Bone remodeling imbalance contributes to osteoporosis. Though current medications enhance osteoblast involvement in bone formation, the underlying pathways remain unclear. This study was aimed to explore the pathways involved in bone formation by osteoblasts, we investigate the protective role of glycolysis and N6-methyladenosine methylation (m6A) against oxidative stress-induced impairment of osteogenesis in MC3T3-E1 cells.

We utilized a concentration of 200 μM hydrogen peroxide (H2O2) to establish an oxidative damage model of MC3T3-E1 cells. Subsequently, we examined the alterations in the m6A methyltransferases (METTL3, METTL14), glucose transporter proteins (GLUT1, GLUT3) and validated m6A methyltransferase overexpression in vitro and in an osteoporosis model. The osteoblast differentiation and osteogenesis-related molecules and serum bone resorption markers were measured by biochemical analysis, Alizarin Red S staining, Western blot and ELISA.

H2O2 treatment inhibited glycolysis and osteoblast differentiation in MC3T3-E1 cells. However, when METTL14 was overexpressed, these changes induced by H2O2 could be mitigated. Our findings indicate that METTL14 promotes GLUT3 expression via YTHDF1, leading to the modulation of various parameters in the H2O2-induced model. Similar positive effects of METTL14 on osteogenesis were observed in an ovariectomized mouse osteoporosis model.

METTL14 could serve as a potential therapeutic approach for enhancing osteoporosis treatment.

Hepatic stellate cell (HSC) activation is crucial in the onset and progression of liver fibrosis, and inhibiting or eliminating activated HSCs is a key therapeutic strategy. Ferroptosis may help eliminate activated HSCs; however, its role and regulatory pathways in liver fibrosis remain unclear. As a DNA demethylase, TET3 regulates gene expression via DNA demethylation. We previously demonstrated that TET3 overexpression alleviates CCL4-induced liver fibrosis in mice; however, the specific mechanisms, including whether TET3 affects ferroptosis in HSCs, remain unexplored. Thus, we aimed to explore the molecular mechanisms wherein TET3 overexpression improves liver fibrosis in mice via ferroptosis in HSCs. Our in vivo observations showed that overexpression of TET3 ameliorate liver fibrosis in mice, and is associated with increased levels of malondialdehyde (MDA) and Fe2+ in liver tissue, as well as decreased protein expression of SLC7A11, GPX4, and FTH1. Further in vitro studies on HSCs showed that TET3 overexpression inhibits the expression of SLC7A11, GPX4, and FTH1, and reduces intracellular GSH levels, leading to accumulation of MDA and iron ions. This induces ferroptosis in HSC-LX2 cells, while simultaneously decreasing ECM accumulation in HSCs. Furthermore, hMeDIP-SEQ and ChIP-qPCR analyses revealed that TET3 directly interacts with the promoter regions of GPX4 and FTH1 to regulate their transcriptional expression. We propose that overexpression of TET3 modulates the gene methylation status of ferroptosis-related proteins, thereby regulating HSC ferroptosis, reducing activated HSCs, and decreasing ECM deposition in the liver. This may represent one of the molecular mechanisms wherein TET3 overexpression ameliorates liver fibrosis in mice.

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

Oxysterols, gut metabolites, and N6-methyladenosine (m6A) are extensively implicated in the pathogenesis of cognitive dysfunction, while their alterations in different stages of mild cognitive impairment (MCI) have not been elucidated. Therefore, this study was conducted to explore the associations of oxysterols, gut metabolites, and m6A methylation profiles in early MCI (EMCI) and late MCI (LMCI) individuals.

Liquid chromatography-mass spectrometry, untargeted metabolomic analysis, and m6A mRNA Epitranscriptomic Microarray were used to detect the characteristics of serum oxysterols (n = 35/group), fecal gut metabolites (n = 30/group), and m6A in whole blood (n = 4/group) respectively. The concentration of serum β-amyloid (Aβ) was detected with ELISA (n = 25/group). The gene expression of amyloid precursor protein (APP) and its key enzyme β-secretase (BACE1) in whole blood were measured by quantitative real-time PCR (n = 25/group).

EMCIs and LMCIs, especially LMCIs, exhibited poorer performance in almost all global and multidimensional cognitive tests. Serum 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) were elevated in EMCI and LMCI groups. Changes in gut metabolites occurred mainly in the EMCI group, in which several gut metabolites, including Procyanidin dimer B7 and Phorbol myristate, were significantly decreased. The m6A methylation landscape of EMCIs and LMCIs obviously differed from Controls. Hypomethylated mRNAs accounted for the majority and were mainly accompanied by downregulated mRNAs, which was consistent with the downregulated expression of the m6A writer methyltransferase-like 4 (METTL4). 27-OHC and 24S-OHC combined with various gut metabolites significantly distinguished between MCI subgroups from healthy controls (EMCI/Control: AUC = 0.877; LMCI/Control: AUC = 0.952). Heatmap revealed the correlation between Phorbol myristate and differentially m6A-methylated mRNAs. Differentially expressed gut metabolites and methylated mRNAs were commonly enriched in 34 KEGG metabolic pathways, including cholesterol metabolism and neurodegenerative disease-related pathways.

Our study explored the altered oxysterols, gut metabolites, and m6A methylation and their associations in different stages of MCI. The potential function of aberrant gut metabolites in oxysterols and m6A methylation driving MCI progression warrants further mechanistic investigation.

Liver fibrosis is pathologically associated with ferroptosis. Osthole (OST) has good therapeutic effects on liver fibrosis. Our study sought to investigate the pharmacological effects of OST on ferroptosis in hepatic stellate cells (HSCs) during the development of liver fibrosis and define the mechanisms involved. The in vivo model of liver fibrosis was established by CCl4 treatment. MTT and EDU assays were used to assess cell viability and proliferation, respectively. The interaction between myocyte enhancer factor 2A (MEF2A) and Y-box binding protein 1 (YBX1) was analyzed by dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays. OST treatment alleviated CCl4-induced liver fibrosis in mice by activating ferroptosis. OST induced ferroptosis in HSCs and inhibited the activation of HSCs in vitro, while these effects of OST were reversed by MEF2A overexpression or YBX1 overexpression. Mechanistically, MEF2A activated the Wnt/β-catenin signaling by transcriptionally facilitating YBX1 expression. As expected, the inactivation of Wnt/β-catenin signaling or YBX1 knockdown could reverse the regulatory effect of MEF2A upregulation on the activation of HSCs and ferroptosis in OST-treated HSCs. OST mitigated liver fibrosis by inducing ferroptosis in HSCs and repressing the activation of HSCs through inhibiting the MEF2A/YBX1/Wnt/β-catenin axis.

