PAD4 mediates the post-translational modification of arginine residues into citrulline which can have profound effects on protein structure, function and interactions. Protein citrullination and neutrophil extracellular trap (NET) formation associated with increased PAD4 activity have been implicated in the development of autoimmune conditions, cardiovascular diseases, neurodegenerative disorders, and cancer. PAD4 inhibitors have been shown to suppress citrullination and NETs formation.

Developing proteolysis-targeting chimeras (PROTACs) is well recognized through target protein degradation (TPD) toward promising therapeutics. While a variety of diseases are driven by aberrant ubiquitination and degradation of critical proteins with protective functions, target protein stabilization (TPS) rather than TPD is emerging as a unique therapeutic modality. Deubiquitinase-targeting chimeras (DUBTACs), a class of heterobifunctional protein stabilizers consisting of deubiquitinase (DUB) and protein-of-interest (POI) targeting ligands conjugated with a linker, can rescue such proteins from aberrant elimination. DUBTACs stabilize the levels of POIs in a DUB-dependent manner, removing ubiquitin from polyubiquitylated and degraded proteins. DUBTACs can induce a new interaction between POI and DUB by forming a POI-DUBTAC-DUB ternary complex. Herein, therapeutic benefits of TPS approaches for human diseases are introduced, and recent advances in developing DUBTACs are summarized. Relevant challenges, opportunities, and future perspectives are also discussed.

Gastric cancer (GC) is one of the most aggressive malignancies worldwide and is characterized by its poor prognosis and resistance to conventional therapies. Autophagy and long non-coding RNAs (lncRNAs) play critical yet complex roles in GC, functioning as both tumor suppressors and promoters depending on the disease stage and context. Autophagy influences cellular homeostasis and metabolism, whereas lncRNAs regulate gene expression through epigenetic modifications, RNA sponging, and protein interactions. Notably, the interplay between lncRNAs and autophagy modulates tumor progression, metastasis, chemoresistance, and the tumor microenvironment. This study explored the intricate relationship between lncRNAs and autophagy in GC, highlighting their roles in pathogenesis and treatment resistance. By addressing current knowledge gaps and proposing innovative therapeutic strategies, we have emphasized the potential of targeting this dynamic interplay for improved diagnostic and therapeutic outcomes.

Epigenetic drug discovery has become an integral part of medicinal chemistry in the past two decades. Targeting epigenetic proteins-enzymes that modify histone proteins and DNA (writers and erasers) and proteins that recognize such modifications (readers)-has been firmly established as a medicinal strategy for treatment of many human diseases, including cancer and neurological disorders. In this chapter, we systematically describe peptide-based inhibitors of structurally and functionally diverse classes of epigenetic proteins. We show that epigenetic writers, such as DNA methyltransferases, histone methyltransferases and histone acetyltransferases, can be efficiently inhibited by peptides possessing nonproteinogenic amino acids. Moreover, the activity of epigenetic erasers, including TET enzymes, histone demethylases, and histone deacetylases, can be selectively modulated by diverse linear and cyclic peptides. Furthermore, we discuss chromatin-binding epigenetic reader proteins that can be inhibited by histone-mimicking peptides. Overall, this chapter highlights that peptides provide an important molecular platform for epigenetic drug discovery programmes in academia and industry.

Ubiquitination is a vital post-translational modification that regulates protein stability and various cellular processes through the addition of ubiquitin molecules. Central to this process are E3 ubiquitin ligases, which determine the specificity of ubiquitination by coordinating the attachment of ubiquitin to target proteins, influencing their degradation, localization, and activity. E3 ubiquitin ligases are involved in numerous cellular pathways, including DNA repair, cell proliferation, and immune responses. Dysregulation of E3 ubiquitin ligases is often associated with cancer, contributing to tumor progression and resistance to therapies. The development of targeted protein degraders, such as proteolysis-targeting chimeras (PROTACs), represents a significant advancement in drug discovery, leveraging the specificity of E3 ubiquitin ligases to selectively eliminate pathogenic proteins. However, challenges remain in translating this knowledge into effective therapies, including issues related to tissue-specific targeting and off-target effects. The limitations also include a limited understanding of ligase-substrate interactions that includes both the identification of novel E3 ligases and their substrates, as well as understanding the dynamic, context-dependent nature of these interactions, which can vary across tissue types or disease states This review emphasizes the therapeutic potential of E3 ubiquitin ligases, exploring their diverse roles in disease, their contribution to targeted degradation strategies while highlighting the need for further research to overcome current limitations and enhance therapeutic efficacy.

