Journal of Molecular Histology最新文献

{"title":"Myrtenol ameliorates ulcerative colitis by modulating ANXA1/PINK1/Parkin-mediated mitophagy","authors":"Yimin Li,&nbsp;Xiaobing Gong,&nbsp;Yinghua Peng,&nbsp;Yadang Kuang,&nbsp;Jiaxuan Huang,&nbsp;Mengli Zheng,&nbsp;Leilei Zhan,&nbsp;Jiewen Liang,&nbsp;Weiyi Guo","doi":"10.1007/s10735-025-10486-4","DOIUrl":"10.1007/s10735-025-10486-4","url":null,"abstract":"<div><p>Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by recurrent and intermittent episodes of inflammation. (-)-Myrtenol (MYR) has been shown to exhibit anti-inflammatory, antioxidant, and gastroprotective properties; however, its therapeutic potential in UC remains unexplored. In this study, we established in vitro UC models using lipopolysaccharide (LPS)-induced Caco-2 cells and in vivo models using dextran sulfate sodium (DSS)-induced mice to investigate the effects of MYR on UC. Our findings demonstrated that MYR protected Caco-2 cells from LPS-induced apoptosis and restored mitochondrial function by activating mitophagy. Mechanistically, MYR exerted its protective effects by upregulating ANXA1 expression in LPS-challenged Caco-2 cells, which subsequently activated the PINK1/Parkin pathway. Consistent with these in vitro results, experiments in the DSS-induced mouse model revealed that MYR alleviated UC symptoms and mitigated mitochondrial damage through the regulation of the ANXA1/PINK1/Parkin pathway-mediated mitophagy. In conclusion, MYR reduced apoptosis in LPS-induced Caco-2 cells and ameliorated UC symptoms in DSS-induced mice by enhancing mitophagy and alleviating mitochondrial dysfunction via the ANXA1/PINK1/Parkin pathway.</p></div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of USP17 knockdown on autophagic ferroptosis in gastric cancer by regulating the BNIP3–NCOA4–FTH1 axis","authors":"Jintao Tang,&nbsp;Lebin Yang,&nbsp;Xiongying Chen,&nbsp;Kai Yin,&nbsp;Chunyun Wang","doi":"10.1007/s10735-025-10526-z","DOIUrl":"10.1007/s10735-025-10526-z","url":null,"abstract":"<div>\u0000 \u0000 <p>Gastric cancer (GC) is one of the most crucial malignancies worldwide because of the high lethality. This study aims to explore the mechanism by which ubiquitin-specific protease 17 (USP17) mediates autophagic ferroptosis in GC. In the present study, we cultured human GC cell line AGS in vitro and knocked BNIP3 or NCOA4 down using specific small interfering-RNA. Erastin was chosen as a ferroptosis inducer while Ferrostatin-1 was utilized as an inhibitor of ferroptosis. Then, the levels of mitophagy-related proteins, USP17, BNIP3, mitochondrial marker proteins, NCOA4, and FTH1 were quantified through RT-qPCR and Western blot tests. Also, the JC-1 method was adopted to detect mitochondrial membrane potential. Additionally, CCK-8 cell viability test was performed. Ultimately, glutathione, reactive oxygen species, malondialdehyde, and active Fe²⁺ were determined as indicators related to ferroptosis using corresponding kits. The interaction between USP17 and BNIP3 was assessed through co-immunoprecipitation. Genetic inhibition of BNIP3 reduced mitophagy and increased ferroptosis in GC cells. Subsequently, upon BNIP3 silencing, we found up-regulated NCOA4 and down-regulated FTH1, with autophagy inhibition resulting in the similar changes in the NCOA4–FTH1 pathway and cellular Fe²⁺ levels. NCOA4 inhibition partly counteracted BNIP3 deficiency-induced ferroptosis, indicating that BNIP3-dependent autophagic ferroptosis was associated with the NCOA4–FTH1 pathway. Furthermore, it was found that USP17 stabilized BNIP3 by reducing its ubiquitination level, which was linked to the regulatory role of USP17 in ferroptosis. USP17 knockdown modulates autophagic ferroptosis in GC by affecting the stability of BNIP3 and mediating the NCOA4–FTH1 pathway.