Pneumonia is a major cause of mortality and health burden in children under five, yet its genetic etiology remains poorly understood. Methyltransferase 4, N6-adenosine (METTL4), is a methyltransferase enzyme responsible for RNA and DNA methylation and is known to be activated under hypoxic conditions. However, its potential link to susceptibility to pneumonia has not been evaluated. This study aimed to explore candidate regulatory single nucleotide polymorphisms (SNPs) within the METTL4 gene and their association with the development of severe pneumonia.

In this study, we recruited a cohort of 1034 children with severe pneumonia and 8426 healthy controls. We investigated the associations of candidate regulatory single nucleotide polymorphisms (SNPs) within METTL4 polymorphisms with severe pneumonia. Our results indicated that the C allele of rs9989554 (P = 0.00023, OR = 1.21, 95% CI: 1.09-1.34) and the G allele of rs16943442 (P = 0.0026, OR = 1.22, 95% CI: 1.07-1.38) were significantly associated with an increased risk of severe pneumonia. The regulatory potential of these two SNPs in the lung was investigated using tools such as expression quantitative trait loci (eQTLs), RegulomeDB, and FORGEdb.

This study represents the first investigation elucidating the role of genetic variations in the METTL4 gene and their influence on susceptibility to severe pneumonia in pediatric populations. METTL4 is identified as a novel predisposing gene for severe pneumonia and a potential therapeutic target. Further research is warranted to validate this correlation and to comprehensively elucidate the biological role of the METTL4 gene in severe pneumonia.

As the major driving factor of hepatic fibrosis, the activated hepatic stellate cells (aHSCs) rely on active glycolysis to support their aberrant proliferation and secretion of the extracellular matrix. Sorafenib (Sor) can combat liver fibrosis by suppressing HIF-1α and glycolysis, but its poor solubility, rapid metabolism, and low bioavailability restrict such a clinical application. Here, Sor was loaded onto polydopamine nanoparticles and then encapsulated by a retinoid-decorated red blood cell membrane, yielding HSC-targeted Sor nanovesicles (PDA/Sor@RMV-VA) with a high Sor-loading capacity and photothermally controlled drug release for antifibrotic treatment. These Sor RMVs not only exhibited a good particle size, dispersity and biocompatibility, prolonged circulation time, enhanced aHSC targetability, and hepatic accumulation both in vitro and in vivo, but also displayed a mild photothermal activity proper for promoting sorafenib release and accumulation in CCl4-induced fibrotic mouse livers without incurring phototoxicity. Compared with nontargeting Sor formulations, PDA/Sor@RMV-VA more effectively downregulated HIF-1α and glycolytic enzyme in both cultured aHSCs and fibrotic mice and reversed myofibroblast phenotype and amplification of aHSCs and thus more significantly improved liver damage, inflammation, and fibrosis, all of which could be even further advanced with NIR irradiation. These results fully demonstrate the antifibrotic power and therapeutic potential of PDA/Sor@RMV-VA as an antifibrotic nanomedicine, which would support a new clinical treatment for hepatic fibrosis.

Hepatic fibrosis (HF) is an intermediate stage in the progression of chronic liver disease to cirrhosis and has been shown to be a reversible pathological process. Known evidence suggests that activation of hepatic stellate cells (HSCs) and degradation of their lipid droplets (LDs) play an indispensable role in the process of HF. Jiawei Taohe Chengqi Decoction (JTCD) can inhibit the activation of HSCs in the process of HF, but the exact mechanism remains to be elucidated.

The aim of this study is to determine whether JTCD inhibits lipophagy and to explore the possible mechanisms of its HF effect in HSCs by regulating the PPARα/TFEB axis.

Network pharmacology and molecular docking were firstly applied to predict the potential mechanism of JTCD for the treatment of HF. In vivo, a mouse model of HF was constructed using carbon tetrachloride (CCl4) solution, and the efficacy of JTCD was assessed by staining of pathological sections, oil red O staining, immunofluorescence (IF), immunohistochemistry (IHC) staining, Western blotting and qRT-PCR. The intervention of JTCD was verified in vitro by induction of activated LX-2 cells with TGF-β solution and intervention using agonists and antagonists of PPARα. Finally, transient transfection of cells using TFEB siRNA was performed for validation studies.

JTCD effectively alleviated CCl4-induced HF in mice and reduced the levels of HF markers α-smooth muscle actin (α-SMA) and collagen I (COL1A1), and inhibited PPARα expression and lipophagy process. In vitro, JTCD delayed the degradation of LDs and reduced lipophagy in LX-2 cells, suggesting a mechanism involving PPARα/TFEB axis signaling regulation.

Liver fibrosis, a pivotal stage in chronic liver disease progression, is driven by hepatic stellate cell (HSC) activation. Ferroptosis is a novel form of programmed cell death, which offers therapeutic potential for liver fibrosis. Although artemether (ART) exhibits antifibrotic properties, its mechanisms in liver fibrosis remain unclear. This study aimed to determine the therapeutic effects of ART on liver fibrosis and explore the role of S-palmitoylation in HSC ferroptosis.

A mouse model of liver fibrosis was constructed by carbon tetrachloride (CCl4) injection. Transforming growth factor-β (TGF-β) was used for stimulating HSC activation in vitro. Histopathological and serological assays were performed to analyze the therapy effects of ART. Liquid Chromatography/Mass Spectrometry (LC/MS) and acyl-biotinyl exchange (ABE) were used to determine the role of S-palmitoylation in ART-induced HSC ferroptosis. Western blot and Co-Immunoprecipitation (Co-IP) were performed to examine the effects of autophagy in ART-induced HSC ferroptosis through regulating BECN1 S-palmitoylation.

ART ameliorated liver fibrosis by inducing HSC ferroptosis, and the ferroptosis inhibitor ferrostatin-1 (Fer-1) impaired the inhibitory effect of ART. Interestingly, the levels of S-palmitoylation were elevated by upregulating the palmitoyltransferase DHHC12 during ART-induced HSC ferroptosis. DHHC12 knockdown reduced S-palmitoylation levels and impaired ART-mediated HSC ferroptosis. RNA-seq analysis indicated that autophagy activation was essential for ART to induce HSC ferroptosis. 3-methyladenine (3-MA) suppressed autophagy and ART-induced HSC ferroptosis. Importantly, BECN1 S-palmitoylation by DHHC12 drove ART to activate autophagy. DHHC12 bound to the cysteine 21 residue of BECN1, thereby stabilizing the BECN1 protein and facilitating autophagy activation. Mutation of the cysteine 21 residue decreased BECN1 protein stability, autophagy activation and ferroptosis in ART-treated HSCs. In a mouse model of hepatic fibrosis, HSC-specific inhibition of BECN1 S-palmitoylation reversed ART-induced HSC ferroptosis and the improvement of fibrotic liver.

