the pathogenesis of digestive system cancers by modulating the expression and activity of cancer-related genes or pathways. Several inhibitors targeting KATs, KDACs, and BRDs are currently in preclinical trials and have demonstrated anti-cancer effects. Digestive tract cancers, including encompass esophageal, gastric, colorectal, liver, and pancreatic cancers, represent a group of heterogeneous malignancies. However, these cancers are typically diagnosed at an advanced stage owing to the lack of early symptoms and are consequently associated with poor 5-year survival rates. Thus, there is an urgent need to identify novel biomarkers for early detection, as well as to accurately predict the clinical outcomes and identify effective therapeutic targets for these malignancies. Although the role of lysine acetylation in digestive tract cancers remains unclear, further analysis could improve our understanding of its role in the pathogenesis of digestive tract cancers. This review aims to summarize the implications and pathogenic mechanisms of lysine acetylation dysregulation in digestive tract cancers, as well as its potential clinical applications.

Mechanical stimulation is the key physical factor in cell environment. Mechanotransduction acts as a fundamental regulator of cell behavior, regulating cell proliferation, differentiation, apoptosis, and exhibiting specific signature alterations during the pathological process. As research continues, the role of epigenetic science in mechanotransduction is attracting attention. However, the molecular mechanism of the synergistic effect between mechanotransduction and epigenetics in physiological and pathological processes has not been clarified. We focus on how histone modifications, as important components of epigenetics, are coordinated with multiple signaling pathways to control cell fate and disease progression. Specifically, we propose that histone modifications can form regulatory feedback loops with signaling pathways, that is, histone modifications can not only serve as downstream regulators of signaling pathways for target gene transcription but also provide feedback to regulate signaling pathways. Mechanotransduction and epigenetic changes could be potential markers and therapeutic targets in clinical practice.

Orthodontic tooth movement (OTM) is a dynamic equilibrium of bone remodeling, involving the osteogenesis of new bone and the osteoclastogenesis of old bone, which is mediated by mechanical force. Periodontal ligament stem cells (PDLCSs) in the periodontal ligament (PDL) space can transmit mechanical signals and regulate osteoclastogenesis during OTM. KAT6A is a histone acetyltransferase that plays a part in the differentiation of stem cells. However, whether KAT6A is involved in the regulation of osteoclastogenesis by PDLSCs remains unclear.

In this study, we used the force-induced OTM model and observed that KAT6A was increased on the compression side of PDL during OTM, and also increased in PDLSCs under compression force in vitro. Repression of KAT6A by WM1119, a KAT6A inhibitor, markedly decreased the distance of OTM. Knockdown of KAT6A in PDLSCs decreased the RANKL/OPG ratio and osteoclastogenesis of THP-1. Mechanistically, KAT6A promoted osteoclastogenesis by binding and acetylating YAP, simultaneously regulating the YAP/TEAD axis and increasing the RANKL/OPG ratio in PDLSCs. TED-347, a YAP-TEAD4 interaction inhibitor, partly attenuated the elevation of the RANKL/OPG ratio induced by mechanical force.

Our study showed that the PDLSCs modulated osteoclastogenesis and increased the RANKL/OPG ratio under mechanical force through the KAT6A/YAP/TEAD4 pathway. KAT6A might be a novel target to accelerate OTM.

In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.

Non-alcoholic fatty liver disease (NAFLD) comprises a range of chronic liver diseases that result from the accumulation of excess triglycerides in the liver, and which, in its early phases, is categorized NAFLD, or hepato-steatosis with pure fatty liver. The mortality rate of non-alcoholic steatohepatitis (NASH) is more than NAFLD; therefore, diagnosing the disease in its early stages may decrease liver damage and increase the survival rate. In the current study, we screened the gene expression data of NAFLD patients and control samples from the public dataset GEO to detect DEGs. Then, the correlation betweenbetween the top selected DEGs and clinical data was evaluated. In the present study, two GEO datasets (GSE48452, GSE126848) were downloaded. The dysregulated expressed genes (DEGs) were identified by machine learning methods (Penalize regression models). Then, the shared DEGs between the two training datasets were validated using validation datasets. ROC-curve analysis was used to identify diagnostic markers. R software analyzed the interactions between DEGs, clinical data, and fatty liver. Ten novel genes, including ABCF1, SART3, APC5, NONO, KAT7, ZPR1, RABGAP1, SLC7A8, SPAG9, and KAT6A were found to have a differential expression between NAFLD and healthy individuals. Based on validation results and ROC analysis, NR4A2 and IGFBP1b were identified as diagnostic markers. These key genes may be predictive markers for the development of fatty liver. It is recommended that these key genes are assessed further as possible predictive markers during the development of fatty liver.

Ferroptosis is an iron-dependent and lipid peroxidation-driven cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is key for cellular antioxidant responses, which promotes downstream genes transcription by binding to their antioxidant response elements (AREs). Numerous studies suggest that NRF2 assumes an extremely important role in the regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. Many pathological states are relevant to ferroptosis. Abnormal suppression of ferroptosis is found in many cases of cancer, promoting their progression and metastasis. While during tissue damages, ferroptosis is recurrently promoted, resulting in a large number of cell deaths and even dysfunctions of the corresponding organs. Therefore, targeting NRF2-related signaling pathways, to induce or inhibit ferroptosis, has become a great potential therapy for combating cancers, as well as preventing neurodegenerative and ischemic diseases. In this review, a brief overview of the research process of ferroptosis over the past decade will be presented. In particular, the mechanisms of ferroptosis and a focus on the regulation of ferroptosis by NRF2 will be discussed. Finally, the review will briefly list some clinical applications of targeting the NRF2 signaling pathway in the treatment of diseases.

Hepatocellular carcinoma (HCC) is a highly malignant type of tumor that is insensitive to cytotoxic chemotherapy and often develops drug resistance. Nevadensin, a bioflavonoid, exhibits anti-cancer properties in some cancers. However, the precise underlying mechanism of nevadensin against liver cancer are poorly understood. We aim to evaluate the efficacy as well as the molecular mechanism of nevadensin in the treatment of liver cancer.

Effects of nevadensin on HCC cell proliferation and apoptosis were detected using EdU labeling and flow cytometry assays. The molecular mechanism of nevadensin on HCC was determined using RNAseq. The effects of nevadensin on hippo-Yap signaling were verified using western blot and RT-PCR.

In this study, we show that nevadensin significantly inhibits growth of HCC cells via inducing cell cycle arrest and apoptosis. RNAseq analysis showed that nevadensin regulates multiple functional signaling pathways associated with cancer including Hippo signaling. Western Blot analysis revealed that nevadensin notably induces activation of the MST1/2- LATS1/2 kinase in HCC cells, further resulting in the primary effector molecule YAP phosphorylation and subsequent degradation. These results indicated that nevadensin might exert its anti-HCC activity through the Hippo-ON mechanism. Moreover, nevadensin could increase the sensitivity of HCC cells to sorafenib by down-regulating YAP and its downstream targets.

The present study indicates that nevadensin could be a potential effective approach to treating HCC, and overcoming sorafeni resistance via inducing activation of Hippo signaling.

Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Video Abstract.