</p>\u0000 </div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14 alleviates sepsis-induced acute kidney injury by targeting Hmox1-mediated ferroptosis through m6A modification","authors":"Chengyi Yang,&nbsp;Le Zhao,&nbsp;Jia Di,&nbsp;Xin Zhou","doi":"10.1007/s10735-025-10521-4","DOIUrl":"10.1007/s10735-025-10521-4","url":null,"abstract":"<div>\u0000 \u0000 <p>The m6A methyltransferase METTL14 plays a role in cellular stress responses, but its function in sepsis-associated acute kidney injury (S-AKI) remains unclear. This study investigates METTL14’s involvement in regulating ferroptosis and inflammation through HMOX1 in S-AKI. We analyzed renal tissues from S-AKI patients and a CLP-induced murine model for histological and molecular changes. In vitro, LPS-treated HK-2 cells were used to mimic S-AKI, with METTL14 expression manipulated via lentiviral transfection. Ferroptosis and inflammatory responses were evaluated using ELISA, qPCR, immunohistochemistry, and western blotting. ROS and lipid peroxidation were assessed with C11-BODIPY, while MeRIP and actinomycin D assays explored m6A modification and mRNA stability of HMOX1. Survival outcomes were assessed over 7 days post-CLP surgery. HMOX1 modulation was further examined using Hemin (inducer) and ZnPP (inhibitor) in vivo. METTL14 was significantly downregulated in both human S-AKI patient tissues and murine CLP models. Its overexpression improved renal function, reduced histological injury and mortality, and suppressed pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). Mechanistically, we identified METTL14 as a novel regulator of HMOX1, promoting its m6A-dependent degradation and thereby limiting iron accumulation and lipid peroxidation associated with ferroptosis. This regulatory axis was confirmed by pharmacological modulation, where Hemin reversed METTL14’s protective effects, while ZnPP rescued METTL14-deficient mice. Additionally, METTL14 reduced ROS generation and stabilized redox homeostasis. METTL14 protects against S-AKI by suppressing ferroptosis via m6A-dependent regulation of HMOX1. These findings reveal a novel epitranscriptomic pathway and suggest METTL14 as a promising therapeutic target for S-AKI.</p>\u0000 </div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the role of xanthine oxidase and aldehyde oxidase in metabolic dysfunction-associated steatotic liver disease (MASLD)","authors":"Neha Gupta,&nbsp;Kavita Singh","doi":"10.1007/s10735-025-10507-2","DOIUrl":"10.1007/s10735-025-10507-2","url":null,"abstract":"<div><p>Globally, metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed as non-alcoholic fatty liver disease (NAFLD), has been affecting millions of people. It includes a spectrum of liver conditions, ranging from simple fat accumulation (steatosis) to advanced stages such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Oxidative stress has been identified as a major contributing factor in driving disease progression. Enzymes such as xanthine oxidase (XO) and aldehyde oxidase (AO) are significant contributors of reactive oxygen species (ROS), which in turn promote inflammation and cause liver damage. While cytochrome (CYP)-P450 enzymes are well studied in MASLD research, the precise roles of XO and AO remain less understood. This review explores the involvement of XO and AO in MASLD, linking their biochemical pathways to oxidative stress, metabolic dysfunction and inflammation. We have also discussed a few other ROS-generating enzymes like NADPH oxidases, lipoxygenases, myeloperoxidase and monoamine oxidases, which exacerbate liver fibrosis and inflammation. Therapeutic strategies targeting these enzymes, such as XO inhibitors (allopurinol, febuxostat) and AO inhibitors (hydralazine), can potentially mitigate the burden of oxidative stress in MASLD treatment. Future research should focus on elucidating enzyme-specific mechanisms and optimizing targeted therapies. A comprehensive approach integrating enzyme inhibition, antioxidants, lifestyle changes and dietary interventions may form the cornerstone of effective management and prevention of MASLD.