Post-translational modifications (PTMs) are biochemical modifications that can significantly alter protein structure, function, stability, localization, and interactions with other molecules, thereby activating or inactivating intracellular processes. A growing body of research has begun to highlight the role of PTMs, including phosphorylation, ubiquitination, acetylation, and redox modifications, during virus-host interactions. Collectively, these PTMs regulate key steps in mounting the host immune response and control critical host pathways required for productive viral replication. This has led to the conception of antiviral therapeutics that focus on controlling host protein PTMs, potentially offering pathogen-agnostic treatment options and revolutionizing our capacity to prevent virus transmission. On the other hand, viruses can hijack the host cellular PTM machinery to modify viral proteins in promoting viral replication and evading immune surveillance. PTM regulation during virus-host interactions is complex and poorly mapped, and the development of effective PTM-targeted antiviral drugs will require a more comprehensive understanding of the cellular pathways essential for virus replication. In this review, we discuss the roles of PTMs in virus infection and how technological advances in mass spectrometry-based proteomics can capture systems-level PTM changes during viral infection. Additionally, we explore how such knowledge is leveraged to identify PTM-targeted candidates for developing antiviral drugs. Looking ahead, studies focusing on the discovery and functional elucidation of PTMs, either on the host or viral proteins, will not only deepen our understanding of molecular pathology but also pave the way for developing better drugs to fight emerging viruses.

The objective of this review is to examine the direct evidence implicating epigenetic mechanisms in manganese (Mn)-induced neurotoxicity, with particular emphasis on the modulation of non-coding RNA (ncRNA) expression and histone modifications. Existing data demonstrate that Mn exposure modulates expression of various types of ncRNAs, especially micro RNAs (miRNAs or miRs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Through regulation of target gene expression, these differentially expressed ncRNAs likely mediate Mn-induced neuronal oxidative stress, ferroptosis, apoptosis, autophagy, inflammation, as well as α-synuclein expression. Additionally, Mn exposure affects histone acetylation in neurons by modulating enzymes such as histone deacetylases (HDACs) and histone acetyltransferases (HATs). These Mn-induced changes in histone acetylation enhance neuronal oxidative stress by down-regulating antioxidant gene expression and promoting neuroinflammation. Alterations in HDACs activity and the ensuing histone acetylation modifications play a role in Mn-induced down-regulation of glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST) expression which results in reduced glutamate uptake and ensuing excitotoxicity. Additionally, Mn exposure impacts the methylation of genes involved in neuroinflammation, neurogenesis, neuronal migration, signal transduction, mitochondrial functioning, cell cycle, and DNA damage response, as well as apoptosis. Detailed analysis reveals that Mn-induced DNA methylation leads to the down-regulation of brain-derived neurotrophic factor (BDNF) expression and the up-regulation of p53. Collectively, current evidence indicates that epigenetic mechanisms are key mediators of manganese (Mn)-induced neurotoxicity in both in vivo and in vitro models. However, the specific target genes and downstream signaling pathways involved in Mn-associated epigenetic regulation have yet to be fully characterized.

Renal cell carcinoma (RCC) is a malignant neoplasm arising from the renal epithelium and constitutes approximately 2% of global cancer diagnoses and mortalities. With increasing prevalence, RCC remains a pressing clinical challenge, particularly because of its resistance to conventional therapies and poor outcomes in advanced stages. Long noncoding RNAs (lncRNAs) have been proposed as key molecular mediators in RCC, orchestrating critical pathways such as epithelial-to-mesenchymal transition (EMT), cellular proliferation, apoptosis, angiogenesis, and metastasis. Their roles in therapeutic resistance, including chemoresistance and radioresistance, further highlight their impact on treatment outcomes. Additionally, the potential of natural compounds such as curcumin, quercetin, and resveratrol to target lncRNA-mediated pathways has garnered attention, offering insights into novel therapeutic strategies. This review examines the biogenic pathways and multifaceted functions of lncRNAs, shedding light on their influence on RCC pathophysiology and posttranscriptional regulation. In addition, this review emphasizes the repercussions of natural compounds as lncRNA-targeted therapies, thus offering a comprehensive perspective on emerging strategies that may lead to more effective and personalized treatments.

