Endoplasmic reticulum (ER) is the critical organelle that regulates essential cellular processes, including protein synthesis, folding, and post-translational modification, as well as lipid metabolism and calcium homeostasis. Disruption in ER homeostasis leads to a condition known as ER stress, characterized by the accumulation of misfolded or unfolded proteins. This triggers the unfolded protein response (UPR), an adaptive pathway mediated by three ER-resident sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Increasing evidence highlights sustained UPR activation in malignant and immune cells within the tumor microenvironment (TME), which promotes tumor progression and metastasis while simultaneously impairing antitumor immunity. This review explores how UPR-driven intercellular signaling influences immunotherapy resistance, focusing on the alterations occurring in tumor cells as well as in the surrounding immune environment. By providing insights into these mechanisms, we aim to highlight the therapeutic potential of targeting the UPR pathways in modulating cancer immunity.

Bacteria adapt to changes in their natural environment through a network of stress responses that enable them to alter their gene expression to survive in the presence of stressors, including antibiotics. These stress responses can be specific to the type of stress and the general stress response can be induced in parallel as a backup mechanism. In Gram-negative bacteria, various envelope stress responses are induced upon exposure to antibiotics that cause damage to the cell envelope or result in accumulation of toxic metabolic by-products, while the heat shock response is induced by antibiotics that cause misfolding or accumulation of protein aggregates. Antibiotics that result in the production of reactive oxygen species (ROS) induce the oxidative stress response and those that cause DNA damage, directly and through ROS production, induce the SOS response. These responses regulate the expression of various proteins that work to repair the damage that has been caused by antibiotic exposure. They can contribute to antibiotic resistance by refolding, degrading or removing misfolded proteins and other toxic metabolic by-products, including removal of the antibiotics themselves, or by mutagenic DNA repair. This review summarizes the stress responses induced by exposure to various antibiotics, highlighting their interconnected nature, as well the roles they play in antibiotic resistance, most commonly through the upregulation of efflux pumps. This can be useful for future investigations targeting these responses to combat antibiotic-resistant Gram-negative bacterial infections.

The fat mass and obesity-associated protein (FTO) catalytically demethylates RNA N6-methyl adenosine (m6A) modification, dynamically regulates gene expression in eukaryotes. Interestingly, FTO is highly expressed and functions as an oncogenic factor in a wide range of cancers. Therefore, using small-molecule inhibitors to target FTO has been established as a promising therapeutic strategy for combating cancers.

Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease characterized by fibroblast proliferation, excessive extracellular matrix buildup, inflammation, and tissue damage, resulting in respiratory failure and death. Recent studies suggest that impaired interactions among epithelial, mesenchymal, immune, and endothelial cells play a key role in IPF development. Advances in bioinformatics have also linked epigenetics, which bridges gene expression and environmental factors, to IPF. Despite the incomplete understanding of the pathogenic mechanisms underlying IPF, recent preclinical studies have identified several novel epigenetic therapeutic targets, including DNMT, EZH2, G9a/GLP, PRMT1/7, KDM6B, HDAC, CBP/p300, BRD4, METTL3, FTO, and ALKBH5, along with potential small-molecule inhibitors relevant for its treatment. This review explores the pathogenesis of IPF, emphasizing epigenetic therapeutic targets and potential small molecule drugs. It also analyzes the structure-activity relationships of these epigenetic drugs and summarizes their biological activities. The objective is to advance the development of innovative epigenetic therapies for IPF.

Thyroid cancer (TC) is the most common endocrine cancer and is a serious health concern due to its aggressiveness and high incidence. Histone modifications affect DNA accessibility and gene transcriptional activity by altering the structure of chromatin. Abnormal histone modifications may affect genome stability and disrupt gene expression patterns, leading to many diseases, including cancer. A growing body of research suggests that histone modifications and TC progression are inextricably linked. This article discusses the impact of aberrant histone modification patterns on TC. By targeting specific histone-modifying enzymes, it may be possible to regulate gene expression and inhibit the growth of TC. Finally, we summarize the relevant histone modification inhibitors to better understand the development stage of the use of these drugs to inhibit histone-modifying enzymes in cancer treatment.

