Malignant gliomas are the most lethal form of brain cancer, characterized by rapid cell growth, substantial molecular heterogeneity, and a propensity for invasion into critical brain regions. Phosducin (PDC) is recognized for its involvement in sensory signal transmission, blood pressure regulation, and thyroid gland endocrine functions. However, the role of PDC in cell proliferation, drug sensitization, and its connection to RNA m6A modification in gliomas remains unclear. In this study, RNA sequencing analysis was performed on U251 glioma cells with knockdown and overexpression of fat mass and obesity-associated protein (FTO). The results revealed that FTO negatively regulates PDC expression. This finding was corroborated in U87, U251, and A172 glioma cells via qRT-PCR and western blot analysis. Additionally, MTT and EdU assays revealed that PDC overexpression inhibited cell proliferation, while PDC knockdown accelerated it. Moreover, the proliferation-enhancing effect of FTO overexpression was reduced by PDC overexpression, and the proliferation-inhibiting effect of FTO knockdown was reversed by PDC knockdown. These findings suggest that PDC serves as a functional target of FTO. Furthermore, PDC enhanced the antitumor efficacy of temozolomide (TMZ). In summary, this study demonstrates for the first time that PDC plays a crucial role in regulating cell proliferation and TMZ sensitivity in glioma cells, providing a potential therapeutic target to improve treatment outcomes for the patients with glioma.

The field of epitranscriptomics is undergoing a technology-driven revolution. During past decades, RNA modifications like N6-methyladenosine (m6A), pseudouridine (ψ), and 5-methylcytosine (m5C) became acknowledged for playing critical roles in cellular processes. Direct RNA sequencing by Oxford Nanopore Technologies (ONT) enabled the detection of modifications in native RNA, by detecting noncanonical RNA nucleosides properties in raw data. Consequently, the field's cutting edge has a heavy component in computer science, opening new avenues of cooperation across the community, as exchanging data is as impactful as exchanging samples. Therefore, we seize the occasion to bring scientists together within the RNA Modification and Processing (RMaP) challenge to advance solutions for RNA modification detection and discuss ideas, problems and approaches. We show several computational methods to detect the most researched mRNA modifications (m6A, ψ, and m5C). Results demonstrate that a low prediction error and a high prediction accuracy can be achieved on these modifications across different approaches and algorithms. The RMaP challenge marks a substantial step towards improving algorithms' comparability, reliability, and consistency in RNA modification prediction. It points out the deficits in this young field that need to be addressed in further challenges.

The involvement of the fat mass and obesity-associated gene (FTO) in the development and advancement of metabolic disorders is widely recognized. However, the existing FTO inhibitor entacapone has been limited in clinical application due to its low potency and short plasma elimination half-life. Here, through drug library screening and in depth structure-activity relationship analysis, title compound 40, eriodictyol was identified as a potent FTO inhibitor, and showed good binding to FTO by surface plasmon resonance (SPR) and Microscale thermophoresis (MST) detection. The residues Arg96, Tyr108, Ser229, Asp233, and Glu234 of FTO are essential for binding. Meanwhile, eriodictyol attenuated obesity-related metabolic diseases by enhancing glucose metabolism pathways via the FTO-FOXO1-G6PC/PCK1 axis and increasing adipose tissue heat production for weight loss via the FTO-FOXO1-Ucp1 axis in vivo. Surprisingly, eriodictyol showed good pharmacokinetic properties and no obvious toxicity. These results could provide the reference for design of new FTO inhibitors against obesity-related metabolic diseases.

The neurotransmitter gamma-aminobutyric acid (GABA) has been thought to be involved in the development of some types of cancer. Yet, the de novo synthesis of GABA and how it functions in hepatocellular carcinoma (HCC) remain unclear. Here, we report that SLC6A12 acts as a transporter of GABA, and that aldehyde dehydrogenase 9 family member A1 (ALDH9A1), not glutamate decarboxylase 1 (GAD1), generates GABA in human HCC. Interestingly, SLC6A12 and ALDH9A1 are upregulated during lung metastases of HCC, and depletion of either of them leads to impaired HCC metastasis. Mechanistically, GABA directly binds and stabilizes β-catenin, resulting in activated Wnt/β-catenin signaling, and thereby enhancing HCC metastasis. Reciprocally, β-catenin transcriptionally upregulates SLC6A12 to import more GABA to stabilize β-catenin. Thus, our findings identify ALDH9A1 as the major GABA synthetase in HCC, demonstrate a positive-feedback regulatory mechanism for sustaining Wnt/β-catenin signaling, and reveal a role for β-catenin in sensing GABA, which contributes to HCC metastasis.

The chemical modification of biological molecules is a critical regulatory mechanism for controlling molecular functions. Although research has long focused on DNA and proteins, RNA modifications have recently attracted substantial interest with the advancement in detection technologies. In oncology, many studies have identified dysregulated RNA modifications including m6A, m1A, m5C, m7G, pseudouridylation and A to I editing, leading to disrupted downstream pathways. As the concept of the tumor microenvironment has gained prominence, studies have increasingly examined the role of RNA modifications in this context, focusing on interactions among cancer cells, immune cells, stromal cells, and other components. Here we review the RNA modifications in the tumor microenvironment through the perspective of the Cancer-Immunity Cycle. The extracellular RNA modifications including exosomes and influence of microbiome in RNA modifications are potential research questions. Additionally, RNA modifying enzymes including FTO, ALKBH5, METTL3, PUS7 are under investigation as potential biomarkers and targets for combination with immunotherapies. ADCs and mimetics of modified RNA could be potential novel drugs. This review discusses the regulatory roles of RNA modifications within the tumor microenvironment.

