WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1

Psoriasis is a chronic inflammation-associated skin disorder, and interleukin-22 (IL-22) is involved in psoriasis pathogenesis by boosting the proliferation and migration of keratinocytes. Mounting evidence has shown that circRNAs might play an important role in several aspects of psoriasis. This study is designed to explore the role and mechanism of circ_0056856 in regulating the phenotypes of IL-22-induced keratinocytes (HaCaT cells). Circ_0056856, microRNA-197-3p (miR-197-3p), Cyclin-dependent kinase 1 (CDK1), and Wilms tumor 1-associated protein (WTAP) levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, proliferation, migration, and invasion were analyzed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Wound scratch, and Transwell assays. After being predicted by Circinteractome or TargetScan, binding between miR-197-3p and circ_0056856 or CDK1 was verified by a dual-luciferase reporter assay. CDK1 and WTAP protein levels were determined using Western blot. Interaction between WTAP and circ_0056856 was assessed using methylated RNA immunoprecipitation (MeRIP) assay. Increased circ_0056856, CDK1, and WTAP were observed in psoriasis patients and IL-22-treated HaCaT cells. Moreover, circ_0056856 knockdown might repress IL-22-induced HaCaT cell proliferation, migration, and invasion in vitro. In mechanism, circ_0056856 might function as a sponge of miR-197-3p to modulate CDK1 expression, and WTAP improved circ_0056856 expression via m6A methylation. WTAP-guided m6A modified circ_0056856 facilitates IL-22-stimulated HaCaT cell damage through the miR-197-3p/CDK1 axis, which could provide novel insights into psoriasis treatment.

Castration-resistant prostate cancer (CRPC) is one of the most prevalent cancers in men. The new generation androgen receptor (AR) inhibitor enzalutamide can improve the therapeutic effectiveness of patients with CRPC. However, these patients eventually develop acquired enzalutamide resistance (ENZR), and the mechanisms underlying resistance are not well understood. Wilms' tumor 1-associating protein (WTAP) plays an important role in m6A modification and has been reported as an oncogene in various cancers. Here, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m6A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors. In this manuscript, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m6A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors.

N6-methyladenosine (m6A) methylation, a well-known modification with new epigenetic functions, has been reported to participate in the progression of osteoporosis (OP), providing novel insights into the pathogenesis of OP. However, as the key component of m6A methylation, Wilms tumor 1-associated protein (WTAP) has not been studied in OP. Here we explored the biological role and underlying mechanism of WTAP in OP and the differentiation of bone marrow mesenchymal stem cells (BMMSCs). We demonstrated that WTAP was expressed at low levels in bone specimens from patients with OP and OVX mice. Functionally, WTAP promoted osteogenic differentiation and inhibited adipogenic differentiation of BMMSCs in vitro and in vivo. In addition, microRNA-29b-3p (miR-29b-3p) was identified as a downstream target of WTAP. M6A modifications regulated by WTAP led to increased miR-29b-3p expression. WTAP interacted with the microprocessor protein DGCR8 and accelerated the maturation of pri-miR-29b-3p in an m6A-dependent manner. Target prediction and dual-luciferase reporter assays identified the direct binding sites of miR-29b-3p with histone deacetylase 4 (HDAC4). WTAP-mediated m6A modification promoted osteogenic differentiation and inhibited adipogenic differentiation of BMMSCs through the miR-29b-3p/HDAC4 axis. Furthermore, WTAP-mediated m6A methylation negatively regulates osteoclast differentiation. Collectively, our study first identified a critical role of WTAP-mediated m6A methylation in BMMSC differentiation and highlighted WTAP as a potential therapeutic target for OP treatment.