ART alleviates liver fibrosis by inducing HSC ferroptosis via DHHC12-mediated BECN1 protein S-palmitoylation.

Autophagy is a lysosome-dependent degradation pathway for recycling intracellular materials and removing damaged organelles, and it is usually considered a prosurvival process in response to stress stimuli. However, increasing evidence suggests that autophagy can also drive cell death in a context-dependent manner. The bulk degradation of cell contents and the accumulation of autophagosomes are recognized as the mechanisms of cell death induced by autophagy alone. However, autophagy can also drive other forms of regulated cell death (RCD) whose mechanisms are not related to excessive autophagic vacuolization. Notably, few reviews address studies on the transformation from autophagy to RCD, and the underlying molecular mechanisms are still vague.

This review aims to summarize the existing studies on autophagy-mediated RCD, to elucidate the mechanism by which autophagy initiates RCD, and to comprehensively understand the role of autophagy in determining cell fate.

This review highlights the prodeath effect of autophagy, which is distinct from the generally perceived cytoprotective role, and its mechanisms are mainly associated with the selective degradation of proteins or organelles essential for cell survival and the direct involvement of the autophagy machinery in cell death. Additionally, this review highlights the need for better manipulation of autophagy activation or inhibition in different pathological contexts, depending on clinical purpose.

Sorafenib resistance is a significant hurdle in the treatment landscape of hepatocellular carcinoma (HCC). Lipocalin 2 (LCN2), a secretory glycoprotein that transports lipophilic molecules across cell membranes, is thought to affect the s therapeutic efficacy of sorafenib. Despite its importance, the detailed regulatory pathways involving LCN2 are still being deciphered. We probed the correlation between LCN2 expression and sorafenib resistance in HCC cells. Through the modulation of LCN2 levels, we investigated its role in cell proliferation, apoptosis, and its regulatory effects on autophagy-driven ferroptosis. With the aid of hTFtarget and JASPAR databases, ESR1 was pinpointed as a transcriptional inhibitor of LCN2. The impact of the ESR1-LCN2 axis on sorafenib resistance in HCC was then examined in vitro and validated in a xenograft tumor mouse model. In HCC cells, elevated LCN2 levels were found to be associated with resistance to sorafenib. Depletion of LCN2 resulted in attenuated HCC cell growth and elevated rates of apoptosis and ferroptosis. Overexpression of LCN2 had the opposite effect, promoting cell proliferation and suppressing cell death pathways, a response that could be overridden by autophagy agonists. ESR1 suppressed LCN2 transcription, which in turn activated autophagy-mediated ferroptosis, mitigating sorafenib tolerance in HCC and enhancing the therapeutic index. ESR1 targets LCN2 transcription to initiate autophagy-driven ferroptosis, thereby reducing sorafenib resistance in HCC cells.

Metastasis is a major determinant of prognosis in gastric cancer (GC), and microRNAs (miRNAs) play crucial roles in driving the metastatic process. This study aimed to identify key miRNAs involved in GC metastasis and elucidate their underlying mechanisms. GC tissues from patients with and without metastasis were subjected to miRNA sequencing to identify differentially expressed miRNAs. Expression differences between GC and normal tissues, as well as their correlation with patient survival, were analyzed using data from The Cancer Genome Atlas and an internal cohort. miR-378d expression was measured by RT-qPCR in the internal cohort, and its association with clinicopathological features and prognosis was analyzed. Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential mechanisms by which miR-378d influences GC metastasis. The findings were validated through in vitro wound healing, transwell assays, western blotting, and immunofluorescence, as well as in vivo models. MiRNA sequencing identified miR-378d as significantly downregulated in GC tissues and associated with poor prognosis. GSEA showed that miR-378d was negatively correlated with epithelial-mesenchymal transition (EMT). In vitro and in vivo experiments demonstrated that upregulation of miR-378d inhibited GC cell migration and invasion. Mechanistically, miR-378d suppressed EMT by downregulating METTL4 expression. miR-378d inhibits GC metastasis by suppressing EMT through the downregulation of METTL4, offering novel insights into the role of miRNAs in GC progression and highlighting potential therapeutic targets for intervention.

Immunotherapy holds notable progress in the treatment of cancer. However, the clinical therapeutic effect remains a significant challenge due to immune-related side effects, poor immunogenicity, and immunosuppressive microenvironment. Nanoparticles have emerged as a revolutionary tool to surmount these obstacles and amplify the potency of immunotherapeutic agents. Prussian blue nanoparticles (PBNPs) exhibit multi-dimensional immune function in cancer immunotherapy, including acting as a nanocarrier to deliver immunotherapeutic agents, as a photothermal agent to improve the efficacy of immunotherapy through photothermal therapy, as a nanozyme to regulate tumor microenvironment, and as an iron donor to induce immune events related to ferroptosis and tumor-associated macrophages polarization. This review focuses on the advances and applications of PBNPs in cancer immunotherapy. First, the biomedical functions of PBNPs are introduced. Then, based on the immune function of PBNPs, we systematically reviewed the multidimensional application of PBNPs in cancer immunotherapy. Finally, the challenges and future developments of PBNPs-based cancer immunotherapy are highlighted.

Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority. Our previous research demonstrated the efficacy of artesunate (ART) in alleviating liver fibrosis by eliminating activated hepatic stellate cells (HSCs). However, the underlying mechanism remains unclear despite these findings. Notably, endocytic adaptor protein (NUMB) has significant implications for treating hepatic diseases, but current research primarily focuses on liver regeneration and hepatocellular carcinoma. The precise function of NUMB in liver fibrosis, particularly its ability to regulate HSCs, requires further investigation. This study aims to elucidate the role of NUMB in the anti-hepatic fibrosis action of ART in HSCs. We observed that the expression level of NUMB significantly decreased in activated HSCs compared to quiescent HSCs, exhibiting a negative correlation with the progression of liver fibrosis. Additionally, ART induced senescence in activated HSCs through the NUMB/P53 tumor suppressor (P53) axis. We identified NUMB as a crucial regulator of senescence in activated HSCs and as a mediator of ART in determining cell fate. This research examines the specific target of ART in eliminating activated HSCs, providing both theoretical and experimental evidence for the treatment of liver fibrosis.

