Integrative Inducer Intervention and Transcriptomic Analyses Reveal the Metabolism of Paralytic Shellfish Toxins in Azumapecten farreri.

Paralytic shellfish toxins (PSTs) are widely distributed neurotoxins, and the PST metabolic detoxification mechanism in bivalves has received increasing attention. To reveal the effect of phase I (cytochrome P450)-II (GST)-III (ABC transport) metabolic systems on the PST metabolism in Azumapecten farreri, this study amplified stress on the target systems using rifampicin, dl-α-tocopherol, and colchicine; measured PST levels; and conducted transcriptomic analyses. The highest toxin content reached 1623.48 µg STX eq/kg in the hepatopancreas and only 8.8% of that in the gills. Inducer intervention significantly decreased hepatopancreatic PST accumulation. The proportional reductions in the rifampicin-, dl-α-tocopherol-, and colchicine-induced groups were 55.3%, 50.4%, and 36.1%, respectively. Transcriptome analysis showed that 11 modules were significantly correlated with PST metabolism (six positive/five negative), with phase I CYP450 and phase II glutathione metabolism significantly enriched in negatively correlated pathways. Twenty-three phase I-II-III core genes were further validated using qRT-PCR and correlated with PST metabolism, revealing that CYP46A1, CYP4F6, GSTM1, and ABCF2 were significantly correlated, while CYP4F11 and ABCB1 were indirectly correlated. In conclusion, phase I-II-III detoxification enzyme systems jointly participate in the metabolic detoxification of PSTs in A. farreri. This study provides key data support to profoundly elucidate the PST metabolic detoxification mechanism in bivalves.

Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4.

Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no effective treatment available for advanced gastric cancer. However, there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4 (EP4) in gastric cancer. In our previous study, we identified a novel small molecule EP4 receptor antagonist called YY001. Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model. Furthermore, administration of YY001 stimulated a robust immune response within the tumor microenvironment, characterized by increased infiltration of antigen-presenting cells, T cells, and M1 macrophages. Additionally, our research revealed that YY001 exhibited remarkable synergistic effects when combined with the PD-1 antibody and the clinically targeted drug apatinib, rather than fluorouracil. These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer, whether used as a standalone treatment or in combination with other drugs.

The role of amino acid metabolism in autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an inflammatory chronic liver disease with persistent and recurrent immune-mediated liver injury. The exact cause of AIH is still not fully understood, but it is believed to be primarily due to an abnormal activation of the immune system, leading to autoimmune injury caused by the breakdown of autoimmune tolerance. Although the pathogenesis of AIH remains unclear, recent studies have shown that abnormalities in amino acid metabolism play significant roles in its development. These abnormalities in amino acid metabolism can lead to remodeling of metabolic processes, activation of signaling pathways, and immune responses, which may present new opportunities for clinical intervention in AIH. In this paper, we first briefly outline the recent progress of clinically relevant research on AIH, focusing on the role of specific amino acid metabolism (including glutamine, cysteine, tryptophan, branched-chain amino acids, etc.) and their associated metabolites, as well as related pathways, in the development of AIH. Furthermore, we discuss the scientific issues that remain to be resolved regarding amino acid metabolism, AIH development and related clinical interventions, with the aim of contributing to the future development of amino acid metabolism-based as a new target for the clinical diagnosis and treatment of AIH.

A novel ZIF-L/PEI thin film nanocomposite membrane for removing perfluoroalkyl substances (PFASs) from water: Enhanced retention and high flux.