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most frequently occurring subtype of lymphoma. Unfortunately, the fundamental processes underlying the pathogenesis of DLBCL remain little understood. N6-methyladenosine (m6A) methylation has been shown to be the most common internal alteration of mRNAs found in eukaryotes, and it is thought to play a key role in cancer pathogenesis. However, the precise relationship between m6A mRNA methylation and DLBCL pathogenesis remains to be fully elucidated.MethodsThe mRNA and protein expression of Wilms tumor 1-associating protein (WTAP) were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis in lymphoma cells lines. The effects of WTAP expression on human lymphoma cells lines were assessed using cell proliferation assays, colony formation assays, and CCK8 assays. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to screen candidate gene targets of WTAP. Finally, the regulatory mechanisms of WTAP in DLBCL were investigated using methylated RNA immunoprecipitation (MeRIP) assays.ResultsThis study investigated the precise function of WTAP in DLBCL formation. The results demonstrated that the levels of m6A RNA methylation and WTAP expression were both elevated in DLBCL cell lines and tissues. Downregulation of WTAP expression in DLBCL cells caused a reduction in cell growth in a functional sense. WTAP knockdown reduced catenin beta 1 (CTNNB1) m6A methylation and CTNNB1 total mRNA levels. Furthermore, CTNNB1 overexpression eliminated the WTAP-induced reduction of cell growth in DLBCL cells.ConclusionsIn conclusion, these findings demonstrated that WTAP promotes DLBCL development via modulation of m6A methylation in CTNNB1.

The long noncoding RNA FAM83H-antisense RNA 1 (FAM83H-AS1) is involved in gastric cancer (GC) development. This study determined whether FAM83H-AS1 was regulated by N6-methyladenosine (m6A) modifications in GC.Real-time quantitative polymerase chain reaction was performed to determine the expression levels of FAM83H-AS1 and Wilms' tumor 1 associated protein (WTAP). The protein content of WTAP was evaluated using western blotting. To assess the m6A alterations in FAM83H-AS1, methylated RNA immunoprecipitation was performed to identify interactions between WTAP and FAM83H-AS1. Functionally, the proliferation, migration, and invasion of GC cells were measured using a Cell Counting Kit-8 and transwell assays, respectively.High expression levels of FAM83H-AS1 and WTAP were detected in GC samples and there was a positive correlation between them. In addition, WTAP mediates FAM83H-AS1 expression in an m6A-dependent manner. Further investigations indicated that WTAP silencing reversed the cancer-promoting role of FAM83H-AS1 overexpression in GC cell migration, proliferation, and invasion.Our results suggest that WTAP-mediated FAM83H-AS1 promotes GC development via m6A modification. Our findings provide new biomarkers for GC diagnosis and targeted therapy.

Hepatocellular carcinoma (HCC) often requires targeted therapy and immunotherapy due to frequent delayed diagnosis. Sorafenib, the first targeted drug applied to treat HCC, has demonstrated a remarkable therapeutic effect in the clinic. However, its clinical application has been limited by drug resistance and the insufficient understanding of the relevant mechanism. Wilms' tumor 1-associated protein (WTAP), associated with tumor progression, remains unstated in sorafenib resistance. In this study, WTAP expression patterns in HCC were systematically characterized through integrative analysis of The Cancer Genome Atlas (TCGA) datasets and spatial transcriptomic profiling. To delineate the potential mechanisms of WTAP-mediated sorafenib resistance in HCC, multimodal approaches integrating gene set enrichment analysis (GSEA), predictions from the "oncoPredict" package in vitro experiments, molecular docking simulations, and western blot validation were applied. To further investigate the role of WTAP in drug resistance, hydrodynamic tail vein injection (HTVi) mouse models and immunohistochemistry were utilized. Significant WTAP upregulation was identified in HCC tissues, showing strong associations with tumor progression and adverse clinical outcomes. The knockdown of WTAP sensitized HCC cells to sorafenib in vitro. GSEA, molecular docking analysis, and western blot analysis demonstrated that WTAP induces the activation of the extracellular signal-regulated kinase (ERK) signaling pathway, a critical link in chemoresistance mechanisms. In the HTVi HCC model, the combination of WTAP knockdown with sorafenib markedly suppressed tumor progression and boosted survival rates. These findings highlight that WTAP positively regulates the ERK pathway in HCC, promoting sorafenib resistance; therefore, targeting WTAP may represent a novel strategy to potentiate sorafenib responsiveness in HCC.