Immunotherapy, particularly immune checkpoint inhibitor therapy, has demonstrated clinical benefits in solid tumours. Despite its satisfactory clinical efficacy, it still faces several issues, such as limited eligibility, low response rates and cytotoxicity. Cancer epigenetics implies that tumour cells exhibit unique phenotypes because of their unique characteristics, thus reprogramming of the epigenome holds promise for cancer therapy. Epigenetic regulation plays an important role in regulating gene expression during tumour development and maintenance. Epigenetic regulators induce cancer cell cycle arrest, apoptosis and differentiation of cancer cells, thereby exerting anti-tumour effects. Recent studies have revealed a significant correlation between epigenetic regulatory factors and immune checkpoint therapy. Epigenetics can modulate various aspects of the tumour immune microenvironment and immune response to enhance the sensitivity of immunotherapy, such as lowering the concentration required and mitigating cytotoxicity. This review primarily discusses DNA methyltransferase inhibitors, histone deacetylase inhibitors, enhancer of zeste homolog 2 inhibitors and lysine-specific demethylase 1 inhibitors, which are associated with transcriptional repression. This repression alters the expression of genes involved in the immune checkpoint, thereby enhancing the effectiveness of immunotherapy. We also discuss the potential and challenges of tumour immunotherapy and highlight its advantages, application challenges and clinical research on integrating epigenetic regulatory factors with tumour immunotherapy.

Endometrial cancer (EC) accounts for approximately 417,336 cases globally, making it the sixth most commonly diagnosed cancer among women. Such factors have led to hesitancy in utilizing aggressive treatments or enrolling older patients in clinical trials. Recent molecular studies have identified unique expression patterns of microRNAs (miRNAs) in endometrial cancer tissue compared to healthy endometrial tissue, highlighting their role in tumorigenesis through pathways that support proliferation, invasion, and metastasis. Polyphenols, bioactive compounds found in a variety of plant-based foods such as fruits, vegetables, tea, and soybeans, have demonstrated diverse physiological benefits, including antioxidant, anti-inflammatory, and anticancer properties. These compounds influence cellular pathways critical to cancer progression, including apoptosis, immune modulation, and inflammation reduction. Emerging evidence suggests that polyphenols may exert anticancer effects in part by modulating miRNAs involved in carcinogenesis. Specifically, compounds like curcumin, quercetin, resveratrol, and genistein have shown potential in targeting oncogenic and tumor-suppressive miRNAs, thereby impacting cellular mechanisms linked to cancer progression. Therefore, this review examines the role of polyphenols in regulating miRNAs within the context of endometrial cancer, focusing on their potential to modulate apoptosis and other cancer hallmarks. By elucidating these mechanisms, this paper aims to contribute to the understanding of polyphenol-mediated miRNA regulation as a promising therapeutic avenue in endometrial cancer management.

The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.

Epigenetic mechanisms play a crucial role in the normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of these processes can result in changes to gene function and the transformation of cells into a malignant state. Cancer is characterized by widespread alterations in the epigenetic landscape, revealing that it involves not only genetic mutations but also epigenetic abnormalities. Recent progress in the field of cancer epigenetics has demonstrated significant reprogramming of various components of the epigenetic machinery in cancer, such as DNA methylation, modifications to histones, positioning of nucleosomes, and the expression of non-coding RNAs, particularly microRNAs. The ability to reverse epigenetic abnormalities has given rise to the hopeful field of epigenetic therapy, which has shown advancement with the recent approval by the FDA of three drugs targeting epigenetic mechanisms for the treatment of cancer. In the present manuscript, a comprehensive review has been presented about the role of understanding the epigenetic link between cancer and mechanisms by which phytomedicine offers treatment avenues. Further, this review deciphers the significance of natural products in the identification of epigenetic therapeutics, the diversity of their molecular targets, the use of nanotechnology, and the creation of new strategies for overcoming the inherent clinical challenges associated with developing these drug leads.