Membrane separation technology is widely recognized as an effective method for removing perfluoroalkyl substances (PFASs) in water treatment. ZIF-L, a metal-organic framework (MOF) family characterized by its mat-like cavities and leaf-like morphology, has garnered considerable interest and has been extensively employed in fabricating thin-film nanocomposite (TFN) membranes. In this study, a robust, high-performance TFN membrane to remove PFASs in a nanofiltration (NF) process was created through an interfacial polymerization approach on the surface of polysulfone (PSF), incorporating ZIF-L within the selective layer. The TFN membrane modified by adding 5 wt% ZIF-L (relative to the weight of ethylene imine polymer (PEI)) exhibits 2.3 times higher water flux (up to 47.56 L·m-2·h-1·bar-1) than the pristine thin film composite membrane (20.46 L·m-2·h-1·bar-1), and the rejection for typical PFASs were above 95 % (98.47 % for perfluorooctanesulfonic acid (PFOS) and 95.85 % for perfluorooctanoic acid (PFOA)). The effectiveness of the ZIF-L/PEI TFN membrane in retaining representative PFASs was examined under various conditions, including different pressures, feed concentrations, aqueous environments, and salt ions. Notably, the experiments demonstrated that even after contamination with humic acid (HA), >88 % of the water flux could be restored by washing. Additionally, density functional theory (DFT) calculations were employed to predict the distinct intermolecular interactions between PFASs and ZIF-L as well as PEI. These calculations provide additional insights into the interception mechanism of TFN membranes towards PFASs. Based on this study, TFN membranes incorporating MOF as nanofillers show great potential as an effective method for purifying PFASs from aqueous environments and possess superior environmental sustainability and cost-effectiveness.

MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells.

Aging is intricately linked to immune system dysfunction. Recent studies have highlighted the biological function of microRNA-7 (miR-7) as a novel regulator of immune cell function and related diseases. However, the potential role of miR-7 in aging remains unexplored. Here, we investigated the contribution of miR-7 to d-gal-induced aging in mice, focusing on its regulation of senescent Kupffer cells. Our findings revealed that miR-7 deficiency significantly ameliorated the aging process, characterized by enhanced CD4+ T-cell activation. However, the adoptive transfer of miR-7-deficient CD4+ T cells failed to improve the age-related phenotype. Further analysis showed that miR-7 deficiency significantly reduced IL-1ß production in liver tissue, and inhibiting IL-1ß in vivo slowed down the aging process in mice. Notably, IL-1ß is mainly produced by senescent Kupffer cells in the liver tissue of aging mice, and miR-7 expression was significantly up-regulated in these cells. Mechanistically, KLF4, a target of miR-7, was down-regulated in senescent Kupffer cells in aging mouse model. Furthermore, miR-7 deficiency also modulated the NF-κB activation and IL-1ß production in senescent Kupffer cells through KLF4. In conclusion, our findings unveil the role of miR-7 in d-gal-induced aging in mice, highlighting its regulation of KLF4/NF-κB/IL-1ß pathways in senescent Kupffer cells. This research may enhance our understanding of miRNA-based aging immune cells and offer new avenues for new intervention strategies in aging process.

Distinct molecular profiles drive multifaceted characteristics of colorectal cancer metastatic seeds.

Metastasis of primary tumors remains a challenge for early diagnosis and prevention. The cellular properties and molecular drivers of metastatically competent clones within primary tumors remain unclear. Here, we generated 10-16 single cell-derived lines from each of three colorectal cancer (CRC) tumors to identify and characterize metastatic seeds. We found that intrinsic factors conferred clones with distinct metastatic potential and cellular communication capabilities, determining organ-specific metastasis. Poorly differentiated or highly metastatic clones, rather than drug-resistant clones, exhibited poor clinical prognostic impact. Personalized genetic alterations, instead of mutation burden, determined the occurrence of metastatic potential during clonal evolution. Additionally, we developed a gene signature for capturing metastatic potential of primary CRC tumors and demonstrated a strategy for identifying metastatic drivers using isogenic clones with distinct metastatic potential in primary tumors. This study provides insight into the origin and mechanisms of metastasis and will help develop potential anti-metastatic therapeutic targets for CRC patients.

Influence of humic acid on the bioaccumulation, elimination, and toxicity of PFOS and TBBPA co-exposure in Mytilus unguiculatus Valenciennes.