</p></div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL5-mediated m6A modification of UBE3C promotes osteosarcoma progression by suppressing ferroptosis via inducing AHNAK ubiquitination","authors":"Ning Chen,&nbsp;Zhenwen Zhang,&nbsp;Fangqin Shen,&nbsp;Daming Lu","doi":"10.1007/s10735-025-10495-3","DOIUrl":"10.1007/s10735-025-10495-3","url":null,"abstract":"<div><p>Ferroptosis, marked by iron-dependent lipid peroxidation, emerges as a promising approach for osteosarcoma (OS) intervention due to its tumor susceptibility. Ubiquitination is a key post-translational modification involved in regulating cell ferroptosis and is closely linked to cancer development. Ubiquitin protein ligase E3C (UBE3C), an E3 ubiquitin ligase plays a carcinogenic role in several cancers. However, the roles and molecular mechanisms of UBE3C in OS cell ferroptosis remain unclear. UBE3C level was enhanced in OS tissues and cells, and UBE3C depletion impeded OS cell proliferation, migration, and invasion and accelerated ferroptosis. Moreover, Fer-1 administration counteracted the inhibitory impact of UBE3C silencing on the malignant behavior of U2OS and 143B cells. Mechanistically, UBE3C promoted the ubiquitination and degradation of AHNAK in U2OS and 143B cells. AHNAK counteracted the effect of UBE3C on promoting cell proliferation, migration, and invasion and inhibiting cell ferroptosis. Further, METTL5-mediated m6A modification enhanced UBE3C mRNA stability by enabling YTHDF1 to bind and protect the modified mRNA from degradation. METTL5 addition inhibited AHNAK level which was abolished by UBE3C silencing. Our work uncovered a new METTL5-YTHDF1-UBE3C-AHNAK signaling axis regulating ferroptosis and driving OS progression. Targeting this axis offers a promising approach to enhance ferroptosis sensitivity against OS.</p></div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial CLK2 promotes chemotherapy resistance in colorectal Cancer by regulating oxidative phosphorylation and ferroptosis","authors":"Xingchun Xiao,&nbsp;Qiling Lin,&nbsp;Wentai Shi","doi":"10.1007/s10735-025-10533-0","DOIUrl":"10.1007/s10735-025-10533-0","url":null,"abstract":"<div>\u0000 \u0000 <p>Chemotherapy resistance remains a major challenge in colorectal cancer (CRC) treatment, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that CDC-like kinase 2 (CLK2) expression is significantly upregulated in CRC tissues and correlates with poor chemotherapeutic outcomes. CLK2 shows distinct nuclear-mitochondrial localization in chemoresistant cells compared to predominantly nuclear localization in parental cells. Mechanistically, mitochondrial CLK2 maintains enhanced oxidative phosphorylation and suppresses ferroptosis in resistant cells. CLK2 depletion or pharmacological inhibition sensitizes resistant cells to 5-fluorouracil and oxaliplatin treatment through disruption of mitochondrial function and enhanced ferroptosis sensitivity. Moreover, combined targeting of CLK2 and mitochondrial function shows synergistic effects in overcoming chemoresistance. Our findings reveal a previously unrecognized role of mitochondrial CLK2 in promoting chemotherapy resistance through regulation of mitochondrial metabolism and ferroptosis, suggesting potential therapeutic strategies for drug-resistant colorectal cancer.</p>\u0000 </div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the effects of monosodium glutamate on the development of the cerebellum in chicken embryos","authors":"Ferhan Bölükbaş,&nbsp;Yasemin Öznurlu","doi":"10.1007/s10735-025-10522-3","DOIUrl":"10.1007/s10735-025-10522-3","url":null,"abstract":"<div><p>Monosodium glutamate (MSG) is a globally used food additive in the modern diet. This study aimed to search the impact of varying doses of MSG administered on embryonic development of the cerebellum. A total of 410 fertilized chicken eggs were randomly assigned to five groups: an untreated control group, a vehicle control group, and groups receiving low-dose (0.12 mg/g egg), medium-dose (0.6 mg/g egg), and high-dose (1.2 mg/g egg) MSG, respectively. The test solutions were injected into the yolk of eggs through a sterile insulin injector. On