Background: Hepatocellular carcinoma (HCC) is a primary aggressive gastrointestinal neoplasm that affects patients worldwide. It has been shown that Wilms' tumor 1-associating protein (WTAP) is frequently upregulated in various cancers. However, the potential role of WTAP in HCC remains largely unknown.Methods: The expression levels of WTAP in human HCC tissues were determined by the western blotting and immunohistochemical (IHC) staining. A correlation between the WTAP expression, clinicopathological features, and the HCC prognosis was analyzed. The WTAP expression was silenced by short hairpin RNA (shRNA), and effects of the knockdown of WTAP on the proliferation and invasion of HCC cells were assessed. The microRNAs (miRNAs) involved in the regulation of the WTAP expression were identified by a bioinformatics analysis and further confirmed by in vitro assays.Results: The expression levels of WTAP in liver cancer tissues were significantly elevated and compared with those in the adjacent normal tissues and significantly correlated with the clinical stage and prognosis in patients with HCC. Further investigation revealed that the knockdown of WTAP drastically suppressed HCC cell proliferation and invasion abilities. Luciferase reporter assay and validation experiments confirmed that WTAP was a direct target of miR-139-5p. Moreover, the overexpression of WTAP could partly abolish the inhibitory effects of miR-139-5p on the HCC cell growth and invasion. Mechanistically, we revealed that the miR-139-5p/WTAP axis regulated the HCC progression by controlling the epithelial to mesenchymal transition (EMT).Conclusions: In summary, the results indicate that WTAP is a potential oncogene in HCC and miR-139-5p negatively regulates the WTAP expression. MiR-139-5p/WTAP can be utilized as a potential therapeutic target for HCC.

Aim: Wilms' tumor 1-associating protein (WTAP), plays a part in colorectal cancer (CRC) progression. However, it is not yet known how WTAP affects cancer progression by influencing leukocyte rich repeat containing proteins (NLR) - family members 3 (NLRP3) - related inflammasomes.Materials & methods: We first validated the expression of WTAP in CRC at the tissue and cellular levels. Subsequently, by transfecting si-NC and si-WTAP into cells, we verified functions of WTAP in proliferation, invasion, migration and apoptosis of CRC cells. Finally, we analyzed the N6-methyladenosine (m6A) modification of NLRP3 by WTAP using methylated RNA immunoprecipitation (MeRIP)-qPCR technology, confirming that WTAP mediated the repression of NLRP3 inflammasome and the malignant progression of tumor cells.Results: WTAP was substantially upregulated in CRC tissues and cells. WTAP reinforced the migration, proliferation and invasion ability of CRC cells, and repressed apoptosis. Mechanistically, WTAP mediated the m6A modification of NLRP3, which suppressed the expression of NLRP3 and dampened the NLRP3/Caspase-1/GSDMD axis activation as well as pyroptosis, thereby facilitating the malignant progression of CRC.Conclusion: WTAP mediates m6A modification to modulate the repression of the NLRP3/Caspase-1/GSDMD axis in pyroptosis, reinforcing the malignant progression of CRC.

Acute kidney injury (AKI) is a serious complication of sepsis patients, but the pathogenic mechanisms underlying AKI are still largely unclear. In this view, the roles of the key component of N6-methyladenosine (m6A)-wilms tumor 1 associated protein (WTAP) in AKI progression were investigated. AKI mice model was established by using cecal ligation and puncture (CLP). AKI cell model was established by treating HK-2 cells with LPS. Cell apoptosis was analyzed by TdT-mediated dUTP Nick-End Labeling (TUNEL) staining and flow cytometry analysis. Cell viability was analyzed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The concentrations of inflammatory factors were examined with ELISA kits. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and Fe2+ levels were detected with related kits. Gene expression was detected by western blot assay or quantitative real-time polymerase chain reaction (qRT-PCR) assay. The relation between WTAP and lamin B1 (LMNB1) was verified by Methylated RNA Immunoprecipitation (meRIP) assay, RIP assay, dual-luciferase reporter assay and Actinomycin D assay. CLP induced significant pathological changes in kidney tissues in mice and promoted inflammation, mitochondrial damage and ferroptosis. LMNB1 level was induced in HK-2 cells by LPS. LMNB1 knockdown promoted LPS-mediated HK-2 cell viability and inhibited LPS-mediated HK-2 cell apoptosis, inflammation, mitochondrial damage and ferroptosis. Then, WTAP was demonstrated to promote LMNB1 expression by m6A Methylation modification. Moreover, WTAP knockdown repressed LPS-treated HK-2 cell apoptosis, inflammation, mitochondrial damage and ferroptosis, while LMNB1 overexpression reversed the effects. Additionally, WTAP affected the pathways of NF-κB and JAK2/STAT3 by LMNB1. WTAP-mediated m6A promoted the inflammation, mitochondrial damage and ferroptosis in LPS-induced HK-2 cells by regulating LMNB1 expression and activating NF-κB and JAK2/STAT3 pathways.