Lymphomas are complex malignancies of blood cells, characterized by the malignant transformation of lymphocytes. This transformation is partially driven by disruptions in epigenetic regulation, particularly the acetylation of histones. Among the key players in this process are histone deacetylases (HDACs), whose aberrant activity contributes significantly to lymphoma development. Consequently, targeting HDACs represents a promising pharmacotherapeutic approach. Several HDAC inhibitors (HDACis) have demonstrated significant anticancer effects, with four FDA-approved molecules-vorinostat, romidepsin, belinostat, and panobinostat-forming critical components of chemotherapy regimens for lymphoma treatment. These HDAC inhibitors exhibit their therapeutic efficacy through mechanisms that indirectly impact cellular memory and induce cancer cell death via apoptosis and cell cycle arrest. Their clinical effectiveness is particularly notable in various types of lymphomas, underscoring their therapeutic potential. The objective of this review is to provide a detailed analysis of FDA-approved HDACis, focusing on their molecular mechanisms of action and clinical applications in lymphoma treatment. Specifically, we aim to elucidate how these inhibitors modulate epigenetic regulation to achieve therapeutic efficacy, highlight their utility across different lymphoma subtypes, and examine their integration into combination therapies with other anticancer agents. Furthermore, this review seeks to identify gaps in current knowledge and propose directions for future research, including the development of next-generation HDAC inhibitors and strategies for optimizing their clinical use. By consolidating existing evidence, we strive to enhance the understanding of HDACis' role in lymphoma therapy and inspire advancements in their therapeutic potential.

Adjuvants are crucial in vaccines and cancer therapies, enhancing therapeutic efficacy through diverse mechanisms. In vaccines, adjuvants are traditionally valued for amplifying immune responses, ensuring robust and long-lasting protection against pathogens. In cancer treatments, adjuvants can boost the effectiveness of chemotherapy or immunotherapy by targeting tumor antigens, rendering cancer cells more vulnerable to treatment. Recent research has uncovered new molecular-level effects of the adjuvants, mainly through epigenetic mechanisms. Epigenetics encompasses heritable modifications in gene expression that do not alter the DNA sequence, impacting processes such as DNA methylation, histone modification, and non-coding RNA expression. These epigenetic changes play a pivotal role in regulating gene activity, influencing immune pathways, and modulating the strength and duration of immune responses. Whether in vaccines or cancer treatments, understanding how adjuvants interact with epigenetic regulators offers significant potential for developing more precise, cell-targeted therapies across various medical fields. This review delves into the evolving role of adjuvants and their interactions with epigenetic mechanisms. It also examines the potential of harnessing epigenetic changes to enhance adjuvant efficacy and explores the novel use of epigenetic inhibitors as adjuvants in therapeutic settings.

In this review, we examine and expound upon the most recent and groundbreaking advancements in the sequencing of tRNA modifications, focusing specifically on the innovative chemical treatment approaches that have revolutionized this field. By delving into the intricate details of these cutting-edge methodologies, we aim to provide an overview of the current state of the art in tRNA modification sequencing, highlighting their unique strengths, limitations, and potential applications.

Human T-cell lymphotropic virus type 1 (HTLV-1) infection causes the uncommon and deadly cancer known as adult T-cell leukemia/lymphoma (ATLL), which affects mature T cells. Its clinical appearance is varied, and its prognosis is often miserable. Drug resistance to conventional therapies confers significant therapeutic challenges in the management of ATLL. This review discusses the emerging role of epigenetic medical advances in the treatment of ATLL, focusing on DNA methyltransferase inhibitors, histone deacetylase inhibitors, histone methyltransferase inhibitors, and BET inhibitors. Indeed, several classes of epigenetic therapies currently exhibit trailed efficacy in preclinical and clinical studies: DNA methyltransferase inhibitors like azacitidine and decitabine reexpression of silenced tumor suppressors; histone deacetylase inhibitors like vorinostat and romidepsin induce cell cycle arrest and apoptosis; bromodomain and extra-terminal inhibitors like JQ1 disrupt oncogenic signaling pathways. Whereas preclinical and early clinical data indicate modest to good efficacy for such treatments, significant challenges remain. Here, we discuss the current state of understanding of epigenetic dysregulation in ATLL and appraise the evidence supporting the use of these epi-drugs. However, despite the opened doors of epigenetic treatment, much more research is required with regard to showing the best combinations of drugs and their resistance mechanisms, the minimization of adverse effects, and how this hope will eventually be translated into benefit for the patient with ATLL.

