Eukaryotic cells contain the endoplasmic reticulum (ER), a prevalent and intricate membranous structural system. During the development of inflammatory bowel disease (IBD), the stress on the ER and the start of the unfolded protein response are very important. Some chemicals, including 4μ8C, small molecule agonists of X-box binding protein 1, and ISRIB, work on the inositol-requiring enzyme 1, turn on transcription factor 6, and activate protein kinase RNA-like ER kinase pathways. This may help ease the symptoms of IBD. Researchers investigating the gut microbiota have discovered a correlation between ER stress and it. This suggests that changing the gut microbiota could help make new medicines for IBD. This study looks at how ER stress works and how it contributes to the emergence of IBD. It also talks about its possible clinical importance as a therapeutic target and looks into new ways to treat this condition.

Air pollution is a major global health threat, responsible for over 8 million deaths in 2021, including 700,000 fatalities among children under the age of five. It is currently the second leading risk factor for mortality worldwide. Key pollutants, such as particulate matter (PM2.5, PM10), ozone, sulfur dioxide, nitrogen oxides, and carbon monoxide, have significant adverse effects on human health, contributing to respiratory and cardiovascular diseases, as well as neurodevelopmental and neurodegenerative disorders. Among these, particulate matter poses the most significant threat due to its highly complex mixture of organic and inorganic compounds with diverse sizes, compositions, and origins. Additionally, it can penetrate deeply into tissues and cross the blood-brain barrier, causing neurotoxicity which contributes to the development of neurodegenerative diseases. Although the link between air pollution and neurological disorders is well documented, the precise mechanisms and their sequence remain unclear. Beyond causing oxidative stress, inflammation, and excitotoxicity, studies suggest that air pollution induces epigenetic changes. These epigenetic alterations may affect the expression of genes involved in stress responses, neuroprotection, and synaptic plasticity. Understanding the relationship between neurological disorders and epigenetic changes induced by specific air pollutants could aid in the early detection and monitoring of central nervous system diseases.

Periodontitis is unanimously accepted to be the sixth complication of diabetes mellitus (DM), while the inverse relationship of causality is still to be deciphered. Among the proposed mechanisms is gut dysbiosis, which is responsible for the systemic release of proinflammatory mediators. In this process, Gram-negative bacteria from the oral cavity enter the general circulation, leading to the emergence of bi-hormonal beta-pancreatic cells that lack the ability to secrete insulin. Additionally, epigenetic and adaptive mechanisms in affected cells may play a role in reducing inflammation. The release of reactive oxygen species, proinflammatory cytokines, and adipokines, such as interleukins, tumor necrosis factor alpha, leptin, prostaglandin E2, C-reactive protein, or matrix metalloproteinases, determine epigenetic changes, such as the methylation of DNA nucleotides or changes in the activity of histone acetylases/deacetylases. The management of periodontitis involves targeting inflammation, and its potential connection to epigenetic modulation observed in other chronic conditions may help to explain its role in preventing DM in affected patients. This review focuses on the key epigenetic changes in periodontitis that might contribute to DM development, and explores the mechanisms and novel multi-drug therapies that could help to prevent these effects.

HIV-1 can establish a lifelong infection by incorporating its proviral DNA into the host genome. Once integrated, the virus can either remain dormant or start active transcription, a process governed by the HIV Tat protein, host transcription factors and the chromatin landscape at the integration site. Histone-modifying enzymes and chromatin-remodeling enzymes play crucial roles in regulating this chromatin environment. Chromatin remodelers, a group of ATP-dependent proteins, collaborate with host proteins and histone-modifying enzymes to restructure nucleosomes, facilitating DNA repair, replication, and transcription. Recent studies have highlighted the importance of chromatin remodelers in HIV-1 latency, spurring research focused on developing small molecule modulators that can either reactivate the virus for eradication approaches or induce long-term latency to prevent future reactivation. Research efforts have primarily centered on the SWI/SNF family, though much remains to be uncovered regarding other chromatin remodeling families. This review delves into the general functions and roles of each chromatin remodeling family in the context of HIV and discusses recent advances in small molecule development targeting chromatin remodelers and the HIV Tat protein, aiming to improve therapeutic approaches against HIV.