Grey hair, a common ageing-associated phenomenon in humans, is mainly attributed to the damage of melanocytes and the absence of melanin. Grey hair has long been treated with traditional medicine, and new research has shown that various plant-derived monomers can increase tyrosinase activity and melanogenesis, indicating that they may have therapeutic value in curing grey hair. In this study, we outlined the role of melanin and pigmentation during hair growth and collected various medicinal plant monomers with the potential value of grey hair reversal. Many active ingredients from medicinal plants, such as fraxinol, tribuloside, morin and naringenin, can upregulate melanogenesis and tyrosinase activity through different signalling pathways. Some of them can promote melanosome quantity, maturation and transportation as well. Monomers isolated from medicinal plants may act as stimulators of melanogenesis. Many plant-derived monomers perform as activators that upregulate melanin synthesis and tyrosinase activity through different signalling pathways. They are of great research value for the treatment of hair greying. Moreover, to further improve experimental effect, safety and reliability, a systematic and comprehensive evaluation system needs to be established in the future before studying their clinical efficacy.

Epigenetic dysregulation has emerged as an important player in the pathobiology of neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, and Huntington's diseases. Aberrant DNA methylation, histone modifications, and dysregulated non-coding RNAs have been shown to contribute to neuronal dysfunction and degeneration. These alterations are often exacerbated by environmental toxins, which induce oxidative stress, inflammation, and genomic instability. Reversing epigenetic aberrations may offer an avenue for restoring brain mechanisms and mitigating neurodegeneration. Herein, we revisit the evidence suggesting the ameliorative effects of epigenetic modulators in toxin-induced models of NDDs. The restoration of normal gene expressions, the improvement of neuronal function, and the reduction in pathological markers by histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors have been demonstrated in preclinical models of NDDs. Encouragingly, in clinical trials of Alzheimer's disease (AD), HDAC inhibitors have caused improvements in cognition and memory. Combining these beneficial effects of epigenetic modulators with neuroprotective agents and the clearance of misfolded amyloid proteins may offer synergistic benefits. Reinforced by the emerging methods for more effective and brain-specific delivery, reversibility, and safety considerations, epigenetic modulators are anticipated to minimize systemic toxicity and yield more favorable outcomes in NDDs. In summary, although still in their infancy, epigenetic modulators offer an integrated strategy to address the multifactorial nature of NDDs, altering their therapeutic landscape.

Cardiovascular disorders (CVDs) are the leading cause of mortality worldwide, highlighting an urgent need for innovative therapeutic strategies. Recent advancements highlight the potential of naturally derived bioproducts with epigenetic properties to offer protection against CVDs. These compounds act on key epigenetic mechanisms, DNA methylation, histone modifications, and non-coding RNA regulation to modulate gene expression essential for cardiovascular health. This review explores the effects of various bioproducts, such as polyphenols, flavonoids, and other natural extracts, on these epigenetic modifications and their potential benefits in preventing and managing CVDs. We discuss recent discoveries and clinical applications, providing insights into the epigenetic regulatory mechanisms of these compounds as potential epidrugs, naturally derived agents with promising therapeutic prospects in epigenetic therapy for CVDs.

Multiple myeloma (MM) remains an incurable hematologic malignancy due to the inevitable development of drug resistance, particularly in relapsed or refractory cases. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, and glycosylation, play pivotal roles in regulating protein function, stability, and interactions, thereby influencing MM pathogenesis and therapeutic resistance. This review comprehensively explores the mechanisms by which dysregulated PTMs contribute to drug resistance in MM, focusing on their impact on key signaling pathways, metabolic reprogramming, and the tumor microenvironment. We highlight how PTMs modulate drug uptake, alter drug targets, and regulate cell survival signals, ultimately promoting resistance to PIs, IMiDs, and other therapeutic agents. Furthermore, we discuss emerging therapeutic strategies targeting PTM-related pathways, which offer promising avenues for overcoming resistance to treatment. By integrating preclinical and clinical insights, this review underscores the potential of PTM-targeted therapies to enhance treatment efficacy and improve patient outcomes in MM.

The purpose of this review is to evaluate the role of epigenetic-targeting approaches in the management of neuroendocrine neoplasms (NENs), particularly as a priming strategy for subsequent therapies. We explore the molecular basis of epigenetic modifications in NENs, and we review preclinical and clinical studies on DNA methyltransferase and histone deacetylase (HDAC) inhibitors.

Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.

Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and have been shown to interfere with the endocrine system, leading to adverse effects on reproductive health. In females, EDC exposure has been linked to menstrual irregularities, infertility, and pregnancy complications. Epigenetic regulation, which involves modifications to DNA and histones that do not alter the underlying genetic code, plays a crucial role in female reproduction. EDCs have been shown to disrupt epigenetic mechanisms, leading to changes in gene expression that can have long-term effects on reproductive outcomes. Several EDCs, including bisphenol A (BPA) and phthalates, dioxins, and polychlorinated biphenyls (PCBs), have been shown to alter DNA methylation patterns and histone modifications in female reproductive tissues. These changes can lead to altered expression of genes involved in ovarian function, implantation, and placental development. Here, we integrate epidemiological and experimental evidence from the last 20 years to profile the types of diseases that EDCs trigger in the female reproductive system in relation to the uterus, and the corresponding molecular mechanisms that have been studied. In addition, this review will outline the state of knowledge of EDC epigenetic regulation in the uterus and how it impacts reproductive health, as well as identify areas for future research.

Temozolomide (TMZ) resistance is one of the critical factors contributing to the poor prognosis of glioblastoma (GBM). As a first-line chemotherapeutic agent for GBM, TMZ exerts its cytotoxic effects through DNA alkylation. However, its therapeutic efficacy is significantly compromised by enhanced DNA damage repair (DDR) mechanisms in GBM cells. Although several DDR-targeting drugs have been developed, their clinical outcomes remain suboptimal. Post-translational modifications (PTMs) in GBM cells play a pivotal role in maintaining the genomic stability of DDR mechanisms, including methylguanine-DNA methyltransferase-mediated repair, DNA mismatch repair dysfunction, base excision repair, and double-strand break repair. This review focuses on elucidating the regulatory roles of PTMs in the intrinsic mechanisms underlying TMZ resistance in GBM. Furthermore, we explore the feasibility of enhancing TMZ-induced cytotoxicity by targeting PTM-related enzymatic to disrupt key steps in PTM-mediated DDR pathways. By integrating current preclinical insights and clinical challenges, this work highlights the potential of modulating PTM-driven networks as a novel therapeutic strategy to overcome TMZ resistance and improve treatment outcomes for GBM patients.

In recent years, metabolic reprogramming has emerged as a significant breakthrough in elucidating the onset and progression of gastrointestinal (GI) malignancies. As central regulatory hubs for lipid metabolism, sterol regulatory element binding proteins (SREBPs) integrate dietary metabolic signals and carcinogenic stimuli through subtype-specific mechanisms, thereby promoting malignant tumour phenotypes. In this review, we first present the molecular background, structural characteristics, and posttranscriptional regulatory networks associated with SREBPs. We subsequently describe a systematic analysis of the distinct activation patterns of SREBPs in liver, gastric, colorectal, and other gastrointestinal cancers. Furthermore, we explore targeted intervention strategies for different SREBP subtypes, including small molecule inhibitors (such as fatostatin, which inhibits SREBP cleavage), natural compounds (such as berberine, which modulates the AMPK/mTOR pathway), and statin-mediated inhibition of the mevalonic acid pathway. These strategies may enhance tumour cell sensitivity to chemotherapeutic agents (such as 5-FU, gezil, and tabine) and improve the response to synergistic chemoradiotherapy by reversing adaptive metabolic resistance driven by the tumour microenvironment. Through this review, we hope to provide new insights into precise interventions targeting various subtypes of the SREBP molecule.

The SWI/SNF (switch/sucrose non-fermentable) related BAF (BRG1/BRM-related factor) chromatin remodeling complex subunit ATPase 4 (SMARCA4) is a gene with a high mutation frequency in the SWI/SNF complex. It plays a role as an ATP-dependent catalytic subunit, participates in remodeling chromatin structure and regulation of gene expression, and is closely related to the poor prognosis of malignant tumors. It is imperative to conduct a comprehensive investigation into the distinctive biological functions and mechanisms by which SMARCA4 contributes to cancer development and to devise targeted therapeutic strategies. Despite numerous studies associating SMARCA4 with the regulation of essential genes, ferroptosis, autophagy, lipid metabolism, and oxidative stress, the precise mechanisms of SMARCA4 in tumors remain unclear. Patients with SMARCA4 mutations exhibit a poor prognosis and demonstrate limited responsiveness to surgery, targeted therapies, immunotherapy, and chemotherapies. Thus, SMARCA4 emerges as a promising biomarker and therapeutic target. However, the development of more effective precision therapy tools remains an urgent unmet need. The unique molecular characteristics of SMARCA4 pose significant challenges for targeted drug development. Notably, the discovery of inhibitors targeting SMARCA4 synthetic lethal partners and associated pathways has marked a breakthrough in this field. Monotherapies directed against SMARCA4 face several limitations, including drug resistance, suboptimal objective response rates, and dose-limiting toxicities. Consequently, the exploration of combinatorial therapeutic strategies for SMARCA4 deficiency populations represents a critical direction for future clinical translation.