RNA methylation is a potential target for cancer therapy, while anoikis, a form of programmed cell death, is linked to cancer metastasis. However, the prognostic and immune significance of RNA methylation- and anoikis-related genes in colorectal cancer (CRC) remains unknown.

Transcriptomic and clinicopathological data for CRC were obtained from TCGA and the GEO databases. A novel signature was constructed based on RNA methylation- and anoikis-related genes using univariate and multivariate Cox regression as well as LASSO Cox regression methods. CRC patients were stratified into low- and high-risk groups based on this signature. Differences in prognosis, immune infiltration, and drug sensitivity between two groups were analyzed. Finally, immunohistochemistry, western blot, and RT-qPCR were employed to validate the expression of the key gene SERPINE1 in CRC tissues and cells, as well as the effect of FTO on its expression.

We identified 79 differentially expressed RNA methylation-associated anoikis-related genes (RMRARGs) in both cancerous and normal tissues. A signature composed of 9 key genes (BID, FASN, PLK1, CDKN3, MYC, EPHA2, SERPINE1, CD36, PDK4) was established. Kaplan-Meier analysis revealed a poorer prognosis in the high-risk group. Compared to the other three published models, this signature demonstrated superior predictive performance based on the ROC curve analysis. Functional analyses highlighted differences in drug sensitivities and signaling pathways between risk groups. Furthermore, immune analysis results showed that risk score was associated with some immune cells and immune checkpoints. Immunohistochemistry showed high SERPINE1 expression in CRC tissues, with FTO expression positively correlated with SERPINE1. Furthermore, RT-qPCR and western blot indicated FTO knockdown markedly downregulated SERPINE1 levels.

Our findings underscore the prognostic value of this signature in CRC patients and its utility in assessing immune status. Additionally, the m6A demethylase FTO regulates the expression of the anoikis-related gene SERPINE1.

Cholestatic liver fibrosis is a common pathological feature of various biliary tract diseases. The underlying pathological mechanisms are not fully understood, posing significant obstacles to the discovery of new drug targets. The aims of the current study were to evaluate protective effects of hyodeoxycholic acid (HDCA) against cholestatic liver fibrosis and to ascertain whether ETV4 is a novel anti-fibrotic target involved in the therapeutic effects of HDCA.

The therapeutic effect of HDCA was verified using bile duct ligation and Abcb4-/- mouse models. Etv4-/- mice were subjected to bile duct ligation to investigate the role of ETV4 in liver fibrogenesis and the therapeutic effects of HDCA. The N6-methyladenosine (m6A) modification was investigated using methylated m6A RNA immunoprecipitation-qPCR and immunofluorescence/fluorescence in situ hybridization techniques.

HDCA levels were decreased in both cholestatic patients and mice, while HDCA supplementation significantly ameliorated cholestatic liver fibrosis. By inducing ETV4 expression in cholangiocytes, HDCA induced MMP9 secretion, facilitating extracellular matrix degradation. Findings in patients with cholestatic fibrosis and Etv4-/- mice further revealed a promising role of ETV4 in improving liver fibrosis and in mediating the therapeutic effects of HDCA. Mechanistically, HDCA promoted m6A modification of ETV4 mRNA, which thereby promotes IGF2BP1 recognition and PABPC1 recruitment to inhibit ETV4 mRNA deadenylation, leading to increased mRNA stability, storage in P-bodies, and prolonged translation. Mutation of the m6A site on ETV4 mRNA or knockdown of critical genes involved in m6A modification significantly abolished the therapeutic effects of HDCA.

The present study underscores ETV4 as a novel anti-fibrotic target and demonstrates that HDCA remodels extracellular matrix by facilitating m6A-regulated ETV4 expression, offering potential therapeutic approaches for cholestatic liver fibrosis.

This study delves into the underlying mechanisms of cholestatic liver fibrosis and reveals potential therapeutic targets. The research highlights ETV4 as a novel anti-fibrotic target that is essential for the therapeutic effects of hyodeoxycholic acid against cholestatic liver fibrosis. These findings are important for both the scientific community and patients with cholestatic liver diseases, offering valuable insights for future therapeutic strategies that focus on regulating m6A-dependent epigenetic modifications of anti-fibrotic targets like ETV4 and developing new interventions utilizing hyodeoxycholic acid.

Arsenic exposure triggers the activation of hepatic stellate cells (HSCs), resulting in liver fibrosis (LF). A significant decrease in lipid droplets marks the activation of HSCs. However, the exact underlying molecular mechanism remains elusive. Lipophagy, a specialized form of selective autophagy, is crucial for the degradation of lipid droplets to maintain intracellular lipid metabolism homeostasis. In this study, arsenic treatment induced lipophagy, as evidenced by the co-localization of LC3 with lipid droplets. Remarkably, arsenic exposure increased the expression levels of Perilipin 5 (PLIN5), a lipid droplet-associated protein, both at the mRNA and protein levels. Moreover, silencing PLIN5 influenced arsenic-induced lipolysis. Consequently, the results of this study indicate that PLIN5 serves as a substrate protein involved in arsenic-induced lipophagy. This research offers a novel perspective on the mechanisms of arsenic-induced HSCs activation and liver lipid metabolism, potentially guiding new strategies for the prevention and treatment of arsenic-related liver diseases.

N(6)-methyladenosine (m6A) modification is the most abundant and prevalent internal modification in eukaryotic mRNAs. The role of m6A modification in cancer has become a hot research topic in recent years and has been widely explored. m6A modifications have been shown to regulate cancer occurrence and progression by modulating different target molecules. This paper reviews the recent research progress of m6A modifications in cancer and provides an outlook on future research directions, especially the development of molecularly targeted drugs. See also the graphical abstract(Fig. 1).

Recent studies indicate that N6-methyladenosine (m6A) RNA modification may regulate ferroptosis in cancer cells, while its molecular mechanisms require further investigation.

Liquid Chromatography-Tandem Mass Spectrometry (HPLC/MS/MS) was used to detect changes in m6A levels in cells. Transmission electron microscopy and flow cytometry were used to detect mitochondrial reactive oxygen species (ROS). RNA sequencing (RNA-seq) was employed to analyze the factors regulating ferroptosis. Chromatin immunoprecipitation (ChIP) was used to assess the binding of regulatory factors to the SLC7A11 promoter, and a Dual-Luciferase reporter assay measured promoter activity of SLC7A11. The dm6ACRISPR system was utilized for the demethylation of specific transcripts. The Cancer Genome Atlas Program (TCGA) database and immunohistochemistry validated the role of the METTL3/SLC7A11 axis in cancer progression.