Endometrial cancer (EC) poses a great threat to women's health worldwide. Splicing factor 3B, subunit 1 (SF3B1) and the methyltransferase Wilms tumor 1-associated protein (WTAP) have been confirmed to be involved in the progression of EC, but the relationship between them and whether they jointly regulate EC is still unclear. The mRNA and protein levels of SF3B1 and WTAP were analyzed by qRT-PCR and western blot. Then, cell proliferation, apoptosis, migration, and invasion behaviors were assessed by EdU, flow cytometry, wound healing, and Transwell assays. Bioinformatics tools were applied to predict the binding sites of WTAP on SF3B1 mRNA and the correlation between WTAP and SF3B1. The binding of the two and the m6A methylation level of SF3B1 were verified by RIP and MeRIP. Finally, the effect of WTAP/SF3B1 on EC tumors in vivo was determined by a xenograft tumor model. SF3B1 was highly expressed in EC and its knockdown inhibited the proliferation, expedited apoptosis, repressed migration and invasion, and promoted ferroptosis of EC cells. Besides, WTAP bound to SF3B1-bound mRNA and induced its m6A methylation modification. Overexpression of WTAP accelerated the malignant progression of EC cells and restrained ferroptosis. Interestingly, overexpression of SF3B1 completely abolished the tumor suppressive effect induced by WTAP knockdown. WTAP stimulated tumor growth in vivo and suppressed ferroptosis by stabilizing SF3B1 expression. In conclusion, WTAP effectively suppressed ferroptosis in EC cells by modulating SF3B1 via m6A methylation, thereby aggravating EC.

N6-methyladenosine modification, especially Wilms tumor 1-associated protein (WTAP), is reportedly associated with a variety of cancers, including colorectal cancer (CRC). Angiogenesis also plays an important role in the occurrence and development of CRC. However, only a few studies have reported the biological mechanisms underlying this connection. Therefore, tissue microarray and public database were used to explore WTAP levels in CRC. Then, WTAP was down-regulated and over-expressed, respectively. CCK8, EdU, colony formation, and transwell experiments were performed to study the role of WTAP in CRC. Combined RNA sequencing and m6A RNA immunoprecipitation (MeRIP) sequencing, we found downstream molecules VEGFA. Moreover, a tube formation assay was executed for tumor angiogenesis. Finally, a subcutaneous tumorigenesis assay in nude mice was used to examine the tumor-promoting effect of WTAP in vivo. In the present study, WTAP was significantly upregulated in CRC cells and patients with CRC. Moreover, higher WTAP expression was observed in the TCGA and CPATC databases in CRC tissues. WTAP over-expression exacerbates cell proliferation, migration, invasion, and angiogenesis. Conversely, WTAP knockdown inhibited the malignant biological behavior of CRC cells. Mechanistically, WTAP positively regulated VEGFA, as identified using RNA sequencing and MeRIP sequencing. Moreover, we identified YTHDC1 as a downstream effector of the YTHDC1-VEGFA axis in CRC. Furthermore, increased WTAP expression activated the MAPK signaling pathway, which led to enhanced angiogenesis. In conclusion, our study revealed that the WTAP/YTHDC1/VEGFA axis promotes CRC development, especially angiogenesis, suggesting that it may act as a potential biomarker of CRC.

Abdominal aortic aneurysm (AAA) is a common aneurysm that is often associated with atherosclerosis and can lead to artery rupture and death. Brain abundant membrane attached signal protein 1 (BASP1) is related to a variety of pathophysiological processes, but its role in AAA has not been reported. Real-time quantitative polymerase chain reaction (qRT-PCR) and western blot were used to detect the expressions of BASP1 and Wilms' tumor 1-associated protein (WTAP). Angiotensin-II (Ang-II) was employed for inducing AAA models in vitro to explore the effects and mechanism of BASP1 in AAA. Cell viability, apoptosis, oxidative stress level, and Fe2+ level were measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT), flow cytometry, and various kits, respectively. In terms of mechanism, the methylated RNA immunoprecipitation (MeRIP)-qPCR, the dual luciferase reporter assay, and the cytochrome experiments were utilized to evaluate the relationship between BASP1 and WTAP. A highly expressed level of BASP1 was observed in aortic tissues of AAA patients and Ang-II could induce AAA models by treating vascular smooth muscle cells (VSMCs). In cellular function, BASP1 knockdown impaired AAA and ferroptosis resulted from Ang-II. Mechanically, WTAP mediated the N6-methyladenosine (m6A) modification and mRNA stability of BASP1. Meanwhile, WTAP was highly expressed in AAA tissues of patients and the effects of WTAP silence in AAA and ferroptosis were diminished by up-regulated BASP1. WTAP promotes cell viability and inhibits apoptosis and ferroptosis resulted from Ang-II in VSMCs by mediating the m6A level of BASP1.