Atrazine (ATZ), a widely utilized herbicide, is notable for its long environmental half-life and high solubility, raising significant concerns regarding its ecological and health impacts. While debates continue over its role as an endocrine disruptor, increasing attention has been directed toward its potential epigenetic effects. Utilizing the zebrafish model, a vertebrate with considerable genetic similarity to humans, provides valuable insights into how ATZ exposure may translate into human health risks. This review systematically examines the differential DNA methylation induced by ATZ's non-competitive inhibition of DNA methyltransferases, miRNA dysregulation resulting from mutations in miRNA processing enzymes, and the complex epigenetic interactions affecting histone modifications. Additionally, potential epigenetic biomarkers for ATZ exposure are proposed, which could advance targeted treatment strategies and improve health risk assessments. This synthesis of current understanding identifies knowledge gaps and guides future research towards a more comprehensive understanding of ATZ's epigenetic mechanisms.

RNA-binding proteins (RBPs) have emerged as critical regulators of cancer progression, influencing virtually all hallmarks of cancer. Their ability to modulate gene expression patterns that promote or inhibit tumorigenesis has positioned RBPs as promising targets for novel anti-cancer therapies. This mini-review summarizes the current state of RBP-targeted cancer treatments, focusing on five examples, eIF4F, FTO, SF3B1, RBM39 and nucleolin. We highlight the diversity of current targeting approaches and discuss ongoing challenges including the complexity of RBP regulatory networks, potential off-target effects and the need for more specific targeting methods. By assessing the future potential of novel therapeutic avenues, we provide insights into the evolving landscape of cancer treatment and the critical role RBPs may play in next-generation therapeutics.

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) and the activation of hepatic stellate cells (HSCs), which are influenced by epitranscriptomic and epigenetic factors. Recent advancements in epigenetic and epitranscriptomic research have revealed new opportunities for therapeutic interventions, particularly through the regulation of ferroptosis, a type of programmed cell death that is specifically linked to iron-dependent lipid peroxidation. In the context of liver fibrosis, a progressive scarring process that can progress to cirrhosis and ultimately end-stage liver disease, targeting these regulatory mechanisms to modulate ferroptosis presents a promising therapeutic strategy. This review aims to consolidate current knowledge on the epigenetic and epitranscriptomic control of ferroptosis and investigate its potential implications for the treatment of liver fibrosis.

Genetic and epigenetic modifications of DNA are involved in cancer initiation and progression. Epigenetic modifications change chromatin structure and DNA accessibility and thus affect DNA replication, DNA repair and transcription. Epigenetic modifications are reversible and include DNA methylation, histone acetylation and histone methylation. DNA methylation is catalysed by DNA methyltransferases, histone acetylation and deacetylation are catalysed by histone acetylases and deacetylases, while histone methylation is catalysed by histone methyltransferases. Epigenetic modifications are dysregulated in several cancers, making them cancer therapeutic targets. Epigenetic drugs (epi-drugs) which are inhibitors of epigenetic modifications and include DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi) and bromodomain and extra-terminal motif protein inhibitors (BETi), have demonstrated clinical success as anti-cancer agents. Furthermore, the combination of epi-drugs with standard chemotherapeutic agents has demonstrated promising anti-cancer effects in pre-clinical and clinical settings. In this review, we discuss the role of epi-drugs in cancer therapy and explore their current and future use in combination with other anti-cancer agents used in the clinic. We further highlight the side effects and limitations of epi-drugs. We additionally discuss novel delivery methods and novel tumour epigenetic biomarkers for the screening, diagnosis and development of personalised cancer treatments, in order to reduce off-target toxicity and improve the specificity and anti-tumour efficacy of epi-drugs.