In recent years, abiotic stresses, including droughts, floods, high temperatures, and salinity, have become increasingly frequent and severe. These stresses significantly hinder crop yields and product quality, posing substantial challenges to sustainable agriculture and global food security. Simultaneously, the rapidly growing global population exacerbates the need to enhance crop production under worsening environmental conditions. Consequently, the development of effective strategies to strengthen the resilience of crop plants against high temperatures, water scarcity, and extreme environmental conditions is critical for mitigating the impacts of abiotic stress. Plants respond to these environmental challenges by reprogramming their transcriptome and metabolome. Common strategies for developing stress-tolerant plants include screening germplasm, generating transgenic crop plants, and employing genome editing techniques. Recently, chemical treatment has emerged as a promising approach to enhance abiotic stress tolerance in crops. This technique involves the application of exogenous chemical compounds that induce molecular and physiological changes, thereby providing a protective shield against abiotic stress. Forward and reverse genetic approaches have facilitated the identification of chemicals capable of modulating plant responses to abiotic stresses. These priming agents function as epigenetic regulators, agonists, or antagonists, playing essential roles in regulating stomatal closure to conserve water, managing cellular signaling through reactive oxygen species and metabolites to sustain plant growth, and activating gluconeogenesis to enhance cellular metabolism. This review summarizes recent advancements in the field of chemical priming and explores strategies to improve stress tolerance and crop productivity, thereby contributing to the enhancement of global food security.

The endoplasmic reticulum (ER) plays a crucial role in protein synthesis, folding and quality control. Disruptions in these processes lead to ER stress (ERS) and activate the unfolded protein response (UPR) to restore cellular homeostasis. In gastrointestinal cancers, inositol-requiring enzyme 1α (IRE1α) is a key regulator of the UPR, enabling cancer cells to adapt to hostile conditions such as hypoxia, oxidative stress and chemotherapy. Elevated IRE1α activity supports tumor survival, progression and metastasis by mitigating ERS-induced apoptosis. However, targeting IRE1α signaling presents a promising therapeutic strategy by impairing cancer cell adaptation to stress, offering promising therapeutic opportunities for gastrointestinal cancers.

The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Recent studies have also highlighted the importance of mitochondria-ER contact sites (MERCs) and ER-associated inflammation in disease progression. This review explores the current pharmacological landscape targeting ER stress, focusing on therapeutic strategies for rare metabolic and neurodegenerative diseases. It examines small molecules such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), repurposed drugs like 17-AAG (17-N-allylamino-17demethoxygeldanamycin (tanespimycin)) and berberine, and phytochemicals such as resveratrol and hesperidin. Additionally, it discusses emerging therapeutic areas, including soluble epoxide hydrolase (sEH) inhibitors for metabolic disorders and MERCs modulation for neurological diseases. The review emphasizes challenges in translating these therapies to clinical applications, such as toxicity, off-target effects, limited bioavailability, and the lack of large-scale randomized controlled trials (RCTs). It also highlights the potential of personalized medicine approaches and pharmacogenomics in optimizing ER stress-targeting therapies.

Manganese (Mn) is an essential trace element crucial for various physiological processes, but excessive exposure can lead to significant health concerns, particularly neurotoxicity. This review synthesizes current knowledge on Mn-induced oxidative stress and its role in cellular dysfunction and disease. We discuss how Mn promotes toxicity through multiple mechanisms, primarily through reactive oxygen species (ROS) generation, which leads to oxidative stress and disruption of cellular processes. The review examines key pathways affected by Mn toxicity, including mitochondrial dysfunction, endoplasmic reticulum stress, inflammasome activation, and epigenetic modifications. Recent studies have identified promising therapeutic compounds, including both synthetic and natural substances such as probucol, metformin, curcumin, resveratrol, and daidzein, which demonstrate protective effects through various mechanisms, including antioxidant enhancement, mitochondrial function preservation, and epigenetic pathway modulation. Understanding these mechanisms provides new insights into potential therapeutic strategies for Mn-induced disorders. This review also highlights future research directions, emphasizing the need for developing targeted therapies and investigating combination approaches to address multiple aspects of Mn toxicity simultaneously.