N6-methyladenosine (m6A), the most abundant internal RNA modification in humans, regulates most aspects of RNA processing. Prostate cancer is characterized by widespread transcriptomic dysregulation; therefore, we characterized the m6A landscape of 162 localized prostate tumors with matched DNA, RNA and protein profiling. m6A abundance varied dramatically across tumors, with global patterns emerging via complex germline-somatic cooperative regulation. Individual germline polymorphisms regulated m6A abundance, cooperating with somatic mutation of cancer driver genes and m6A regulators. The resulting complex patterns were associated with prognostic clinical features and established the biomarker potential of global and locus-specific m6A patterns. Tumor hypoxia dysregulates m6A profiles, bridging prior genomic and proteomic observations. Specific m6A sites, such as those in VCAN, drive disease aggression, associating with poor outcomes, tumor growth and metastasis. m6A dysregulation is thus associated with key events in the natural history of prostate cancer: germline risk, microenvironmental dysregulation, somatic mutation and metastasis.

N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.

The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.

This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

The m6A modification is an RNA modification that impacts various processes of RNA molecules, including transcription, splicing, stability, and translation. Recently, researchers have discovered that the presence of m6A modification can influence the interaction between tumor cells and immune cells and also play a role in regulating the expression of immune response-related genes. Additionally, m6A modification is intricately involved in the regulation of tumor immune evasion and drug resistance. Specifically, certain tumor cells can manipulate the gene expression through m6A modification to evade immune system attacks. Therefore, it might be possible to enhance tumor immune surveillance and improve the effectiveness of immune-based therapies by manipulating m6A modification. This review systematically discusses the role of m6A modification in tumor immunity, specifically highlighting its regulation of immune cells and immune-related genes in tumor cells. Furthermore, we explore the potential of m6A modification inhibitors as anti-cancer therapies and the significance of m6A regulatory factors in predicting the efficacy of tumor immune therapy.

Both obesity and metabolic disorders are global medical problems. Driven by prolonged inflammation, obesity increases the risk of developing metabolic syndromes such as fatty liver, diabetes, cardiovascular diseases and cancers. The fat mass and obesity-associated protein (FTO) is an m6A demethylase, elevated activity of which is known to promote the pathogenesis of many metabolic disorders, leading to the establishment of various FTO inhibitors. By combing through intrinsic connections among obesity and the four primary metabolic problems, we attribute their shared pathological cause to prolonged inflammation. By reviewing the roles of FTO in promoting these disorders and the current status of existing FTO inhibitors in treating these syndromes, we underpinned the paramount potential of resolving these clinical issues by targeting FTO and the urgent need of establishing novel FTO inhibitors with maximized efficacy and minimized side effect. Cold atmospheric plasma (CAP) is the fourth state of matter with demonstrated efficacy in treating various diseases associated with chronic inflammation. By introducing the medical characteristics of CAP, we proposed it as a possible solution to unresolved issues of current FTO inhibitors given its anti-inflammation feature and demonstrated clinical safety. We also emphasized the need of intensive investigations in exploring the feasibility of using CAP in treating obesity and associated metabolic syndromes that might function through targeting FTO.

Maintaining genomic integrity and faithful transmission of genetic information is essential for the survival and proliferation of cells and organisms. DNA damage, which threatens the integrity of the genome, is rapidly sensed and repaired by mechanisms collectively known as the DNA damage response. The RNA demethylase FTO has been implicated in this process; however, the underlying mechanism by which FTO regulates DNA repair remains unclear. Here, we use an unbiased quantitative proteomic approach to identify the proximal interactome of endogenous FTO protein. Our results demonstrate a direct interaction with the DNA damage sensor protein PARP1, which dissociates upon ultraviolet stimulation. FTO inhibits PARP1 catalytic activity and controls its clustering in the nucleolus. Loss of FTO enhances PARP1 enzymatic activity and the rate of PARP1 recruitment to DNA damage sites, accelerating DNA repair and promoting cell survival. Interestingly, FTO regulates PARP1 function and DNA damage response independent of its catalytic activity. We conclude that FTO is an endogenous negative regulator of PARP1 and the DNA damage response in cells beyond its role as an RNA demethylase.

N6-methyladenosine (m6A), a prevalent and essential RNA modification, serves a key function in driving autoimmune disease pathogenesis. By modulating immune cell development, activation, migration, and polarization, as well as inflammatory pathways, m6A is crucial in forming innate defenses and adaptive immunity. This article provides a comprehensive overview of m6A modification features and reveals how its dysregulation affects the intensity and persistence of immune responses, disrupts immune tolerance, exacerbates tissue damage, and promotes the development of autoimmunity. Specific examples include its contributions to systemic autoimmune disorders like lupus and rheumatoid arthritis, as well as conditions that targeting specific organs like multiple sclerosis and type 1 diabetes. Furthermore, this review explores the therapeutic promise of target m6A-related enzymes ("writers," "erasers," and "readers") and summarizes recent advances in intervention strategies. By focusing on the mechanistic and therapeutic implications of m6A modification, this review sheds light on its role as a promising tool for both diagnosis and treatment in autoimmune disorders, laying the foundation for advancements in customized medicine.