Tetrabromobisphenol A (TBBPA) and Perfluorooctane sulfonate (PFOS) are emerging contaminants which coexist in marine environments, posing significant risks to ecosystems and human health. The behavior of these contaminants in the presence of dissolved organic matter (DOM), specifically the co-contamination of TBBPA and PFOS, is not well understood. The bioaccumulation, distribution, elimination, and toxic effects of TBBPA and PFOS on thick-shell mussels (Mytilus unguiculatus V.), with the absence and presence of humic acid (HA), a typical DOM, were studied. The results showed that the uptake of TBBPA decreased and the uptake of PFOS increased when exposed to 1 mg/L HA. However, at higher concentrations of HA (5 and 25 mg/L), the opposite effect was observed. Combined exposure to HA, TBBPA, and PFOS resulted in oxidative stress in the digestive gland, with the severity of stress dependent on exposure time and HA dose. Histological analysis revealed a positive correlation between HA concentration and tissue damage caused by TBBPA and PFOS. This study provides insights into the influence of HA on the bioaccumulation-elimination patterns and toxicity of TBBPA and PFOS in marine bivalves, offering valuable data for ecological and health risk assessments of combined pollutants in aquatic environments rich in DOM.

Effectively Enhancing the Conductance of Asymmetric Molecular Wires by Aligning the Energy Level and Symmetrizing the Coupling.

An asymmetric structure is an important strategy for designing highly conductive molecular wires for a gap-fixed molecular circuit. As the conductance enhancement in the current strategy is still limited to about 2 times, we inserted a methylene group as a spacer in a conjugated structure to modulate the structural symmetry. We found that the conductance drastically enhanced in the asymmetric molecular wire to 1.5 orders of magnitude as high as that in the symmetric molecular wire. First-principles quantum transport studies attributed the effective enhancement to the synchronization of improved energy alignment and nearly symmetric coupling between the frontier orbitals and the electrodes.

Promoter A1312C mutation leads to microRNA-7 downregulation in human non-small cell lung cancer.

MicroRNA-7 (miRNA-7, miR-7) is a unique class of tumor suppressors, plays an important role in various physiological and pathological processes including human non-small cell lung cancer (NSCLC). In previous works, we revealed that miR-7 could regulate the growth and metastasis of human NSCLC cells. However, the mechanism of dysregulated miR-7 expression in NSCLC remains to be further elucidated. In this study, based on clinical sample analysis, we found that the downregulated expression of miR-7 was dominantly attributed to the decreased level of pri-miR-7-2 in human NSCLC. Furthermore, there were four site mutations in the miR-7-2 promoter sequence. Notably, among these four sites, mutation at -1312 locus (A â†’ C, termed as A1312C mutation) was dominate, and A1312C mutation further led to decreased expression of miR-7 in human NSCLC cells, accompanied with elevated transduction of NDUFA4/ERK/AKT signaling pathway. Mechanistically, homeobox A5 (HOXA5) is the key transcription factors regulating miR-7 expression in NSCLC. A1312C mutation impairs HOXA5 binding, thereby reducing the transcriptional activity of miR-7-2 promoter, resulting in downregulation of miR-7 expression. Together, these data may provide new insights into the dysregulation of specific miRNA expression in NSCLC and ultimately prove to be helpful in the diagnostic, prognostic, and therapeutic strategies against NSCLC.

Contamination Status and Risk Assessment of Paralytic Shellfish Toxins in Shellfish along the Coastal Areas of China.

Paralytic shellfish toxins (PSTs) are widely distributed in shellfish along the coast of China, causing a serious threat to consumer health; however, there is still a lack of large-scale systematic investigations and risk assessments. Herein, 641 shellfish samples were collected from March to November 2020, and the PSTs' toxicity was detected via liquid chromatography-tandem mass spectrometry. Furthermore, the contamination status and potential dietary risks of PSTs were discussed. PSTs were detected in 241 shellfish samples with a detection rate of 37.60%. The average PST toxicities in mussels and ark shells were considerably higher than those in other shellfish. The PSTs mainly included N-sulfonylcarbamoyl toxins (class C) and carbamoyl toxins (class GTX), and the highest PST toxicity was 546.09 µg STX eq. kg-1. The PST toxicity in spring was significantly higher than those in summer and autumn (p < 0.05). Hebei Province had the highest average PST toxicity in spring. An acute exposure assessment showed that consumers in Hebei Province had a higher dietary risk, with mussels posing a significantly higher dietary risk to consumers. This research provides reference for the green and sustainable development of the shellfish industry and the establishment of a shellfish toxin prevention and control system.

Targeting lipid metabolism of macrophages: A new strategy for tumor therapy.