Nanoplastics (NPs) represent a major challenge in environmental contamination resulting from the physical, chemical, and biological degradation of plastics. Their characterization requires advanced and expensive methods, which limit routine analyses. The biological effects of NPs depend on their chemical and physical properties, which influence toxicity and interactions with biological systems. Studies in animal models, such as Daphnia magna and Danio rerio, show that NPs induce oxidative stress, inflammation, DNA damage, and metabolic alterations, often related to charge and particle size. NPs affect endocrine functions by acting as endocrine disruptors, interfering with thyroid and sex hormones and showing potential transgenerational effects through epigenetic modifications, including DNA hyper- and hypomethylation. Behavioral and neurofunctional alterations have been observed in Danio rerio and mouse models, suggesting a link between NP exposure and neurotransmitters such as dopamine and serotonin. Despite limited human studies, the presence of NPs in breast milk and placenta underscores the need for further investigation of health effects. Research focusing on genetic and epigenetic markers is encouraged to elucidate the molecular mechanisms and potential risks associated with chronic exposure.

Gastrointestinal (GI) cancers, which mainly include malignancies of the esophagus, stomach, intestine, pancreas, liver, gallbladder, and bile duct, pose a significant global health burden. Unfortunately, the prognosis for most GI cancers remains poor, particularly in advanced stages. Current treatment options, including targeted and immunotherapies, are less effective compared to those for other cancer types, highlighting an urgent need for novel molecular targets. NEK (NIMA related kinase) kinases are a group of serine/threonine kinases (NEK1-NEK11) that play a role in regulating cell cycle, mitosis, and various physiological processes. Recent studies suggest that several NEK members are overexpressed in human cancers, including gastrointestinal (GI) cancers, which can contribute to tumor progression and drug resistance. Among these, NEK2 stands out for its consistent overexpression in all types of GI cancer. Targeting NEK2 with specific inhibitors has shown promising results in preclinical studies, particularly for gastric and pancreatic cancers. The development and clinical evaluation of NEK2 inhibitors in human cancers have emerged as a promising therapeutic strategy. Specifically, an NEK2 inhibitor, T-1101 tosylate, is currently undergoing clinical trials. This review will focus on the gene expression and functional roles of NEKs in GI cancers, as well as the progress in developing NEK inhibitors.

Epigenetic aging biomarkers are used for evaluating morbidity and mortality, monitoring therapies, and direct-to-consumer testing. However, the influence of environmental exposures on epigenetic age acceleration (EAA), also known as epigenetic age deviation, has not been systematically evaluated. In this systematic review, we synthesized findings from human epidemiologic studies on chemical and climatic environmental exposures, particularly air pollution, chemicals, metals, climate, and cigarette smoke, and EAA. A total of 102 studies analyzing epigenetic data from over 180,000 subjects were evaluated. Overall, studies in each exposure category frequently included adult participants, used a variety of epigenetic clocks, analyzed whole blood samples, and had a low risk of bias. Exposure to air pollution (15/19 of studies; 79%), cigarette smoke (53/66; 80%), and synthetic and occupational chemicals (5/8; 63%) were notably associated with increased EAA. Results for essential and non-essential metal exposure were more equivocal: 7/13 studies (54%) reported increased EAA. One study reported increased EAA with greater temperature exposure. In summary, we identified environmental exposures, such as air pollution and cigarette smoke, that were strongly associated with increased EAA. Further research is needed with larger and more diverse samples and high-quality exposure assessment.

The use of platinum-based drugs in cancer treatment is one of the most common methods in chemotherapy. Especially, cisplatin induces cell death by interrupting DNA synthesis by binding to the DNA bases, thereby leading to the apoptosis via multiple pathways. However, the major hurdle in chemotherapy is drug resistance. To overcome drug resistance, the ubiquitin-proteasome system (UPS) has emerged as a potential therapeutic target. The UPS is a pivotal signaling pathway that regulates the majority of cellular proteins by attaching ubiquitin to substrates, leading to proteasomal degradation. Conversely, deubiquitinating enzymes (DUBs) remove tagged ubiquitin from the substrate and inhibit degradation, thereby maintaining proteostasis. Recently, studies have been conducted to identify the substrates of DUBs and investigated the cellular mechanisms, and now the development of therapeutics using DUB inhibitors is in clinical trials. However, the mechanism of the DUB response to cisplatin remains still unclear. In this review, we summarize the research reported on the function of DUBs responding to cisplatin.