The fat mass and obesity-associated protein (FTO) is identified as regulating mammalian development and diseases by removing methyl groups from RNAs. However, the roles of FTO in the context of oral lichen planus (OLP) remain unknown. Here, we demonstrated that the protein levels of FTO in the keratinocytes from OLP patients were down-regulated compared to those from healthy participants. At the molecular level, we explained that GSK-3β-induced phosphorylation promoted FTO protein degradation in diseased oral keratinocytes. Using a cell co-culture model, we further confirmed that FTO deficiency facilitated NF-κB activation and apoptosis in oral keratinocytes under inflammatory conditions. Vitamin D receptor (VDR), which plays a protective role in OLP, was mediated by FTO in an RNA N 6-methyladenosine (m6A) methylation-dependent way. FTO overexpression failed to suppress NF-κB and caspase-3 activities upon VDR ablation in oral keratinocytes, suggesting that FTO insufficiency damages oral epithelial by targeting VDR. Collectively, these data reveal that FTO deficiency facilitates epithelial dysfunction in OLP by decreasing VDR expression.

The prevalent eukaryotic RNA modification N6-methyladenosine (m6A), which is distributed in more than 50% of cases, has demonstrated significant implications in both normal development and disease progression, particularly in the context of cancer. This review aims to discuss the potential efficacy of targeting tumor cells through modulation of m6A RNA levels. Specifically, we discuss how the upregulation or downregulation of integral or specific targets is effective in treating different tumor types and patients. Additionally, we will cover the factors influencing the efficacy of m6A RNA targeting in tumor treatment. Our review will focus on the impact of targeting m6A mRNA on genes and cells and assess its potential as a therapeutic strategy for tumors. Despite the challenges involved, further research on m6A RNA in tumors and its integration with existing tumor therapy approaches is warranted.

Colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the application of anti-ferroptosis therapy. Through drug screening, it is found that histone deacetylase inhibitor (HDACi) significantly sensitized CRC to ferroptosis. The combination of HDACi and ferroptosis inducers synergically suppresses CRC growth both in vivo and in vitro. Mechanically, HDACi reduces ferroptosis suppressor protein (FSP1) by promoting its mRNA degradation. Specifically, it is confirmed that HDACi specifically targets HDAC1 and promotes the H3K27ac modification of fat mass- and obesity-associated gene (FTO) and AlkB Homolog 5, RNA Demethylase (ALKBH5), which results in significant activation of FTO and ALKBH5. The activation of FTO and ALKBH5 reduces N6-methyladenosine (m6A) modification on FSP1 mRNA, leading to its degradation. Crucially, lactylation of HDAC1K412 is essential for ferroptosis regulation. Both Vorinostat (SAHA) and Trichostatin A (TSA) notably diminish HDAC1K412 lactylation in comparison to other HDAC1 inhibitors, exhibiting a consistent trend of increasing susceptibility to ferroptosis. In conclusion, the research reveals that HDACi decreases HDAC1K412 lactylation to sensitize CRC to ferroptosis and that the combination of HDACi and ferroptosis inducers can be a promising therapeutic strategy for CRC.

RNA methylation and the machinery that regulates or "reads" its expression has recently been implicated in the pathogenesis of acute myeloid leukemia (AML) and other hematologic malignancies. Modulation of these epigenetic marks has started to become a reality as several companies around the world seek to leverage this knowledge therapeutically in the clinic. Although the bases of observed activity in AML have been described by numerous groups, the exact context in which these therapies will ultimately be used remains to be properly determined. While context is likely to be of great importance here, a more "global" mechanism of action might allow for more widespread applicability to multiple disease subtypes. In other areas such as the myelodysplastic and other preleukemic syndromes, data remain sparse. Ongoing work is needed to determine whether therapeutic modulation of RNA modifications is a viable and biologically plausible approach in these cases. Regardless of the outcomes, this is an exciting era for "epitranscriptomics" as we navigate a pathway forward. Here, I describe the current knowledge around RNA methylation and hematologic malignancies at the end of 2024 including some of the relevant questions that are yet to be answered.

Brain metastasis represents a significant challenge in oncology, driven by complex molecular and epigenetic mechanisms that distinguish it from primary tumors. While recent research has focused on identifying genomic mutation drivers with potential clinical utility, these strategies have not pinpointed specific genetic mutations responsible for site-specific metastasis to the brain. It is now clear that successful brain colonization by metastatic cancer cells requires intricate interactions with the brain tumor ecosystem and the acquisition of specialized molecular traits that facilitate their adaptation to this highly selective environment. This is best exemplified by widespread transcriptional adaptation during brain metastasis, resulting in aberrant gene programs that promote extravasation, seeding, and colonization of the brain. Increasing evidence suggests that epigenetic mechanisms play a significant role in shaping these pro-brain metastasis traits. This review explores dysregulated chromatin patterns driven by chromatin remodeling, histone modifications, DNA/RNA methylation, and other epigenetic regulators that underpin brain metastatic seeding, initiation, and outgrowth. We provide novel insights into how these epigenetic modifications arise within both the brain metastatic tumor and the surrounding brain metastatic tumor ecosystem. Finally, we discuss how the inherent plasticity and reversibility of the epigenomic landscape in brain metastases may offer new therapeutic opportunities.