BACKGROUND: Lipid metabolism has been implicated in a variety of normal cellular processes and strongly related to the development of multiple diseases, including tumor. Tumor-associated macrophage (TAM) has emerged as a crucial regulator in tumorigenesis and promising target for tumor treatment. AIM OF REVIEW: A thorough understanding of TAM lipid metabolism and its value in tumorigenesis may provide new ideas for TAM-based anti-tumor therapy. Key scientific concepts of review: TAMs can be divided into two main types, M1-like TAMs and M2-like TAMs, which play anti-tumor and pro-tumor functions in tumor occurrence and development, respectively. Accumulating evidence has shown that lipid metabolic reprogramming, including fatty acid uptake and utilization, cholesterol expulsion, controls the polarization of TAMs and affects the tumorgenesis. These advances in uncovering the intricacies of lipid metabolism and TAMs have yielded new insights on tumor development and treatment. In this review, we aim to provide an update on the current understanding of the lipid metabolic reprogramming made by TAMs to adapt to the harsh tumor microenvironment (TME). In particular, we emphasize that there is complex lipid metabolism connections between TAMs and distinct tumors, which influences TAM to bias from M1 to M2 phenotype in tumor progression, and ultimately promotes tumor occurrence and development. Finally, we discuss the existing issues on therapeutic strategies by reprogramming TAMs based on lipid metabolism regulation (or increasing the ratio of M1/M2-like TAMs) that could be applied in the future to clinical tumor treatment.

Benzosceptrin C induces lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting DHHC3.

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade has become a mainstay of cancer immunotherapy. Targeting the PD-1/PD-L1 axis with small molecules is an attractive approach to enhance antitumor immunity. Here, we identified a natural marine product, benzosceptrin C (BC), that enhances the cytotoxicity of T cells to cancer cells by reducing the abundance of PD-L1. Furthermore, BC exerts its antitumor effect in mice bearing MC38 tumors by activating tumor-infiltrating T cell immunity. Mechanistic studies suggest that BC can prevent palmitoylation of PD-L1 by inhibiting DHHC3 enzymatic activity. Subsequently, PD-L1 is transferred from the membrane to the cytoplasm and cannot return to the membrane via recycling endosomes, triggering lysosome-mediated degradation of PD-L1. Moreover, the combination of BC and anti-CTLA4 effectively enhances antitumor T cell immunity. Our findings reveal a previously unrecognized antitumor mechanism of BC and represent an alternative immune checkpoint blockade (ICB) therapeutic strategy to enhance the efficacy of cancer immunotherapy.

The miR-7/EGFR axis controls the epithelial cell immunomodulation and regeneration and orchestrates the pathology in inflammatory bowel disease.

INTRODUCTION: The epithelial immunomodulation and regeneration are intrinsic critical events against inflammatory bowel disease (IBD). MiR-7 is well documented as a promising regulator in the development of various diseases including inflammatory diseases. OBJECTIVES: This study aimed to assess the effect of miR-7 in intestinal epithelial cells (IECs) in IBD. METHODS: MiR-7def mice were given dextran sulfate sodium (DSS) to induce enteritis model. The infiltration of inflammatory cells was measured by FCM and immunofluorescence assay. 5'deletion assay and EMSA assays were performed to study the regulatory mechanism of miR-7 expression in IECs. The inflammatory signals and the targets of miR-7 were analyzed by RNA-seq and FISH assay. IECs were isolated from miR-7def, miR-7oe and WT mice to identify the immunomodulation and regeneration capacity. IEC-specific miR-7 silencing expression vector was designed and administered by the tail vein into murine DSS-induced enteritis model to evaluate the pathological lesions of IBD. RESULTS: We found miR-7 deficiency improved the pathological lesions of DSS-induced murine enteritis model, accompanied by elevated proliferation and enhanced transduction of NF-κB/AKT/ERK signals in colonic IECs, as well as decreased local infiltration of inflammatory cells. MiR-7 was dominantly upregulated in colonic IECs in colitis. Moreover, the transcription of pre-miR-7a-1, orchestrated by transcription factor C/EBPα, was a main resource of mature miR-7 in IECs. As for the mechanism, EGFR, a miR-7 target gene, was downregulated in colonic IECs in colitis model and Crohn's disease patients. Furthermore, miR-7 also controlled the proliferation and inflammatory-cytokine secretion of IECs in response to inflammatory-signals through EGFR/NF-κB/AKT/ERK pathway. Finally, IEC-specific miR-7 silencing promoted the proliferation and transduction of NF-κB pathway in IECs and alleviated the pathological damage of colitis. CONCLUSION: Our results present the unknown role of miR-7/EGFR axis in IEC immunomodulation and regeneration in IBD and might provide clues for the application of miRNA-based therapeutic strategies in colonic diseases.