The m6A methyltransferase METTL3 was upregulated during cancer cell ferroptosis and facilitated erastin-induced ferroptosis by enhancing mitochondrial ROS. Mechanistic studies showed that METTL3 negatively regulated the transcription and promoter activity of SLC7A11. Specifically, METTL3 induced H3K27 trimethylation of the SLC7A11 promoter by suppressing the mRNA stability of H3K27 demethylases KDM6B. Furthermore, METTL3 suppressed the expression of GATA3, which regulated SLC7A11 transcription by binding to the putative site at - 597 to - 590 of the SLC7A11 promoter. METTL3 decreased the precursor mRNA stability of GATA3 through m6A/YTHDF2-dependent recruitment of the 3'-5' exoribonuclease Dis3L2. Targeted demethylation of KDM6B and GATA3 m6A using the dm6ACRISPR system significantly increased the expression of SLC7A11. Moreover, the transcription factor YY1 was responsible for erastin-induced upregulation of METTL3 by binding to its promoter-proximal site. In vivo and clinical data supported the positive roles of the METTL3/SLC7A11 axis in tumor growth and progression.

METTL3 regulated the transcription of SLC7A11 through GATA3 and KDM6B to modulate ferroptosis in an m6A-dependent manner. This study provides a novel potential strategy and experimental support for the future treatment of cancer.

Background: Stem cell-like properties are known to promote the recurrence and metastasis of hepatocellular carcinoma (HCC), contributing to a poor prognosis for HCC patients. Betaine, an important phytochemical and a methyl-donor related substance, has shown protective effects against liver diseases. However, its effect on HCC stem cell-like properties and the underlying mechanisms remains uninvestigated. Methods: We measured the effects of betaine on the stem cell-like properties and malignant progression of HCC using patient-derived xenografts, cell-derived xenografts, tail vein-lung metastasis models, in vitro limiting dilution, tumor sphere formation, colony formation, and transwell assays. Mechanistic exploration was conducted using western blots, dot blots, methylated RNA immunoprecipitation-qPCR, RNA stability assays, RNA immunoprecipitation-qPCR, RNA pull-down, and gene mutation assays. Results: A cohort study of HCC found that a higher serum concentration of betaine was associated with decreased levels of stemness-related markers. Furthermore, in HCC cells and xenograft mice, betaine suppressed the stem cell-like properties of HCC by activating autophagy. Mechanistically, betaine increased the m6A modification in HCC by producing S-adenosylmethionine (SAM) via betaine-homocysteine S-methyltransferase (BHMT). This increase in SAM subsequently triggered autophagy by enhancing the stability of autophagy-related protein 3 (ATG3) via YTHDF1 in an m6A-dependent manner, thereby inhibiting the stem cell-like properties of HCC cells. Conclusions: These findings indicate that betaine inhibits the stem cell-like properties of HCC via the SAM/m6A/YTHDF1/ATG3 pathway. This study underscores the potential anti-tumor effects of betaine on HCC and offers novel therapeutic prospects for HCC patients.

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids. Since its identification in 2012, extensive research has unveiled its involvement in the pathophysiology of numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious diseases, autoimmune conditions, metabolic disorders, and skin diseases. Oxidizable lipids, overload iron, and compromised antioxidant systems are known as critical prerequisites for driving overwhelming lipid peroxidation, ultimately leading to plasma membrane rupture and ferroptotic cell death. However, the precise regulatory networks governing ferroptosis and ferroptosis-targeted therapy in these diseases remain largely undefined, hindering the development of pharmacological agonists and antagonists. In this review, we first elucidate core mechanisms of ferroptosis and summarize its epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, and N6-methyladenosine modification) and nonepigenetic modifications (e.g., genetic mutations, transcriptional regulation, and posttranslational modifications). We then discuss the association between ferroptosis and disease pathogenesis and explore therapeutic approaches for targeting ferroptosis. We also introduce potential clinical monitoring strategies for ferroptosis. Finally, we put forward several unresolved issues in which progress is needed to better understand ferroptosis. We hope this review will offer promise for the clinical application of ferroptosis-targeted therapies in the context of human health and disease.

Liver injury-induced activation of hepatic stellate cells (HSCs) is a crucial step in the progression of liver fibrosis. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is highly expressed in the liver. However, the role of AHR in liver fibrosis remains controversial. Our study revealed that the nontoxic ligand YH439 directly activated the AHR and regulated the expression of multidrug-resistant protein 1 (Mrp1) in mouse hepatic stellate cells (mHSCs), thereby diminishing the antioxidant capacity of mHSCs by promoting GSH efflux, and specifically inducing mHSCs ferroptosis without affecting hepatocytes. In a chronic liver fibrosis model, YH439 activated AHR to promote mHSC ferroptosis without causing hepatocyte ferroptosis, thereby alleviating liver fibrosis. Conclusively, this study shows that AHR alleviates liver fibrosis in mice by selectively inducing mHSC ferroptosis without causing hepatocyte ferroptosis and suggests that AHR is a potential target for the treatment of liver fibrosis.

Methyltransferase-like 3 (METTL3) is extensively reported to be involved in organ fibrosis. Ovarian fibrosis is a main characteristic of polycystic ovary syndrome (PCOS). However, the reaction mechanism of METTL3 in PCOS is poorly investigated. This paper was intended to reveal the role and the mechanism of METTL3 in PCOS. Animal and cell models of PCOS were induced by dehydroepiandrosterone (DHEA). H&E staining was performed to detect the pathological alterations in ovary tissues. Masson staining, immunofluorescence, along with western blot measured fibrosis both in vitro and in vivo. To evaluate estrous cycle, vaginal smear was performed. Lipid peroxidation and ferroptosis were evaluated by MDA assay kits, GSH assay kits, immunohistochemistry, Prussian blue staining and western blot. qRT-PCR and western blot were adopted to estimate METTL3 and GPX4 expression. The m6A and hormone secretion levels were respectively assessed by m6A RNA Methylation Quantitative Kit and corresponding kits. The interaction between METTL3 and GPX4 was testified by immunoprecipitation. The fibrosis and ferroptosis were aggravated and m6A and METTL3 expression were increased in ovarian tissues of DHEA-induced PCOS mice. METTL3 silencing alleviated pathological changes, affected hormone secretion level, and repressed fibrosis, lipid peroxidation and ferroptosis in the ovarian tissues of PCOS mice. In vitro, DHEA stimulation increased m6A and METTL3 expression and induced ferroptosis and fibrosis. METTL3 knockdown promoted GPX4 expression in DHEA-induced granulosa cells by m6A modification and restrained DHEA-induced fibrosis, lipid peroxidation and ferroptosis in granulosa cells via elevating GPX4. METTL3 silence inhibited ovarian fibrosis in PCOS, which was mediated through suppressing ferroptosis by upregulating GPX4 in m6A-dependent manner.