B-cell lymphoma (BCL) is a hematological malignancy with high heterogeneity and represents an aggressive proliferation of mature B-cells. Despite the initial success of traditional treatments for BCL in clinical trials, a majority of patients eventually develop resistance to therapy and have poor clinical outcomes. Epigenetic dysregulation is a major contributor to the pathogenesis of BCL, and therapies targeting epigenetic pathways is a promising alternative strategy for treating BCL. Herein, we developed a metal-organic framework (MOF)-based nano-sonosensitizer for ultrasound-driven cascade immunotherapy against BCL. The nano-sonosensitizer was synthesized by encapsulating copper complex of the m6A-mRNA demethylase inhibitor into UiO-66-NH2, which possesses a Z-scheme heterostructure and allows efficient electron-hole pair separation for generating reactive oxygen species (ROS) under ultrasound activation. These CuR@UiO66 sonosensitizers were functionalized with mPEG-PO3 and anti-CD19 antibody, and the resulting CRUPPA19 particles could specifically accumulate in the BCL tissue and also target lymphoma cells that infiltrated into the bone marrow. Once internalized, CRUPPA19 could induce intracellular ROS production and apoptosis under ultrasound irradiation. Subsequently, ultrasonic stimulation triggered autophagy-mediated release of Cu and Rhein from CRUPPA19, thereby increasing protein lipoylation and global mRNA methylation, which led to cuproptosis and the transcriptional repression PDL1, respectively. These cascades synergistically induced immunogenic cell death in the tumors and promoted activation of CD8+ T cells, eventually leading to an antilymphoma immune response. CRUPPA19-mediated sono-immunotherapy not only eliminated the primary and metastatic lymphomas but also cleared lymphoma cells from the bone marrow. This study provided an insight into a MOF-based nanoepigenetic therapy platform with ultrasound-triggered cascade amplification for enhanced antihematological tumor immunity.

The tumor microenvironment plays a pivotal role in the metabolic reprogramming of cancer cells. A better understanding of the underlying mechanisms regulating cancer metabolism could help identify potential therapeutic targets. Here, we identified circEPB41(2) as a metabolically regulated circular RNA that mediates lipid metabolism in hepatocellular carcinoma (HCC). circEPB41(2) was induced in response to glucose deprivation via HNRNPA1-dependent alternative splicing. Upregulation of circEPB41(2) led to enhanced lipogenic gene expression that promoted lipogenesis. Mechanistically, circEPB41(2) cooperated with the N6-methyladenosine demethylase FTO to decrease the mRNA stability of the histone deacetylase sirtuin 6, thereby increasing histone H3 lysine 9 acetylation and histone H3 lysine 27 acetylation levels to activate lipogenic gene expression. Silencing of circEPB41(2) inhibited both in vitro proliferation of HCC cells and in vivo growth of tumor xenografts. Clinically, circEPB41(2) was elevated in HCC, and high circEPB41(2) expression was associated with poor patient prognosis. Overall, this study reveals that circEPB41(2) is an important regulator of lipid metabolic reprogramming and indicates that targeting the circEPB41(2)-FTO-sirtuin 6 axis could represent a promising anticancer strategy for treating HCC. Significance: circEPB41(2) is induced by glucose deprivation and mediates epigenetic alterations to drive lipogenesis and tumor growth in hepatocellular carcinoma, suggesting circEPB41(2) could be a potential therapeutic target in liver cancer.

Fat mass obesity-associated protein (FTO) has been emerging as a potential therapeutic target for drug discovery in RNA epigenetics. In this work, a series of novel FTO inhibitors featuring an acylhydrazone scaffold were identified, and the optimized compounds 8t-v showed potent FTO inhibitory activities with IC50 values ranging from 7.1 to 9.4 μM. FTO inhibitor 8t, as the lead compound, exhibited potent antiproliferative capacities against MOLM13, NB4, and THP-1 with IC50 values of 0.35, 0.59, and 0.70 μM, respectively, and remarkably induced NB4 cell apoptosis. Compound 8t also inhibited the FTO demethylation, enhanced the abundance of m6A, stabilized FTO protein folding, and regulated the oncogenic FTO signaling pathway. Importantly, compound 8t significantly caused a tumor volume reduction and tumor weight loss with a tumor growth inhibition (TGI) value of 51% in NB4 xenograft mice. Overall, our work provided valuable lead compounds for FTO inhibitors featuring an acylhydrazone scaffold with potent antileukemia activity both in vitro and in vivo.