MiR-7 deficiency promotes Th1 polarization of CD4+T cells and enhances the antitumor effect in adoptive cell therapy for lung cancer.

Adoptive-cell-therapy (ACT) is important therapeutic approach against cancer. We previously showed that miR-7 deficiency endowed CD4+T cells with hyperactivation status in liver injury. However, whether CD4+T cells with miR-7 deficiency could elicit antitumor effect in ACT is still unclear. Naïve CD4+CD62Lhi T cells were purified from CD45.2 WT or CD45.2 miR-7def mice and transferred into syngeneic CD45.1WT mice bearing with lung tumor cells. The infiltration and function of T cells were measured by FCM and immunofluorescence assay. And naïve CD4+CD62Lhi T cells were purified from CD45.2 WT or CD45.2 miR-7def mice, then the cells were activated with CD3 antibody plus CD28 antibody in vitro for 24 h. Then, the cultured supernatant of LLC tumor cells or cytokines IFN-γ and IL-12 was added to establish Th1 polarization. Under these conditions, Th1 polarization-related molecules in these cells were analyzed by flow cytometry. Our data demonstrated a significant reduction in the growth and metastasis of lung cancer cells in the miR-7def CD4+T cell-transferred group, accompanied by a significant enhancement in the infiltration, proliferation, activation, and Th1 polarization of CD4+ T cells. Moreover, we observed the proliferation; activation of tumor-infiltrating CD8+ T cells was significantly increased in the local tumor of the CD45.2 miR-7def CD4+ T cell-transferred group, compared to the CD45.2 WT CD4+ T cell-transferred group. It is noteworthy that MAPK4, a target molecule of miR-7, was upregulated in CD4+ T cells from lung tumor tissues, resulting in an altered transduction of phosphorylation of NF-κB as well as AKT and ERK in vivo and in vitro. miR-7 deficiency promoted Th1-polarization of CD4+ T cells and elicited effective antitumor immune responses in ACT.

Risk characteristics of shellfish toxins in Mytilus unguiculatus around the Zhoushan Islands, East China Sea.

The Zhoushan Islands, are an important area for Mytilus unguiculatus aquaculture, and are threatened by potentially harmful algal blooms. However, a full understanding of the risks posed by their toxin residues is still lacking. M. unguiculatus samples were collected from the area between 2020 and 2021 and analyzed for their toxin profiles to assess the contamination status of shellfish toxins. The main toxins detected were the paralytic shellfish toxins (PSTs), gymnodimine (GYM), and domoic acid (DA). Nine PSTs components were detected, the dominant ones being C1, C2, and GTX5, with an overall detection rate of 85.7 %. The detection rate of DA was 55.05 %, and GYM was detected in all samples. The toxin levels in the samples were significantly lower than the European Union regulatory limits, but toxin contamination was generally universal.

Eukaryotic Translation Initiation Factor 2 Subunit ß as a Prognostic Biomarker Associates With Immune Cell Infiltration in Breast Cancer.