Colorectal cancer (CRC) remains an alarming global health concern despite advancements in treatment modalities over recent decades. Among the various factors contributing to CRC, this review emphasizes the critical role of epigenetic mechanisms in its pathogenesis and progression. This review also describes the potential role of natural compounds in altering the epigenetic landscape, focused mainly on DNA methylation, histone modification, and non-coding RNAs. Publications from the previous five years were searched and retrieved using well-known search engines and databases like PubMed, Google Scholar, and ScienceDirect. Keywords like CRC/colorectal cancer, CAC/Colitis associated CRC, inflammasomes, epigenetic modulation, genistein, curcumin, quercetin, resveratrol, anthocyanins, sulforaphane, and epigallocatechin-3-gallate were used in various combinations during the search. These natural compounds predominantly affect pathways such as Wnt/β-catenin, NF-κB, and PI3K/AKT to suppress CRC cell proliferation and oxidative stress and enhance anti-inflammation and apoptosis. However, their clinical use is restricted due to their low bioavailability. However, multiple methods exist to overcome challenges like this, including but not limited to structural modifications, nanoparticle encapsulations, bio-enhancers, and novel advanced delivery systems. These methods improve their potential as supportive therapies that target CRC progression epigenetically with fewer side effects. Current research focuses on enhancing epigenetic targeting to control CRC progression while minimizing side effects, emphasizing improved specificity, bioavailability, and efficacy as standalone or synergistic therapies.

MYC is an important transcription factor involved in physiological processes such as cell growth, proliferation and differentiation. However, aberrant MYC expression has oncogenic-driving potential and is observed in the majority of human cancers. XPO1 is a member of the exportin family of proteins which regulate protein and RNA export from the nucleus to the cytoplasm. XPO1 is aberrantly expressed in cancer, especially with the advancing of the disease. XPO1 inhibition is able to decrease MYC levels through various pathways leading to decreased cancer cell viability. These pathways include other undruggable targets such as p53 and KRAS, DNA damage repair proteins, immune response mediators including IκB, and other transcription factors such as eIF4E. Herein, we describe the potential pathways and mechanisms through which XPO1 inhibition promotes MYC downregulation and subsequent downregulation of its targets. We also describe possible drug combinations with potential clinical applications.

Preeclampsia (PE) is a critical complication of pregnancy that affects 3% to 5% of all pregnancies and has been linked to aberrant placentation, causing severe maternal and fetal illness and death.

Valproic acid (VPA) is an antiepileptic and mood-stabilizing drug with well-established teratogenic risks when taken during pregnancy. While its harmful effects on fetal development are well known, less attention has been given to its impact on placental development and function, despite the placenta's critical role in pregnancy.

As living conditions improve and diagnostic capabilities advance, the incidence of tumors has increased, with cancer becoming a leading cause of death worldwide. Surgery, chemotherapy, and radiotherapy are the most common treatments. Despite advances in treatment options, chemotherapy remains a routine first-line treatment for most tumors. Due to the continuous and extensive use of chemotherapy drugs, tumor resistance often develops, becoming a significant cause of treatment failure and poor prognosis. Recent research has increasingly focused on how long stranded non-coding RNAs (LncRNAs) influence the development of malignant tumors and drug resistance by regulating gene expression and other biological mechanisms during cell growth. Studies have demonstrated that variations in lncRNA expression levels, influenced by both interpatient variability and intratumoral genetic and epigenetic differences, are closely linked to tumor drug resistance. Therefore, this review advocates using lncRNA as a framework to investigate the regulation of genes associated with drug resistance, proposing lncRNA-targeted therapeutic strategies to potentially increase the efficacy of chemotherapy, improve patient outcomes, and guide future research directions.