Uveal melanoma (UM) is the most prevalent primary ocular malignancy in adults, with high lethality and limited effective treatment options. Despite identified driver mutations in GNAQ, GNA11, and BAP1, therapeutic advancements have been minimal. This study highlights the pivotal role of N6-methyladenosine (m6A) modifications in UM pathogenesis and progression, focusing on the demethylase FTO as a therapeutic target. Elevated FTO expression in UM tissues correlates with decreased m6A levels, increased aggressiveness, and poor prognosis. The FTO inhibitor meclofenamic acid (MA) restored m6A levels, upregulated SLC7A11, and induced disulfidptosis, a unique form of cell death triggered by GSH depletion and NADPH consumption. To address MA's limitations in bioavailability and tumor targeting, we developed an MA-loaded nucleic acid nanodrug (SNAMA). SNAMA demonstrated effective tumor growth inhibition in orthotopic and metastatic UM models through GSH-responsive release and m6A-mediated disulfidptosis activation. Incorporating a PD-L1 aptamer into SNAMA further improved tumor targeting and immune modulation, enhancing therapeutic efficacy. This study identifies FTO as a critical target for UM therapy and introduces SNAMA-apt as a promising nanodrug. The findings offer a foundation for m6A-targeted approaches in UM and other malignancies, addressing bioavailability, targeting, and immune evasion challenges.

Immunosuppression significantly contributes to treatment failure in nasopharyngeal carcinoma (NPC). Messenger RNA (mRNA) modifications such as methylation and acetylation play crucial roles in immunosuppression. However, N4-acetylcytidine (ac4C), the only acetylation modification event has rarely been studied in NPC.

First, clinical tissue samples and nude mouse models were used to explore the expression of N-acetyltransferase 10 (NAT10) in NPC and its influence on it. Second, The Cancer Genome Atlas immune database and transgenic mouse peripheral blood immune cell panel were used to verify the immune cells mainly affected by NAT10. Then, NAT10 ac4C acetylation modification and expression of significantly upregulated transcription factors were explored by acetylated RNA immunoprecipitation sequence binding to RNA sequencing. Then, the downstream regulatory genes of CCAAT enhancer binding protein γ (CEBPG), dead box helicase 5 (DDX5) and helicase-like transcription factors (HLTF) were analyzed by luciferase report and chromatin Immunoprecipitation. Finally, the effect of inhibition of NAT10 on anti-programmed cell death protein 1 (PD-1) treatment sensitivity was verified by animal models.

In this study, we aimed to explore the role of NAT10, the enzyme responsible for ac4C modification, in NPC progression and patient prognosis. Elevated NAT10 promoted NPC progression and correlated with poor prognosis in patients with NPC. NAT10-mediated ac4C modification of CEBPG, DDX5, and HLTF mRNA improved their stability and translation efficiency, with the NAT10/ac4C/DDX5 axis upregulating high mobility group box 1 (HMGB1) and inhibiting CD4+ and CD8+ T cells. Inhibition of NAT10 increased the sensitivity to PD-1 therapy. Additionally, HLTF was found to transcriptionally regulate NAT10, indicating the formation of an HLTF-NAT10 positive feedback loop.

Our study elucidates the mechanism by which the NAT10/DDX5/HMGB1 axis promotes the immunosuppression of NPC by promoting T-cell dysfunction. In addition, NAT10 knockdown can enhance anti-PD-1 treatment sensitivity as a combination therapy for NPC.

D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in breast cancer remains largely unexplored.

We applied an advanced biosensor approach to detect the D-2HG levels in breast cancer samples. We then investigated the biological functions of D-2HG through multiple in vitro and in vivo assays. A joint MeRIP-seq and RNA-seq strategy was used to identify the target genes regulated by D-2HG-mediated N6-methyladenosine (m6A) modification. RNA pull-down assays were further applied to identify the reader that could specifically recognize the m6A modification on angiopoietin like 4 (ANGPTL4) mRNA and RNA immunoprecipitation was used to confirm the findings.

We found that D-2HG accumulated in triple-negative breast cancer (TNBC), exerting oncogenic effects both in vitro and in vivo by promoting TNBC cell growth and metastasis. Mechanistically, D-2HG enhanced global m6A RNA modifications in TNBC cells, notably upregulating m6A modification on ANGPTL4 mRNA, which was mediated by the inhibition of Fat-mass and obesity-associated protein (FTO), resulting in increased recognition of m6A-modified ANGPTL4 by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), thereby promoting the enhanced translation of ANGPTL4. As a secretory protein, ANGPTL4 subsequently activated the integrin-mediated JAK2/STAT3 signaling cascade in TNBC cells through autocrine signaling. Notably, the knockdown of ANGPTL4 or treatment with GLPG1087 (an integrin antagonist) significantly reduced D-2HG-induced proliferation and metastasis in TNBC cells. Additionally, ANGPTL4 was found to promote macrophage M2 polarization within the tumor microenvironment via paracrine signaling, further driving TNBC progression. The association of ANGPTL4 with poor prognosis in TNBC patients underscores its clinical relevance.

Our study unveils a previously unrecognized role for D-2HG-mediated RNA modification in TNBC progression and targeting the D-2HG/FTO/m6A/ANGPTL4/integrin axis can serve as a promising therapeutic target for TNBC patients.

RNA modifications, a central aspect of epitranscriptomics, add a regulatory layer to gene expression by modifying RNA function without altering nucleotide sequences. These modifications play vital roles across RNA species, influencing RNA stability, translation, and interaction dynamics, and are regulated by specific enzymes that add, remove, and interpret these chemical marks.