Aging represents a complex biological phenomenon marked by the progressive deterioration of physiological functions over time, reduced resilience, and increased vulnerability to age-related diseases, ultimately culminating in mortality. Recent research has uncovered diverse molecular mechanisms through which metformin extends its benefits beyond glycemic control, presenting it as a promising intervention against aging. This review delves into the anti-aging properties of metformin, highlighting its role in mitochondrial energy modulation, activation of the AMPK-mTOR signaling pathway, stimulation of autophagy, and mitigation of inflammation linked to cellular aging. Furthermore, we discuss its influence on epigenetic modifications that underpin genomic stability and cellular homeostasis. Metformin's potential in addressing age-associated disorders including metabolic, cardiovascular, and neurodegenerative diseases is also explored. The Targeting Aging with Metformin (TAME) trial aims to provide key evidence on its efficacy in delaying aging in humans. Despite these promising insights, significant challenges persist in gaining a more comprehensive understanding into its underlying mechanisms, determining optimal dosing strategies, and evaluating long-term safety in non-diabetic populations. Addressing these challenges is crucial to fully realizing metformin's potential as an anti-aging therapeutic.

Polyphenols have been shown to be utilized as an effective treatment for cancer by acting as a DNMT or HDAC inhibitor, reducing inflammatory processes, and causing cell cycle arrest. While there have been many studies demonstrating the anti-cancerous potential of individual polyphenols, there are limited studies on the combinatorial effects of polyphenols. This review focuses on how combinations of different polyphenols can be used as a chemotherapeutic treatment option for patients. Specifically, we examine the combinatorial effects of three commonly used polyphenols: curcumin, resveratrol, and epigallocatechin gallate. These combinations have been shown to induce apoptosis, prevent colony formation and migration, increase tumor suppression, reduce cell viability and angiogenesis, and create several epigenetic modifications. In addition, these anti-cancerous effects were synergistic and additive. Thus, these findings suggest that using different combinations of polyphenols at the appropriate concentrations can be used as a better and more efficacious treatment against cancer as compared to using polyphenols individually.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated remarkable efficacy in treating non-small cell lung cancer (NSCLC), but acquired resistance greatly reduces efficacy and poses a significant challenge to patients. While numerous studies have investigated the mechanisms underlying EGFR-TKI resistance, its complexity and diversity make the existing understanding still incomplete. Traditional approaches frequently struggle to adequately reveal the process of drug resistance development through mean value analysis at the overall cellular level. In recent years, the rapid development of single-cell RNA sequencing technology has introduced a transformative method for analyzing gene expression changes within tumor cells at a single-cell resolution. It not only deepens our understanding of the tumor microenvironment and cellular heterogeneity associated with EGFR-TKI resistance but also identifies potential biomarkers of resistance. In this review, we highlight the critical role of single-cell RNA sequencing in lung cancer research, with a particular focus on its application to exploring the mechanisms of EGFR-TKI-acquired resistance in NSCLC. We emphasize its potential for elucidating the complexity of drug resistance mechanism and its promise in informing more precise and personalized treatment strategies. Ultimately, this approach aims to advance NSCLC treatment toward a new era of precision medicine.