The vast array of cellular ribonucleic acid (RNA) modifications hold a crucial role in regulating RNA stability, folding, localization, and the accuracy of translation. Numerous diseases have been associated with mutations found in genes of RNA-modifying enzymes that can lead to truncated or misfolded proteins incapable of modifying their RNA substrates, causing downstream defects. In contrast, dysregulated levels of RNA-modifying enzymes and the resulting changes in RNA modifications on their substrates are increasingly linked to the activation of oncogenic pathways. This phenomenon has been especially studied through the lens of methyltransferases such as METTL1 and METTL3. The field has developed several small molecule inhibitors of RNA-modifying enzymes to mitigate their related diseases, including targeting the upregulation of METTL3 in cancer. However, increasing evidence suggests that RNA-modifying enzymes play essential roles in numerous cellular processes, including the immune response, neural health, and regeneration, among others. This could lead to off-target effects when treating proteins with small molecules, particularly when these enzymes are upregulated. We propose that developing treatments to specifically target the RNA substrates mis-regulated due to abnormal levels of RNA-modifying enzymes responsible for malignant hallmarks may offer an alternative strategy for treating diseases. We review current RNA-targeted therapies and the diseases they target, including advancements in oligonucleotide modalities and small molecules. We also identify gaps in knowledge that need to be addressed to enhance drug development in the epitranscriptome field to use these therapies to target mis-regulated RNA stemming from altered RNA-modifying enzyme levels.

Sickle cell disease (SCD) is one of the most prevalent hereditary blood disorders characterized by aberrant hemoglobin synthesis that causes red blood cells (RBCs) to sickle and result in vaso-occlusion. The complex pathophysiological mechanisms that underlie SCD are explored in this study, including hemoglobin polymerization, the formation of fetal hemoglobin (HbF), and hemoglobin switching regulation. Notably, pharmaceutical approaches like hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, in addition to therapeutic techniques like gene therapies like Casgevy and Lyfgenia, signify noteworthy advancements in the management of issues connected to SCD. Furthermore, the deciphering of the molecular mechanisms that dictate hemoglobin switching has revealed several potentially therapeutic targets, including key transcriptional repressors such as β-cell lymphoma/leukemia 11A (BCL11A), Zinc finger and BTB domain-containing 7A (ZBTB7A), Nuclear Factor IX (NFIX), and Nuclear Factor IA (NFIA), which play crucial roles in γ-globin silencing. Additionally, transcriptional activators such as Nuclear Factor Y (NF-Y), and Hypoxia-inducible factor 1α (HIF1α) have emerged as promising regulators that can disrupt repression and enhance HbF synthesis. Other epigenetic regulators, such as lysine-specific histone demethylase 1 (LSD1), euchromatic histone methyltransferases 1/2 (EHMT1/2), histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and protein arginine methyltransferases (PRMTs). It has been demonstrated that inhibiting these targets can prevent the silencing of the gene encoding for the formation of γ-chains and, in turn, increase the synthesis of HbF, providing a possible treatment option for SCD symptoms. These approaches could pave the way for innovative, mechanism-driven therapies that address the unmet medical needs of SCD patients.

Acetylation is an increasing area of focus for cancer research as it is closely related to a variety of cellular processes through modulation of histone and non-histone proteins. However, broadly targeting acetylation threatens to yield nonselective toxic effects owing to the vital role of acetylation in cellular function. There is thus a pressing need to elucidate and characterize the specific cancer-relevant roles of acetylation for future therapeutic design. Acetylation-mediated protein homeostasis is an example of selective acetylation that affects a myriad of proteins as well as their correlated functions. We review recent examples of acetylation-mediated protein homeostasis that have emerged as key contributors to tumorigenesis, tumor proliferation, metastasis, and/or drug resistance, and we discuss their implications for future exploration of this intriguing phenomenon.