This review examines the role of aberrant RNA modifications in cancer progression, exploring their potential as diagnostic and prognostic biomarkers and as therapeutic targets. We focus on how altered RNA modification patterns impact oncogenes, tumor suppressor genes, and overall tumor behavior.

We performed an in-depth analysis of recent studies and advances in RNA modification research, highlighting key types and functions of RNA modifications and their roles in cancer biology. Studies involving preclinical models targeting RNA-modifying enzymes were reviewed to assess therapeutic efficacy and potential clinical applications.

Aberrant RNA modifications were found to significantly influence cancer initiation, growth, and metastasis. Dysregulation of RNA-modifying enzymes led to altered gene expression profiles in oncogenes and tumor suppressors, correlating with tumor aggressiveness, patient outcomes, and response to immunotherapy. Notably, inhibitors of these enzymes demonstrated potential in preclinical models by reducing tumor growth and enhancing the efficacy of existing cancer treatments.

RNA modifications present promising avenues for cancer diagnosis, prognosis, and therapy. Understanding the mechanisms of RNA modification dysregulation is essential for developing targeted treatments that improve patient outcomes. Further research will deepen insights into these pathways and support the clinical translation of RNA modification-targeted therapies.

Osteosarcoma (OS) is the most commonly diagnosed primary malignant bone tumor in children and adolescents. Despite significant advancements in therapeutic strategies against OS over the past few decades, the prognosis for this disease remains poor, largely due to its high invasiveness and challenges associated with its treatment. N6-methyladenosine (m6A) modification is one of the most abundant epigenetic modifications of RNAs, and many studies have highlighted its crucial role in OS. This article provides a comprehensive summary and introduction to m6A regulators, including methyltransferases, demethylases, and binding proteins. The article emphasizes how regulated m6A modifications can either promote or inhibit OS. It also delves into the mechanisms by which m6A-modified messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs) participate in signaling pathways such as the Wnt/β-catenin, PI3K/AKT, and STAT3 pathways, and discusses these mechanisms in detail. Given the abnormal expression of m6A regulators in OS, the article also explores their potential applications as biomarkers or therapeutic targets in clinical settings. It is anticipated that this review will provide new insights into the diagnosis and treatment of OS.

Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca2+) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca2+ homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca2+ regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. The Fat mass and obesity-associated protein (FTO), a genetic variant associated with obesity, significantly impact the energetic metabolism of mechanical tumors. However, research on the function of FTO in CRC is scarce.

Bioinformatics analysis of TCGA and UALCAN databases was conducted to examine FTO expression in CRC. Immunohistochemistry was used to assess FTO and PKM2 protein expression in clinical specimens. In vitro experiments utilized five human colon cancer cell lines and a normal colon epithelial cell line, with Western blotting and RT-PCR for protein and mRNA quantification, respectively, and lentiviral transfection to modulate FTO expression. Cellular behaviors such as proliferation, migration, invasion, and apoptosis were evaluated using various assays. Immunofluorescence and Seahorse Xfe96 metabolic analysis were employed to study PKM2 expression changes and glycolytic stress. The effects of PKM2 inhibition by shikonin on cell viability and glycolytic activity were assessed using CCK-8 assay and Seahorse analysis.

An upregulation of FTO was observed in colon cancer through data mining and analysis of pathological specimens. Besides, we discovered that the impact of FTO on colon cancer glycolysis has significant implications for colon proliferation, invasion, and metastasis. The protein expression of PKM2 and the intensity of fluorescence staining in the nucleus of PKM2 were detected to be increased in colon carcinoma cells with over-expression of FTO.

FTO plays a significant role in CRC progression by regulating PKM2 and promoting glycolysis.

Objective: Despite N6-methyladenosine (m6A) being closely involved in various pathophysiological processes, its potential role in liver injury is largely unknown. We designed the current research to study the potential role of fat mass and obesity-associated protein (FTO), an m6A demethylase, on hepatic ischemia-reperfusion injury (IRI). Methods: Wild-type mice injected with an adeno-associated virus carrying fat mass and obesity-associated protein (AAV-FTO) or adeno-associated virus carrying green fluorescent protein (GFP) (AAV-GFP) were subjected to a hepatic IRI model in vivo. Hematoxylin-eosin staining was performed to observe IRI. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to observe the cell apoptosis. Reverse transcription polymerase chain reaction (RT-PCR) was used to observe the expression of FTO. The protein levels of FTO, apoptosis, or autophagy-associated signaling proteins were detected by western blot. Reactive oxygen species (ROS) levels were determined by flow cytometry, and immunohistochemistry was used to detect the FTO and LC3-II expression. For in vitro experiments, cultured hepatocytes were subjected to hypoxia/reoxygenation (H/R) stimulation. Monodansylcadaverine (MDC) staining was used to visualize autophagic vesicles. Results: In the present study, we showed that FTO was involved in hepatic IRI, apoptosis, and autophagy. Specifically, the expression level of FTO was significantly reduced in the hepatic IRI. Besides, increasing FTO expression (AAV-FTO) ameliorated the hepatic IRI in animal models, accompanied by decreased apoptosis and autophagy. Furthermore, the FTO inhibitor (FB23-2) aggravated autophagy in hepatocytes upon H/R-induced damage. Conclusion: FTO could act as a protective effector during hepatic IRI, associated with decreased apoptosis and autophagy. FTO-mediated m6A demethylation modification may be an important therapeutic target for hepatic IRI.