In cisplatin-induced premature ovarian failure (POF) mice, granulosa cells showed a high level of ferroptosis. Previous research has indicated that the fat mass and obesity-associated protein/activating transcription factor 4 (FTO/ATF4) axis was involved in the regulation of ferroptosis. The purpose of this study was to explore the role of the FTO/ATF4 axis in cisplatin-induced ferroptosis in granulosa cell.

The extent of ferroptosis was assessed by transmission electron microscopy (TEM) and ROS, GPX, GSH, and MDA assays. Western blotting was used to evaluate the protein expression levels of ferroptosis-related molecules. Ferroptosis activator and inhibitor were also used.

We found that ferroptosis increased in a concentration-dependent manner in cisplatin-induced injured granulosa cells, accompanied by the downregulation of FTO. In addition, gain- and loss-of-function studies showed that FTO affects ferroptosis in injured cells by regulating ATF4 expression. Ferrostatin-1 inhibited the effect of FTO downregulation on injured granulosa cells ferroptosis, and erastin reversed the protective effect of FTO on ferroptosis in injured granulosa cells. Finally, melatonin was used, and we found that melatonin reduced ferroptosis in cisplatin-induced injured granulosa cells by upregulating FTO expression.

Our study demonstrated that cisplatin induced granulosa cell ferroptosis by downregulating the expression of FTO. ATF4 was identified as a downstream target of FTO, and overexpression of ATF4 reversed the effects of decreased FTO on ferroptosis. Additionally, melatonin mitigates the cytotoxic effects of cisplatin by upregulating FTO expression. The melatonin-FTO-ATF4 signaling pathway plays a vital role in the treatment of cisplatin-induced POF.

The abundance and activity of estrogen receptor alpha (ERα) are tightly regulated by ubiquitin-specific peptidase 22 (USP22) during the progression of breast cancer (BCa). However, the post-transcriptional modifications on the USP22-ERα axis remain elusive. N6-methyladenosine (m6A) is critical to modulate RNA status in eukaryotic cells. Here, we find that METTL14 positively regulates the mRNA expression of USP22 and ERα. Mechanistically, METTL14 potently binds to the USP22 and ERα mRNA, and thereby enhancing their stability through m6A modification. YTHDC1 and YTHDF1 function as readers for m6A-modified USP22 and ERα, respectively. Additionally, METTL14 promotes the growth and migration of ERα+ BCa via the USP22-ERα-Cyclin D1 axis. Enforced expression of USP22/ERα significantly reverses the METTL14 depletion-induced growth and migration inhibition in BCa. Moreover, our analysis of clinical samples shows that the expression of METTL14, USP22, and ERα is upregulated and correlated in BCa tissues. Overall, our findings reveal the key role of the METTL14-USP22-ERα axis in BCa progression, which further provides a druggable target to treat BCa.

N6-Methyladenosine (m6A) is an evolutionarily highly conserved epigenetic modification that affects eukaryotic RNAs, especially mRNAs, and m6A modification is commonly linked to tumor proliferation, progression, and therapeutic resistance by participating in RNA metabolism. Autophagy is an intracellular degradation and recycling biological process by which cells remove damaged organelles, protein aggregates, and other intracellular wastes, and release nutrients to maintain cell survival when energy is scarce. Recent studies have shown that m6A modification plays a critical role in the regulation of autophagy, affecting the initiation of autophagy, the formation and assembly of autophagosomes, and lysosomal function by regulating critical regulatory molecules involved in the process of autophagy. Moreover, autophagy can also affect the expression of the three types of regulators related to m6A, which in turn affects the levels of their target genes via m6A modification. Thus, m6A modification and autophagy form a sophisticated regulatory network through mutual regulation, which plays an important role in tumor progression and therapeutic resistance. In this manuscript, we reviewed the effects of m6A modification on autophagy as well as the effects of autophagy on m6A modification and the roles of the m6A-autophagy axis in tumor progression and therapy resistance. Additionally, we summarized the value and application prospects of key molecules in the m6A-autophagy axis in tumor diagnosis and therapy.

N6-methyladenosine (m6A) has been shown to mediate ferroptosis but its role in atherosclerosis (AS) is unclear.

Differentially expressed m6A-associated ferroptosis-related genes (DE-m6A-Ferr-RGs) were obtained using differential expression analysis and Pearson correlation analysis. Weighted gene co-expression network analysis (WGCNA) was also performed. The intersection of the module genes and the DE-m6A-Ferr-RGs were recorded as candidate m6A-Ferr-related signature genes. Finally, the m6A-Ferr-related signature genes were screened using least absolute shrinkage and selection operator (LASSO) analysis. Expression validation, receiver operating characteristic ( mapping, and immune correlation analysis were also performed based on the m6A-Ferr-related signature genes. The expression of m6A-Ferr-related signature genes was further validated using a real-time polymerase chain reaction (RT-qPCR).

In total, 6,167 differentially expressed genes were intersected with 24 m6A- and 259 ferroptosis-related genes, respectively, resulting in 113 DE-m6A-Ferr-RGs obtained using Pearson's correlation analysis. The module genes obtained from the WGCNA and the 113 DE-m6A-Ferr-RGs were intersected to obtain 48 candidate m6A-Ferr-related signature genes. LASSO analysis was performed and six m6A-Ferr-related signature genes were screened. In addition, the area under the curve values of all six m6A-Ferr-related signature genes were greater than 0.7, indicating that they had potential diagnostic value. Furthermore, the RT-qPCR results revealed that the expression of SLC3A2, NOX4, and CDO1 was consistent with the transcriptome level. Moreover, there was a significant difference in two types of immune cells between the AS and control groups. Naive B cells, CD8+ T cells, regulatory T cells, and activated natural killer cells were positively correlated with CDO1 and NOX4 but negatively correlated with ATG7, CYBB, and SLC3A2.

In total, three m6A-Ferr-related signature genes (NOX4, CDO1, and SLC3A2) were obtained through a series of bioinformatics analyses and an RT-qPCR.