the 15th, 18th, and 21st days of incubation, the eggs from each group were randomly opened, and six live embryos were obtained. Cerebellum samples of embryos from each group were taken. The number of Purkinje cells in the cerebellum demonstrated a reduction in MSG-treated groups by the 15th, 18th, and 21st days of incubation (<i>p </i>&lt; 0.05). It was noted that the organization of Purkinje cells was irregular, and degeneration and necrosis were also observed in the MSG-treated groups. A notable decrease in the thickness of both the outer and inner granular layers was observed in the MSG-treated groups on the 15th, 18th, and 21st day of incubation. While molecular layer thickness increased on day 15 and 21, decreased on day 18 (<i>p</i> &lt; 0.05). Total cortex thickness decreased significantly in MSG-treated groups. PCNA-positive cells in the cerebellum were found in Purkinje cells, molecular layer cells, and outer and inner granular layer cells. However, there was a decrease in PCNA ( +) cell density in MSG-treated groups (<i>p</i> &lt; 0.05).</p></div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lagerstroemia Speciosa (L.) Pers mitigates acetaminophen-induced acute liver toxicity in rats through modulations of oxidative stress, inflammation, apoptosis and the NF-κB/TNF-α/iNOS, Nrf2/HO-1, signaling pathways","authors":"Nagham E. Elsheshtawy,&nbsp;Fatma M. Abdelhamid,&nbsp;Engy F. Risha,&nbsp;Hebatallah A. Mahgoub,&nbsp;Ahmed I. Ateya,&nbsp;Mohamed E. El-Boshy","doi":"10.1007/s10735-025-10493-5","DOIUrl":"10.1007/s10735-025-10493-5","url":null,"abstract":"<div><p>Acetaminophen (APAP) is a widely used analgesic and antipyretic, but its toxicity can lead to liver injury or failure. This study evaluated the hepatoprotective mechanisms of <i>L. speciosa</i> ethanolic leaf extract (LSE) against APAP-induced hepatic damage. Rats were randomly divided into five groups: Control (Cont), APAP (2 g/kg b.w. single oral dose on day 22), LSE (500 mg/kg b.w./day), APAP + LSE, and APAP + NAC (initial NAC dose of 100 mg/kg b.w. two hours post-APAP, followed by maintenance doses every 12 h). APAP-intoxicated rats showed leukocytosis, decreased erythrocyte count, Hb, and PCV, increased serum bilirubin, and elevated ALT, AST, and ALP activities. APAP intoxication also decreased plasma protein levels, albumin, and globulin while increasing liver MDA and depleting GSH. The expressions of hepatic SOD and CAT were reduced, while NF-κB, TNF-α, iNOS, Nrf2, and HO-1 were significantly upregulated. Also, APAP increased Bax and decreased Bcl-2. LSE improved most parameters, suppressing oxidative stress, inflammation, and apoptosis and regulating NF-κB, TNF-α, iNOS, Nrf2, HO-1, Bax, and Bcl-2 expression. Nevertheless, the deeper upstream molecular targets of LSE require further exploration. Its effects were comparable to NAC, with NAC showing slightly superior outcomes in some markers. Our findings suggest that LSE contains hepatoprotective phytochemicals capable of mitigating oxidative damage, inflammation, and apoptosis induced by APAP, supporting its potential as a natural alternative for managing drug-induced liver injury.</p></div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding phillygenin’s dual attack on breast cancer: ferroptosis induction and immune evasion suppression","authors":"Yan Zhang,&nbsp;Xiaohong Lu,&nbsp;Ruie Li,&nbsp;Jingheng Zhang,&nbsp;Jiayu Peng,&nbsp;Yafei Li","doi":"10.1007/s10735-025-10525-0","DOIUrl":"10.1007/s10735-025-10525-0","url":null,"abstract":"<div><p>Ferroptosis and immune evasion are pivotal mechanisms in the pathogenesis of breast cancer (BC), making them promising therapeutic targets. Phillygenin (PHI), a lignan compound derived from <i>Forsythiae Fructus</i>, has demonstrated broad pharmacological properties, including anti-tumor effects. To discuss the impact of PHI on BC. The study examined PHI’s anti-tumor properties and mechanisms using CCK-8 assays, biochemical analyses, DCHF-DA staining, ELISA, immunofluorescence, and western blot