Osteoporosis, recognised as a metabolic disorder, has emerged as a significant burden on global health. Although available treatments have made considerable advancements, they remain inadequately addressed. In recent years, the role of epigenetic mechanisms in skeletal disorders has garnered substantial attention, particularly concerning m6A RNA modification. m6A is the most prevalent dynamic and reversible modification in eukaryotes, mediating various metabolic processes of mRNAs, including splicing, structural conversion, translation, translocation and degradation and serves as a crucial component of epigenetic modification. Research has increasingly validated that m6A plays a vital role in the proliferation, differentiation, migration, invasion,and repair of bone marrow mesenchymal stem cells (BMSCs), osteoblasts and osteoclasts, all of which impact the whole process of osteoporosis pathogenesis. Continuous efforts have been made to target m6A regulators and natural products derived from traditional medicine, which exhibit multiple biological activities such as anti-inflammatory and anticancer effects, have emerged as a valuable resources for m6A drug discovery. This paper elaborates on m6A methylation and its regulatory role in osteoporosis, emphasising its implications for diagnosis and treatment, thereby providing theoretical references.

Hepatocellular carcinoma (HCC) is a lethal malignancy characterized by rapid growth. The interaction between tumor cells and cancer-associated fibroblasts (CAFs) significantly influences HCC progression. CCL15, a CC chemokine family member, is predominantly expressed in HCC and strongly correlates with tumor size, indicating its critical role in HCC growth. However, previous studies suggest that CCL15 does not directly stimulate cancer cell proliferation. The specific role and mechanism of CCL15 in HCC proliferation remain unknown. Here, we identified that CCL15 was predominantly overexpressed by HCC cells through single-cell RNA sequencing data and immunofluorescence. We discovered that CCL15 promotes HCC growth by stimulating the crosstalk between HCC cells and CAFs via CCR1 signaling, as evidenced by co-culture assays, organoid models, and allograft models. Mechanistically, CCL15 induced the expression of FTO in CAFs through the STAT3 pathway. By m6A sequencing and RNA sequencing, we found that CEBPA mRNA, a transcription factor regulating CXCL5 expression, was a target of FTO. CXCL5, secreted by CAFs, activated the CXCR2 receptor on HCC cells and enhanced their proliferation. Notably, we found that interfering with CCL15 signaling using a neutralizing antibody attenuated HCC growth in heterotypic co-injection and patient-derived xenograft murine models. Finally, CXCL5 also upregulated CCL15 expression in HCC cells by modulating P53 expression through MDM2, forming a positive feedback loop. Our study unveiled CCL15 as a key mediator in HCC progression, facilitating communication between HCC cells and CAFs. This highlights a novel regulatory axis in HCC and suggests that targeting CCL15 could be a potential therapeutic strategy.

N6-methyladenosine is one of the most common and reversible post-transcriptional modifications in eukaryotes, and it is involved in alternative splicing and RNA transcription, degradation, and translation. It is well known that cancer cells acquire energy through metabolic reprogramming to exhibit various biological behaviors. Moreover, numerous studies have demonstrated that m6A induces cancer metabolic reprogramming by regulating the expression of core metabolic genes or by activating metabolic signaling pathways. Meanwhile, m6A modifications and related regulators are key targets in the regulation of immune effects. We further summarize how m6A modifications contribute to tumor metabolism, and how these events affect the tumor immune microenvironment, with a specific focus on different cell types. Finally, we focus on the specific applications of this field to tumor immunotherapy. We review the potential role of m6A in metabolic reprogramming of tumor immune microenvironment and its regulatory mechanism, with the aim of providing new targets for tumor metabolic regulation and immunotherapy.

Genetic mutations arising from various internal and external factors drive cells to become cancerous. Cancerous cells undergo numerous changes, including metabolic reprogramming and epigenetic modifications, to support their abnormal proliferation. This metabolic reprogramming leads to the altered expression of many metabolic enzymes and the accumulation of metabolites. Recent studies have shown that these enzymes and metabolites can serve as substrates or cofactors for chromatin-modifying enzymes, thereby participating in epigenetic modifications and promoting carcinogenesis. Additionally, epigenetic modifications play a role in the metabolic reprogramming and immune evasion of cancer cells, influencing cancer progression. This review focuses on the origins of cancer, particularly the metabolic reprogramming of cancer cells and changes in epigenetic modifications. We discuss how metabolites in cancer cells contribute to epigenetic remodeling, including lactylation, acetylation, succinylation, and crotonylation. Finally, we review the impact of epigenetic modifications on tumor immunity and the latest advancements in cancer therapies targeting these modifications.