Based on the current knowledge of the molecular mechanisms by which m6A influences ferroptosis, our objective is to underscore the intricate and interdependent relationships between m6A and the principal regulatory pathways of ferroptosis, as well as other molecules, emphasizing its relevance to diseases associated with this cell death mode.

We conducted a literature search using the keywords "m6A and ferroptosis" across PubMed, Web of Science, and Medline. The search was limited to English-language publications from 2017 to 2024. Retrieved articles were managed using Endnote software. Two authors independently screened the search results and reviewed the full texts of selected articles.

Abnormal m6A levels are often identified as critical regulators of ferroptosis. Specifically, "writers", "readers" and "erasers" that dynamically modulate m6A function regulate various pathways in ferroptosis including iron metabolism, lipid metabolism and antioxidant system. Additionally, we provide an overview of the role of m6A-mediated ferroptosis in multiple diseases and summarize the potential applications of m6A-mediated ferroptosis, including its use as a therapeutic target for diseases and as diagnostic as well as prognostic biomarkers.

N6-methyladenosine (m6A) modification, a prevalent RNA modification in eukaryotic cells, is crucial in regulating various aspects of RNA metabolism. Notably, accumulating evidence has implicated m6A modification in ferroptosis, a form of iron-dependent cell death characterized by elevated iron levels and lipid peroxide accumulation. Overall, this review sheds light on the potential diagnostic and therapeutic applications of m6A regulators in addressing conditions associated with ferroptosis.

As common clinical-pathological processes, wound healing and tissue remodelling following injury or stimulation are essential topics in medical research. Promoting the effective healing of prolonged wounds, improving tissue repair and regeneration, and preventing fibrosis are important and challenging issues in clinical practice. Ferroptosis, which is characterized by iron overload and lipid peroxidation, is a nontraditional form of regulated cell death. Emerging evidence indicates that dysregulated metabolic pathways and impaired iron homeostasis play important roles in various healing and regeneration processes via ferroptosis. Thus, we review the intrinsic mechanisms of tissue repair and remodeling via ferroptosis in different organs and systems under various conditions, including the inflammatory response in skin wounds, remodeling of joints and cartilage, and fibrosis in multiple organs. Additionally, we summarize the common underlying mechanisms, key molecules, and targeted drugs for ferroptosis in repair and regeneration. Finally, we discuss the potential of therapeutic agents, small molecules, and novel materials emerging for targeting ferroptosis to promote wound healing and tissue repair and attenuate fibrosis.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a prominent global health concern associated with high risk of metabolic syndrome, and has impacted a substantial segment of the population. The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC) and is increasingly becoming a prevalent indication for liver transplantation. The existing therapeutic options for NAFLD, NASH, and HCC are limited, underscoring the urgent need for innovative treatment strategies. Insights into gene expression, particularly RNA modifications such as N6 methyladenosine (m6A), hold promising avenues for interventions. These modifications play integral roles in RNA metabolism and cellular functions, encompassing the entire NAFLD-NASH-HCC progression. This review will encompass recent insights on diverse RNA modifications, including m6A, pseudouridine (ψ), N1-methyladenosine (m1A), and 5-methylcytidine (m5C) across various RNA species. It will uncover their significance in crucial aspects such as steatosis, inflammation, fibrosis, and tumorigenesis. Furthermore, prospective research directions and therapeutic implications will be explored, advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.

Liver fibrosis is a pathological process caused by a variety of chronic liver diseases. Currently, therapeutic options for liver fibrosis are very limited, highlighting the urgent need to explore new treatment approaches. Epigenetic modifications and epitranscriptomic modifications, as reversible regulatory mechanisms, are involved in the development of liver fibrosis. In recent years, researches in epitranscriptomics and epigenetics have opened new perspectives for understanding the pathogenesis of liver fibrosis. Exploring the epigenetic mechanisms of liver fibrosis may provide valuable insights into the development of new therapies for chronic liver diseases. This review primarily focus on the regulatory mechanisms of N6-methyladenosine (m6A) modification, non-coding RNA, and DNA methylation in organ fibrosis. It discusses the interactions between m6A modification and DNA methylation, as well as between m6A modification and non-coding RNA, providing a reference for understanding the interplay between epitranscriptomics and epigenetics.

Acute lung injury (ALI) is a serious disorder characterized by the release of pro-inflammatory cytokines and cascade activation of macrophages. Ferroptosis, a form of iron-dependent cell death triggered by intracellular phospholipid peroxidation, has been implicated as an internal mechanism underlying ALI. In this study, we investigated the effects of m6A demethylase fat mass and obesity-associated protein (FTO) on the inhibition of macrophage ferroptosis in ALI. Using a mouse model of lipopolysaccharide (LPS)-induced ALI, we observed the induction of ferroptosis and its co-localization with the macrophage marker F4/80, suggesting that ferroptosis might be induced in macrophages. Ferroptosis was promoted during LPS-induced inflammation in macrophages in vitro, and the inflammation was counteracted by the ferroptosis inhibitor ferrostatin-1 (fer-1). Given that FTO showed lower expression levels in the lung tissue of mice with ALI and inflammatory macrophages, we further dissected the regulatory capacity of FTO in ferroptosis. The results demonstrated that FTO alleviated macrophage inflammation by inhibiting ferroptosis. Mechanistically, FTO decreased the stability of ACSL4 mRNA via YTHDF1, subsequently inhibiting ferroptosis and inflammation by interrupting polyunsaturated fatty acid consumption. Moreover, FTO downregulated the synthesis and secretion of prostaglandin E2, thereby reducing ferroptosis and inflammation. In vivo, the FTO inhibitor FB23-2 aggravated lung injury, the inflammatory response, and ferroptosis in mice with ALI; however, fer-1 therapy mitigated these effects. Overall, our findings revealed that FTO may function as an inhibitor of the inflammatory response driven by ferroptosis, emphasizing its potential as a target for ALI treatment.

This study aimed to investigate the effect of the N6-methyladenosine (m6A) dependent ferroptosis on cisplatininduced Sertoli cell injury.

A cisplatin exposure mouse model was established by intraperitoneal injection of cisplatin in our study. TM4 cell lines was used for in vitro study. Ferroptosis was detected according to metabolomic analysis and a series of assays, including malondialdehyde, glutathione, and glutathione disulfide concentration detection, 2',7'-dichlorodihydrofluorescein diacetate and BODIPY 581/591 C11 probe detection, and transmission electron microscope imaging. Key ferroptosis-related genes were identified via transcriptomic analysis, western blot and immunohistochemistry. The m6A modification was demonstrated via m6A RNA immunoprecipitation and luciferase reporter assays. Immune cell infiltration was detected by mass cytometry, and verified by flow cytometry and immunofluorescence.