Adenosine kinase (ADK, EC: 2.7.1.20) is an evolutionarily ancient ribokinase, which acts as a metabolic regulator by transferring a phosphoryl group to adenosine to form AMP. The enzyme is of interest as a therapeutic target because its inhibition is one of the most effective means to raise the levels of adenosine and hence adenosine receptor activation. For these reasons, ADK has received significant attention in drug discovery efforts in the early 2000s for indications such as epilepsy, chronic pain, and inflammation; however, the report of adverse events regarding cardiovascular and hepatic function as well as instances of microhemorrhage in the brain of preclinical models prevented further development efforts. Recent findings emphasize the importance of compartmentalization of the adenosine system reflected by two distinct isoforms of the enzyme, ADK-S and ADK-L, expressed in the cytoplasm and the cell nucleus, respectively. Newly identified adenosine receptor independent functions of adenosine as a regulator of biochemical transmethylation reactions, which include DNA and histone methylation, identify ADK-L as a distinct therapeutic target for the regulation of the nuclear methylome. This newly recognized role of ADK-L as an epigenetic regulator points toward the potential disease-modifying properties of the next generation of ADK inhibitors. Continued efforts to develop therapeutic strategies to separate nuclear from extracellular functions of adenosine would enable the development of targeted therapeutics with reduced adverse event potential. This review will summarize recent advances in the discovery of novel ADK inhibitors and discuss their potential therapeutic use in conditions ranging from epilepsy to cancer.

The frameshifting element (FSE) comprises a slippery heptanucleotide sequence followed by a downstream RNA structure, such as a pseudoknot or stem-loop. Found in various RNA viruses, FSE regulates viral replication via programmed -1 ribosomal frameshifting (-1 PRF), making it a potential broad-spectrum antiviral target. Advances in RNA structural analysis have elucidated the dynamic conformations and cross-viral diversity of FSE, with the SARS-CoV-2 outbreak further highlighting its role in viral replication. Efforts to develop antiviral drugs targeting FSE have progressed through virtual and phenotypic screening. In this review, we explore the evolution, structure, and function of FSE in coronaviruses, evaluate recent advances in FSE-targeted drug development, and discuss their design advantages, efficacy, and challenges, providing insights for future antiviral strategies.

Chemotherapeutic resistance is a major obstacle to chemotherapeutic failure. Cancer cell resistance involves several mechanisms, including epithelial-to-mesenchymal transition (EMT), signaling pathway bypass, drug efflux activation, and impairment of drug entry. P-glycoproteins (P-gp) are an efflux transporter that pumps chemotherapeutic drugs out of cancer cells, resulting in chemotherapeutic resistance. Several types of long noncoding RNA (lncRNAs) have been identified in resistant cancer cells, including ODRUL, MALAT1, and ANRIL. The high expression level of ODRUL is related to the induction of ATP-binding cassette (ABC) gene expression, resulting in the emergence of doxorubicin resistance in osteosarcoma. lncRNAs are observed to be regulators of drug transporters in cancer cells such as MALAT1 and ANRIL. Targeting P-gp expression using natural products is a new strategy to overcome cancer cell resistance and improve the sensitivity of resistant cells toward chemotherapies. This review validates the inhibitory effects of natural products on P-gp expression and activity using in silico molecular docking. In silico analysis showed that Delphinidin and Asparagoside-f are the most significant natural product inhibitors of p-glycoprotein-1. These inhibitors can reverse multi-drug resistance and induce the sensitivity of resistant cancer cells toward chemotherapy based on in silico molecular docking. It is important to validate that pre-elementary docking can be confirmed using in vitro and in vivo experimental data.