While therapeutic strategies targeting epigenetic dysregulation hold promise for leukemia, epigenetic drugs face several limitations, including low utilization rates, the emergence of resistance, and off-target effects. The hypoxic microenvironment in leukemia further impairs drug sensitivity. Here, we synthesized an MOF-based erythrocyte biomimetic nanoplatform to enhance immune responses against leukemia by targeting three epigenetic modifications. UiO-66-NH2 was loaded with two epigenetic drugs, along with oxygen-rich erythrocytes (red blood cells, RBCs). MA272@MOF@RBC suppressed hypoxia-induced factor (HIF-1α) and its downstream oncogenes, thereby enhancing the efficacy of the epigenetic drugs. The drugs inhibited the growth of leukemia cells by targeting DNA and histone methylation while enhancing m6A-RNA methylation. MA272@MOF@RBC activated cytotoxic and memory T cells by increasing the antigenicity of leukemia cells. MA272@MOF@RBC also demonstrated immunotherapeutic effects on solid tumors. This was the first study to report the synthesis of triple epigenetic regulatory biomimetic MOFs with significant clinical potential for tumor immunotherapy.

Long non-coding RNAs (lncRNAs) and RNA N6-methyladenosine (m6A) have been linked to leukemia drug resistance. However, whether and how lncRNAs and m6A coordinately regulate resistance remain elusive. Here, we show that many differentially expressed lncRNAs enrich m6A, and more lncRNAs tend to have higher m6A content in CML cells resistant to tyrosine kinase inhibitors (TKIs). We demonstrate broad clinical relevance of our findings, showing that upregulation of top-ranked lncRNAs (e.g., SENCR, PROX1-AS1, LN892) in TKI resistant cell lines occurs in CML patients at the diagnostic stage, blast crisis phase or not-responding to TKIs compared to chronic phase or TKI responders, respectively. Higher lncRNAs predict drug resistance and shorter survival duration. Knockdown of SENCR, PROX1-AS1 or LN892 restores TKI sensitivity. Mechanistically, upregulation of PROX1-AS1, SENCR and LN892 results from FTO-dependent m6A hypomethylation that stabilizes lncRNA transcripts, and empowers resistant cell growth through overexpression of PI3K signaling mediators (e.g., ITGA2, F2R, COL6A1). Treatment with PI3K inhibitor alpelisib eradicates resistant cells in vitro and in vivo with prolonged survival of leukemic mice through downregulation of F2R, ITGA2 and COL6A1. Thus, the lncRNA-m6A-PI3K cascade represents a new non-genetic predictor for drug resistance and poorer prognosis in cancer, and a pan-cancer mechanism underlying TKI resistance.

Cellular context profiling of modification effector proteins is critical for an in-depth understanding of their biological roles in RNA N6-methyladenosine (m6A) modification regulation and function. However, challenges still remain due to the high context complexities, which call for a versatile toolbox for accurate live-cell monitoring of effectors. Here, we propose a demethylation-switchable aptamer sensor engineered with a site-specific m6A (DSA-m6A) for lag-free monitoring of the m6A demethylase FTO activity in living cells. As a proof of concept, a DNA aptamer against adenosine triphosphate (ATP) is selected to construct the DSA-m6A model, as the "universal energy currency" role of ATP could guarantee the equally fast and spontaneous conformation change of DSA-m6A sensor upon demethylation and ATP binding in living organisms, thus enabling sensitive monitoring of FTO activity with neither time delay nor recourse to extra supply of substances. This ATP-driven DSA-m6A design facilitates biomedical research, including live-cell imaging, inhibitor screening, single-cell tracking of dynamic FTO nuclear translocation upon starvation stimuli, FTO characterization in a biomimetic heterotypic three-dimensional (3D) multicellular spheroid model, as well as the first report on the in vivo imaging of FTO activity. This strategy provides a simple yet versatile toolbox for clinical diagnosis, drug discovery, therapeutic evaluation, and biological study of RNA demethylation.

Here, we show that vitamin E succinate (VES) acts as a degrader for the m6A RNA demethylase fat mass and obesity-associated protein (FTO), thus suppressing tumor growth and resistance to immunotherapy. FTO is ubiquitinated by its E3 ligase DTX2, followed by UFD1 recruitment and subsequent degradation in the proteasome. VES binds to FTO and DTX2, leading to enhanced FTO-DTX2 interaction, FTO ubiquitination, and degradation in FTO-dependent tumor cells. VES suppressed tumor growth and enhanced antitumor immunity and response to immunotherapy in vivo in mouse models. Genetic FTO knockdown or VES treatment increased m6A methylation in the LIF (Leukemia Inhibitory Factor) gene and decreased LIF mRNA decay, and thus sensitized melanoma cells to T cell-mediated cytotoxicity. Taken together, our findings reveal the underlying molecular mechanism for FTO protein degradation and identify a dietary degrader for FTO that inhibits tumor growth and overcomes immunotherapy resistance.

Significant advances in the development of new cancer therapies have given rise to multiple novel therapeutic options in chemotherapy, radiotherapy, immunotherapy, and targeted therapies. Although the development of resistance is often reported along with temporary disease remission, there is often tumor recurrence of an even more aggressive nature. Resistance to currently available anticancer drugs results in poor overall and disease-free survival rates for cancer patients. There are multiple mechanisms through which tumor cells develop resistance to therapeutic agents. To date, efforts to overcome resistance have only achieved limited success. Epitranscriptomics, especially related to m6A RNA modification dysregulation in cancer, is an emerging mechanism for cancer therapy resistance. Here, recent studies regarding the contributions of m6A modification and its regulatory proteins to the development of resistance to different cancer therapies are comprehensively reviewed. The promise and potential limitations of targeting these entities to overcome resistance to various anticancer therapies are also discussed.