Ferroptosis, but not other types of programmed cell death, is a significant phenomenon in cisplatin-induced testis damage and Sertoli cell loss. Ferroptosis induced by cisplatin in Sertoli cell/TM4 cell is GPX4 independent but is regulated by SLC7A11 and ALOX12. Both SLC7A11 and ALOX12 are regulated via m6A dependent manner by METTL3. Furthermore, overexpressed ALOX12-12HETE pathway may result in macrophage polarization and inflammatory response in cisplatin exposure testis.

Cisplatin-induced Sertoli cell injury via ferroptosis and promoted ferroptosis in an m6A dependent manner. m6A modification of both SLC7A11 and ALOX12 mRNA could result in ferroptosis in our in vitro model. Further, overexpressed ALOX12 can cause more production of 12-HETE, which may be responsible for testis inflammation caused by cisplatin.

Given the substantial risks associated with ultraviolet B (UVB) radiation-induced solar dermatitis, enhancing current strategies to combat UVB regarding skin diseases is imperative. The cross-talk between ferroptosis and inflammation has been proven to be an essential factor in UVB-induced solar dermatitis, whereas detailed process of how their interaction contributes to this remains unclear. Therefore, further investigation of ferroptosis-mediated processes and identification of corresponding inhibitory approaches hold promise for repairing skin damage. Senkyunolide I (Sen I), a bioactive component mainly extracted from the traditional Chinese medicinal plants, Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has demonstrated efficacy in combating oxidative stress and inflammation. In this study, we utilized UVB-irradiated HaCaT cells as an in vitro model and C57BL/6J mice as an in vivo model of solar dermatitis. Our findings revealed the pivotal roles of autophagy and ferroptosis in inducing skin inflammation, particularly emphasizing the activation of ferroptosis through macroautophagy. Surprisingly, this mechanism operated independently of ferritinophagy, a classical autophagy-driven ferroptosis pathway. Instead, our results highlighted Transferrin Receptor 1 (TfR1), tightly controlled by autophagy, as a crucial mediator of ferroptosis execution and amplifier of subsequent lethal signals. Furthermore, extracellular High Mobility Group Box 1 protein (HMGB1), released following UVB-induced ferroptotic cells from activated autophagic flux, initiated a feedback loop with TfR1, propagating ferroptosis to neighboring cells and exacerbating damage. Remarkably, Sen I administration showed a significant protective effect against UVB damage in both in vitro and in vivo models by interrupting this cascade. Consequently, we have illuminated a novel therapeutic pathway post-UVB exposure and identified Sen I as a potent natural molecule that safeguarded against UVB-induced solar dermatitis by suppressing the autophagy-ferroptosis-HMGB1-TfR1 axis, highlighting a new frontier in photoprotection.

Fibrosis is an abnormal tissue healing process characterized by the excessive accumulation of ECM components, such as COL I and COL III, in response to tissue injury or chronic inflammation. Recent advances in epitranscriptomics have underscored the importance of m6A modification in fibrosis. m6A, the most prevalent modification in eukaryotic RNA, is catalyzed by methyltransferases (e.g., METTL3), removed by demethylases (e.g., FTO), and recognized by reader proteins (e.g., YTHDF1/2). These modifications are crucial in regulating collagen metabolism and associated diseases. Understanding the role of m6A modification in fibrosis and other collagen-related conditions holds promise for developing targeted therapies. This review highlights the latest progress in this area.

Tendinopathy is one of the most prevalent sports injury diseases in orthopedics. However, there is no effective treatment or medicine. Recently, the discovery of tendon stem cells (TSCs) provides a new perspective to find new therapeutic methods for Tendinopathy. Studies have shown that oxidative stress will inevitably cause TSCs injury during tendinopathy, but the mechanism has not been fully elucidated. Here, we report the oxidative damage of TSCs induced by H2O2 via ferroptosis, as well, treatment with H2O2 raised the proportion of mitochondria engulfed by autophagosomes in TSCs. The suppression of mitophagy by Mdivi-1 significantly attenuates the H2O2-induced ferroptosis in TSCs. Mechanically, H2O2 actives the cGAS-STING pathway, which can regulate the level of mitophagy. Interfering with cGAS could impair mitophagy and the classical ferroptotic events. In the rat model of tendinopathy, interference of cGAS could relieve tendon injury by inhibiting ferroptosis. Overall, these results provided novel implications to reveal the molecular mechanism of tendinopathy, by which pointed to cGAS as a potential therapeutic target for the treatment of tendinopathy.

N6-methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion, and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications (PTMs), as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death mechanisms and affecting the tumor microenvironment through various cancer-associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism-associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes.

According to statistics, colon adenocarcinoma (COAD) ranks third in global incidence and second in mortality. The role of N6-methyladenosine (m6A) modification-dependent ferroptosis in tumor development and progression is gaining attention. Therefore, it is meaningful to explore the biological functions mediated by m6A ferroptosis related genes (m6A-Ferr-RGs) in the prognosis and treatment of COAD. This study aimed to explore the regulatory mechanisms and prognostic features of m6A-Ferr-RGs in COAD based on the COAD transcriptome dataset.

The expression data of Ferr-RGs and the correlated analysis with prognosis related m6A regulators were conducted to obtain candidate m6A-Ferr-RGs. Then, the differentially expressed genes (DEGs) between COAD and normal samples were intersected with candidate m6A-Ferr-RGs to obtain differentially expressed m6A Ferr-RGs (DE-m6A-Ferr-RGs) in COAD. Cox regression analyses were performed to establish risk model and validated in the GSE17538 and GSE41258 datasets. The nomogram was constructed and verified by calibration curves. Moreover, tumor immune dysfunction and exclusion (TIDE) was used to assess immunotherapy response in two risk groups. Finally, the expression of m6A-Ferr-related prognostic genes was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR).

In total, 6 model genes (HSD17B11, VEGFA, CXCL2, ASNS, FABP4, and GPX2) were obtained to construct the risk model. The nomogram was established based on the independent prognostic factors for predicting survival of COAD. TIDE assessed that the high-risk group suffered from greater immune resistance. Ultimately, the experimental results confirmed that the expression trends of all model genes were consistent among data from public database.

In this study, m6A-Ferr-related prognostic model for COAD was constructed using transcriptome data and clinical data of COAD in public database, which may have potential immunotherapy and chemotherapy guidance implications.