Gastric cancer (GC) is an aggressive malignancy among all Gastrointestinal cancer (GIC) types. Worldwide, among all cancer types, gastric cancer incidence and related mortality remain in fifth position. Multidrug resistance (MDR) in GC presents a major challenge to chemotherapy, and it significantly affects patient survival. A better understanding of the dynamic interaction of cellular factors contributing to MDR phenotype, e.g., the presence and expression of variants of MDR-related genes, including various drug-detoxifying and drug-efflux transporters, and expression of regulatory ncRNAs affecting the expression of MDR-related genes, is required to comprehend the molecular mechanisms for MDR development in GCs. This review article provides a holistic discussion of the cellular factors involved in the MDR development in GC cells, i.e., their roles and cross-talk between specific molecules that give rise to drug-sensitive and drug-resistant phenotypes. Moreover, the pharmacological perspective of drug resistance and the underlying biological processes that allow the escape of GC cells from the cytotoxic effects of drugs have also been discussed. Additionally, this review article provides an in-depth discussion on most potential candidates that can serve as MDR biomarkers in GIC cancer and the growing research interest in non-coding RNAs (ncRNAs) in GC. Notably, the miRNAs, circRNAs, and lncRNAs are not only emerging as crucial prognostic biomarkers of MDR in gastric cancers but also as potential targets for personalized medicine to combat the MDR challenge in GC patients.

Hepatocellular carcinoma (HCC) continues to pose a substantial worldwide health concern, marked by elevated mortality rates and restricted therapeutic alternatives. Recent studies have highlighted the potential of natural compounds as therapeutic agents in cancer management. This review focuses on the diagnostic and prognostic potential of microRNAs (miRNAs) as biomarkers in HCC, alongside the therapeutic promise of natural products. We explore the intricate role of miRNAs in the pathogenesis of HCC, detailing their regulatory functions in cellular processes such as proliferation, apoptosis, and metastasis. Additionally, we discuss the emerging evidence supporting the use of natural compounds, including phytochemicals, in modulating miRNA expression and their potential synergistic effects with conventional therapies. Key miRNAs discussed include miR-21, an oncogenic factor that promotes tumor growth by targeting the tumor suppressor phosphatase and tensin homolog (PTEN); miR-34a, which enhances apoptosis and may improve treatment efficacy when combined with c-MET inhibitors; miR-203, whose downregulation correlates with poor outcomes and may serve as a prognostic marker; miR-16, which acts as a tumor suppressor and has diagnostic potential when measured alongside traditional markers like alpha-fetoprotein (AFP); and miR-483-3p, associated with resistance to apoptosis and tumor progression. By integrating insights from recent studies, this review aims to highlight the dual role of miRNAs as both biomarkers and therapeutic targets, paving the way for enhanced diagnostic strategies and novel treatment modalities in HCC management.

Epigenetics describes itself as heritable modifications in gene function that eventually alter gene and protein expression levels without any alterations in the genome sequence. Epigenetic alterations are closely association with several neurological diseases and neurodevelopmental disorders. In recent years, growing shreds of evidences suggested the crucial role of epigenetic modifications especially histone modifications in environmental toxicants-induced neurotoxicity. This review will give an overview of the state of knowledge on histone alterations and the ways in which environmental pollutants bisphenol-A, heavy metals, pesticides, and phthalates affects post-translational modifications to alter gene transcription and cause neurological abnormalities. We provide a brief summary of the results of recent research on the effects of environmental toxins on each of the prior identified processes of histone modifications, including the neurological consequences and changes in histones. There is also discussion of the limitations of current research findings. Furthermore, this review aims to provide viewers a comprehensive knowledge regarding the role of histone modifications in various environmental toxicants-induced neurological diseases and offers insights for future research.

This review is centered around the cardiotoxic effects of fumonisin B1 (FB1), particularly its impact on sphingolipid metabolism, inflammation, and epigenetics. FB1 is a mycotoxin produced by Fusarium fungi, which mainly contaminates cereal grains and poses an adverse health risk to both humans and animals; however, its disease-causing capabilities remain to be uncovered, specifically its ability to exacerbate and cause cardiovascular disease. It disrupts sphingolipid metabolism by inhibiting ceramide synthase, leading to cellular dysfunction and contributes to conditions such as hypertension and eventual heart failure. FB1 is responsible for an altered inflammatory response, whereby it increases pro-inflammatory cytokines such as IL-6 and IL-1β, which contribute to cardiovascular diseases. Moreover, FB1 induces significant epigenetic changes, including DNA hypermethylation, histone modifications such as increased H3K9me2 and H3K9me3, inhibition of histone acetyltransferase activity, and changes in microRNA expression profiles. These epigenetic alterations can silence or activate inflammatory genes, exacerbating disease progression. This review thus highlights the need for further research to elucidate the connections between FB1, inflammation, epigenetic modifications, and cardiotoxicity, which could lead to better strategies for managing FB1-related adverse health risks.