INTRODUCTION: The present study aims to explore the expression level of eukaryotic translation initiation factor 2 subunit ß (EIF2S2) in breast cancer tissue, and its role both in breast cancer prognosis and in the immune microenvironment. METHODS: To assess the association between the expression levels of EIF2S2 and prognosis, the Gene Expression Profiling Interactive Analysis database was initially applied to determine differences in the gene expression of EIF2S2 in various malignant and normal tissues. Furthermore, the expression levels of EIF2S2 were determined in the clinical breast cancer tissues and corresponding para-neoplastic tissues using immunohistochemical analysis. In addition, Kaplan-Meier survival and Cox regression analyses were employed to explore the association between EIF2S2 expression levels and patient prognosis. Finally, the correlation between the expression levels of EIF2S2 and immune cell infiltration in breast cancer was analyzed using the TIMER2.0 database, and subsequently validated by immunohistochemical experiments. RESULTS: The Gene Expression Profiling Interactive Analysis database revealed the presence of higher expression levels of EIF2S2 in various different types of cancer compared with normal cells, also correlating its expression with both the age and the tumor stage of patients with breast cancer. The survival analysis results revealed that high expression levels of EIF2S2 could be a risk factor for poor prognosis in patients with breast cancer. Moreover, the EIF2S2 expression level was found to be closely associated with the infiltration levels of various immune cells, including regulatory T cells, CD4+, CD8+, and natural killer cells, in breast cancer. CONCLUSIONS: In conclusion, the present study has demonstrated that an upregulated expression level of EIF2S2 in breast cancer may be associated with poor patient prognosis, affecting immune cell infiltration in breast cancer. Taken together, the findings of the present study have shown that EIF2S2 expression may be a novel therapeutic target for breast cancer.

Discovery of a Highly Potent and Selective MYOF Inhibitor with Improved Water Solubility for the Treatment of Gastric Cancer.

Myoferlin (MYOF) mediates the growth and metastasis of various cancers as an emerging therapeutic target by regulating exocytosis and endocytosis. However, the previously reported MYOF inhibitor, 6y, failed to be a favorable candidate agent due to its poor physicochemical properties, such as water solubility, in preclinical studies. Naturally, a novel range of MYOF inhibitors was synthesized and optimized based on the lead compound 6y. The optimal compound HJ445A potently repressed the proliferation of gastric cancer cells with IC50 values of 0.16 and 0.14 µM in MGC803 and MKN45, respectively. Moreover, HJ445A bound to the MYOF-C2D domain with a KD of 0.17 µM, and HJ445A prevented the migration of gastric cancer cells by reversing the epithelial-mesenchymal transition (EMT) process and inhibited the colony formation of the MKN45 cells in a concentration-dependent manner. Notably, the water solubility of HJ445A was significantly improved compared to 6y, with about 170-fold enhancement. Additionally, HJ445A also demonstrated superior antitumor efficacy in vivo.

Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway.

Pyroptosis, a mode of inflammatory cell death, has recently gained significant attention. However, the underlying mechanism remains poorly understood. HGS-ETR1/2 is a humanized monoclonal antibody that can bind to DR4/5 on the cell membrane and induce cell apoptosis by activating the death receptor signalling pathway. In this study, by using morphological observation, fluorescence double staining, LDH release and immunoblot detection, we confirmed for the first time that HGS-ETR1/2 can induce GSDME-mediated pyroptosis in hepatocellular carcinoma cells. Our study found that both inhibition of the AKT signalling pathway and silencing of CPA4 promote pyroptosis, while the overexpression of CPA4 inhibits it. Furthermore, we identified a positive regulatory feedback loop is formed between CPA4 and AKT phosphorylation. Specifically, CPA4 modulates AKT phosphorylation by regulating the expression of the AKT phosphatase PP2A, while inhibition of the AKT signalling pathway leads to a decreased transcription and translation levels of CPA4. Our study reveals a novel mechanism of pyroptosis induced by HGS-ETR1/2, which may provide a crucial foundation for future investigations into cancer immunotherapy.

3ß-hydroxysteroid-Δ24 reductase dampens anti-viral innate immune responses by targeting K27 ubiquitination of MAVS and STING.

IMPORTANCE: The precise regulation of the innate immune response is essential for the maintenance of homeostasis. MAVS and STING play key roles in immune signaling pathways activated by RNA and DNA viruses, respectively. Here, we showed that DHCR24 impaired the antiviral response by targeting MAVS and STING. Notably, DHCR24 interacts with MAVS and STING and inhibits TRIM21-triggered K27-linked ubiquitination of MAVS and AMFR-triggered K27-linked ubiquitination of STING, restraining the activation of MAVS and STING, respectively. Together, this study elucidates how one cholesterol key enzyme orchestrates two antiviral signal transduction pathways.

YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer.

Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the FSP1 3'-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR contained FSP1 mRNA, whereas YTHDC1 downregulation generated the longer 3'-UTR contained FSP1 mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1high lung cancer.