Sepsis is a syndrome of organ dysfunction caused by the invasion of pathogenic microorganisms. In clinical practice, patients with sepsis are prone to concurrent acute kidney injury, which has high morbidity and mortality rates. Thus, understanding the pathogenesis of sepsis-associated acute kidney injury is of significant clinical importance. Ferroptosis is an iron-dependent programmed cell death pathway, which is proved to play a critical role in the process of sepsis-associated acute kidney injury through various mechanisms. Epigenetic regulation modulates the content and function of nucleic acids and proteins within cells through various modifications. Its impact on ferroptosis has garnered increasing attention; however, the role of epigenetic regulation targeting ferroptosis in sepsis-associated acute kidney injury has not been fully elucidated. Growing evidence suggests that epigenetic regulation can modulate ferroptosis through complex pathway networks, thereby affecting the development and prognosis of sepsis-associated acute kidney injury. This paper summarizes the impact of ferroptosis on sepsis-associated acute kidney injury and the regulatory mechanisms of epigenetic regulation on ferroptosis, providing new insights for the targeted therapy of sepsis-associated acute kidney injury.

Mycobacterium species show distinctive characteristics with significant medical implications. Mycobacteria, including Mycobacterium tuberculosis and non-tuberculous mycobacteria, can form biofilms that facilitate their survival in hostile environments and contribute to development of antibiotic resistance and responses by the host immune system. Mycobacterial biofilm development is a complex process involving multiple genetic determinants, notably mmpL genes, which regulate lipid transport and support cell wall integrity, and the groEL gene, which is essential for biofilm maturation. Sliding motility, a passive form of surface movement observed across various mycobacterial species, is closely associated with biofilm formation and colony morphology. The unique sliding motility and biofilm-forming capabilities of Mycobacterium spp. are pivotal for their pathogenicity and persistence in diverse environments. A comprehensive understanding of the regulatory mechanisms governing these processes is crucial for the development of novel therapeutic strategies against mycobacterial infections. This review provides a detailed examination of our current knowledge regarding mycobacterial biofilm formation and motility, with a focus on regulation of these processes, their impact on pathogenicity, and potential avenues for therapeutic intervention. To this end, the potential of natural and synthetic compounds, including nanomaterials, in combating mycobacterial biofilms and inhibiting sliding motility are discussed as well. These compounds offer new avenues for the treatment of drug-resistant mycobacterial infections.

The focus on breast cancer treatment has shifted from the cytotoxic effects of single drugs on tumor cells to multidimensional multi‑pathway synergistic intervention strategies targeting the tumor microenvironment (TME). The activation of the Wnt signaling pathway in the TME of breast cancer cells serves a key regulatory role in tissue homeostasis and is a key driver of the carcinogenic process. Modulating the crosstalk between the Wnt pathway and TME of breast cancer is key for understanding the biological behavior of breast cancer and advancing the development of novel antitumor drugs. The present review aimed to summarize the complex mechanisms of the Wnt signaling pathway in the breast cancer TME, interactions between the Wnt signaling pathway and components of the breast cancer TME and breast cancer‑associated genes, as well as the interactions between the Wnt signaling pathway and other signaling cascades at the molecular level. Furthermore, the present review aimed to highlight the unique advantages of the Wnt signaling pathway in the macro‑regulation of the TME and the current therapeutic strategies targeting the Wnt signaling pathway, their potential clinical value and future research directions in breast cancer treatment.

Given the high prevalence of cannabis use among people with HIV (PWH) and its potential to modulate immune responses and reduce inflammation, this systematic review examines preclinical evidence on how tetrahydrocannabinol (THC), a key compound in cannabis, affects gene and micro-RNA expression in simian immunodeficiency virus (SIV)-infected macaques and HIV-infected human cells. Through a comprehensive search, 19 studies were identified, primarily involving SIV-infected macaques, with a pooled sample size of 176, though methodological quality varied across the studies. Pathway analysis of differentially expressed genes (DEGs) and miRNAs associated with THC revealed enrichment in pathways related to inflammation, epithelial cell proliferation, and adhesion. Notably, some DEGs were targets of the differentially expressed miRNAs, suggesting that epigenetic regulation may contribute to THC's effects on gene function. These findings indicate that THC may help mitigate chronic immune activation in HIV infection by altering gene and miRNA expression, suggesting its potential immunomodulatory role. However, the evidence is constrained by small sample sizes and inconsistencies across studies. Further research employing advanced methodologies and larger cohorts is essential to confirm THC's potential as a complementary therapy for PWH and fully elucidate the underlying mechanisms, which could inform targeted interventions to harness its immunomodulatory effects.

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.

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.