Poly(ADP-ribosyl)ation (PARylation) is a dynamic protein post-translational modification (PTM) mediated by ADP-ribosyltransferases (ARTs), which regulates a plethora of essential biological processes, such as DNA repair, gene expression, and signal transduction. Among these, PAR-dependent ubiquitination (PARdU) plays a pivotal role in tagging PARylated substrates for subsequent ubiquitination and degradation events through the coordinated action of enzymes, including the E3 ligase RNF146 and the ADP-ribosyltransferase tankyrase. Notably, this pathway has emerged as a key regulator of tumorigenesis, immune modulation, and cell death. This review elucidates the molecular mechanisms of the PARdU pathway, including the RNF146-tankyrase interaction, substrate specificity, and upstream regulatory pathways. It also highlights the biological functions of PARdU in DNA damage repair, signaling pathways, and metabolic regulation, with a focus on its therapeutic potential in cancer treatment. Strategies targeting PARdU, such as tankyrase and RNF146 inhibitors, synthetic lethality approaches, and immune checkpoint regulation, offer promising avenues for precision oncology. These developments underscore the potential of PARdU as a transformative therapeutic target in combating various types of human cancer.

Esophageal cancer is a significant global health concern, with esophageal squamous cell carcinoma being the predominant subtype in high-incidence regions like China. Despite advances in multidisciplinary treatments, the prognosis for ESCC remains poor, with systemic chemotherapy facing the challenge of drug resistance. Epigenetic alterations, particularly DNA methylation, play a crucial role in ESCC carcinogenesis and therapeutic response. Aberrant DNA methylations, including global hypomethylation and promoter-specific hyper-methylation, disrupt critical pathways such as cell cycle regulation, apoptosis, and DNA repair, contributing to chemoresistance. Several studies have identified methylation markers that predict treatment response, particularly for chemotherapy, targeted therapy and immunotherapy, such as p16 and GPX3 for cisplatin, MTHFR for 5-FU, CHFR for paclitaxel. DNA methyltransferase inhibitors and other epigenetic therapies are being explored to reverse these methylation changes and enhance therapeutic efficacy. However, the clinical utility of these markers remains limited due to the lack of large-scale validation and concerns over off-target effects. This review aims to summarize all aberrant methylation alterations in ESCC and the clinical implications of aberrantly methylated candidate genes identified in ESCC systemic chemotherapy, with the goal of further understanding the underlying molecular mechanisms, refining methylation-targeting therapies, and integrating them with conventional treatments to improve patient outcomes.

Cancer is a major public health problem facing contemporary society. Notwithstanding considerable progress in medicine in recent decades, a cure for numerous cancer kinds continues to be unattainable. Thus, the pursuit of innovative therapeutic targets and methodologies remains paramount in medical research. The advancement of lipidomics has progressively revealed the essential roles of lipid metabolic pathways. Sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) are essential molecules in sphingolipid metabolism, significantly influencing physiological functions. Two isoforms of SphK exist including SphK1 and SphK2, both of which exhibit significant expression levels within a spectrum of cancers. The involvement of SphK1 in carcinogenesis has been thoroughly documented, whereas the significance of SphK2 in cancer remains inadequately elucidated. This review retrospectively and extensively elucidates the expression and distribution of SphK2 in cancer, its methods of action, and advancements in inhibitor research, emphasizing the varied functions of the SphK2 in oncogenesis. The objective is to furnish novel insights for study and therapeutic applications concerning SphK2 in oncology.

Depression, often stress-induced, is closely related to neuroinflammation, in which microglia, the brain's immune cells, are the leading players. Microglia shift between a quiescent and an active state, promoting both pro- and anti-inflammatory responses. Cannabinoid type 2 (CB2) receptor encoded by the CNR2 gene is a key player to modulate inflammatory activity. CB2 receptor is highly controlled at the epigenetic level, especially in response to stressful stimuli, positioning it between stress, neuroinflammation, and depression. The following review addresses how epigenetic regulation of CNR2 expression affects depression and the dissection, further, of molecular pathways driving neuroinflammation-related depressive states. The present study emphasizes the therapeutic potential of CB2 receptor agonists that selectively interact with activated microglia and opens a new avenue for the treatment of depression associated with neuroinflammation. The review, therefore, provides a framework of underlying mechanisms for developing novel therapeutic strategies that focus on relieving symptoms by modulating the neuroinflammatory response. Finally, this review underlines the possibilities of therapeutic interventions taking into account CB2 receptors in combating depression.