techniques. Tumor-bearing mice were utilized for studies in vivo, with tumor tissues being analyzed by H&amp;E staining, immunohistochemistry, and western blotting. The viability of MDA-MB-231 and MCF7 cells was notably repressed by PHI, with respective IC50 values of 81.44 µM and 95.72 µM. PHI elevated intracellular Fe²⁺ levels, an effect synergistically enhanced by erastin but attenuated by ferrostatin-1. Furthermore, PHI increased reactive oxygen species (ROS) levels while downregulating GPX4 and SLC7A11 expression in both cell lines. PHI also enhanced CD8⁺ T cell cytotoxicity and upregulated IFN-γ and IL-2 levels, but suppressing PD-L1 expression. Mechanistically, PHI repressed the phosphorylation of AKT and GSK3β, along with the β-catenin expression, effects that were reversed by the AKT activator SC79. SC79 also counteracted PHI-induced changes in proliferation, ferroptosis, and immune evasion markers in MDA-MB-231 cells. PHI decreased tumor size and mass, lowered GPX4, p-AKT/AKT, p-GSK3β/GSK3β, and β-catenin levels, and elevated IFN-γ levels in MDA-MB-231 xenograft models. PHI inhibited BC cell proliferation and immune evasion while promoting ferroptosis through suppression of the AKT/β-catenin axis, highlighting its possible as a therapeutic agent for BC.</p></div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14 induces ferroptosis to inhibit colorectal cancer progression by inhibiting TRIB3 via an m6A-YTHDF2-dependent manner","authors":"Daquan Zhang,&nbsp;Xiaoyu Liu,&nbsp;Binyu Luo,&nbsp;Xiao Zhang,&nbsp;Qing Teng,&nbsp;Xingmei Xia,&nbsp;Bin liao","doi":"10.1007/s10735-025-10496-2","DOIUrl":"10.1007/s10735-025-10496-2","url":null,"abstract":"<div><p>Ferroptosis, a form of regulated cell death caused by iron-dependent accumulation of lipid peroxides, is recently demonstrated as a vital player in cancer development. Tribbles homolog 3 (TRIB3) is a contributing factor to the malignant progression of several human cancers, including colorectal cancer (CRC). However, its regulatory effect and mechanism in CRC are obscure. qRT-PCR and western blot assays determined the mRNA and protein expression of TRIB3, methyltransferase-like 14 (METTL14), and YT521-B homology domain family 2 (YTHDF2). Cell ferroptosis was evaluated by measuring the levels of intracellular reactive oxygen species (ROS), lipid ROS, malondialdehyde (MDA), and glutathione (GSH). Cell malignant progression were assessed by CCK-8, EdU, transwell, and xenograft assays. The m6A sites of TRIB3 were confirmed using m6A RNA immunoprecipitation (Me-RIP) assay. The binding between TRIB3 and METTL14 or YTHDF2 was validated using RIP or luciferase reporter experiments. We observed higher expression of TRIB3 and lower expression of METTL14 in CRC tissues and cells. Knockdown of TRIB3 increased ferroptosis by promoting the generation of intracellular ROS, lipid ROS, and MDA and inhibiting the production of GSH. Suppressing TRIB3 also decreased tumor growth by increasing ferroptosis in mice. Mechanistically, knockdown of METTL14 reduced the m6A modification of TRIB3 and elevated TRIB3 mRNA expression. Moreover, METTL14-methylated TRIB3 was was recognized by YTHDF2, which resulted in the degradation of TRIB3 mRNA. TRIB3 overexpression reversed METTL14-mediated ferroptosis in CRC cells. Silencing YTHDF2 also abrogated the promotive effect of METTL14 on ferroptosis in CRC cells. Additionally, knockdown of TRIB3 induced ferroptosis by inactivating the SLC7A11/GPX4 signaling. METTL14 suppressed the SLC7A11/GPX4 signaling by targeting TRIB3. METTL14 suppressed CRC cell proliferation, migration, and invasion by downregulating TRIB3. Our findings suggest that METTL14 suppressed TRIB3 expression via an m6A-YTHDF2-dependent manner, thus inducing ferroptosis to inhibit the malignant progression of CRC. TRIB3 is potentially exploited as a molecular target for CRC treatment based on ferroptosis.</p></div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 4","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}