Wilms' tumor 1-associating protein (WTAP) is ubiquitously expressed in many tissues and plays an important role in physiological processes and tumor development. Here, we investigated the specific biological role and underlying mechanism of WTAP in melanoma. We determined the expression of WTAP and its correlation with clinicopathological features in paraffin-embedded tissues. We investigated the effects of WTAP on melanoma cells via a CCK-8 assay, a colony formation assay, an EdU assay, a Transwell assay, and subcutaneous xenograft experiments. We then applied RNA sequencing to further screen candidate targets, and NT5E was selected as the downstream gene of WTAP. Finally, a series of rescue assays, together with nucleotidase assays and ELISA, were adopted to confirm the function of NT5E in melanoma progression. We demonstrated that WTAP expression was downregulated in melanoma, which was associated with a poor prognosis, and that WTAP expression served as an independent predictor of melanoma survival. Functionally, WTAP hindered the proliferation, growth, migration, and invasion of melanoma cells. Furthermore, NT5E was identified as the downstream effector of WTAP and was subsequently found to rescue the increased proliferation, migration, and invasion of melanoma cells induced by WTAP deficiency. Moreover, knockdown of WTAP increased the expression of NT5E, MMP2, and N-cadherin, and simultaneous transfection with siNT5E reversed the increased expression of MMP2 and N-cadherin. Moreover, increased NT5E expression caused by forced WTAP inhibition in melanoma promoted the hydrolysis of AMP to produce more adenosine and further abrogated the secretion of IFN-γ by PBMCs. We found that WTAP expression is significantly downregulated and restrains the progression of melanoma via the downstream effects of NT5E on immunosuppression and molecular adhesion. This study revealed that WTAP plays a crucial inhibitory role in melanoma oncogenesis and highlighted WTAP as a potential novel diagnosis and therapeutic target for melanoma.

Acute myeloid leukemia (AML) is a heterogenous disease and the survival of AML patients is largely attributed to the improvement of supportive treatment. Wilms' tumor 1-associated protein (WTAP) is a nuclear protein functions in many physiological and pathological processes. Although its expression and function in many malignant diseases have been reported, its prognostic and epigenetic roles in AML are largely unknown. Peripheral blood or bone marrow samples were collected from AML patients. The WTAP expression was detected by western blot. WTAP expression level and patients clinical features were analyzed using statistical methods. WTAP knockdown AML cells were constructed. The experiments on proliferation, tumorigenic ability, cell cycle, and apoptosis were performed. Transcriptome sequencing was performed and analyzed. M6A methylation level was measured and m6A-RIP was performed to quantify m6A methylation level of MYC mRNA. RNA stability assay was performed to measure the half-life of mRNA. WTAP was overexpressed in AML patients and was an independent poor-risk factor in AML (p = 0.0140). Moreover, we found that WTAP regulated proliferation, tumorigenesis, cell cycle, and differentiation of AML cells. Furthermore, WTAP made AML cells resistant to daunorubicin. In further investigations, m6A methylation level was downregulated when knocking down WTAP, and c-Myc was upregulated due to the decreased m6A methylation of MYC mRNA. High WTAP expression predicts poor prognosis in AML and WTAP plays an epigenetic role in AML.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by aortic wall degeneration and inflammation. The molecular mechanisms underlying AAA development remain unclear. Wilms tumor 1-associated protein (WTAP) has been implicated in various biological processes, but its role in AAA pathogenesis, particularly in cardiomyocyte regulation, has not been fully explored. Quantitative real-time PCR (qRT-PCR) was performed to detect the mRNA levels of WTAP and proprotein convertase subtilisin/kexin type 9 (PCSK9). Western blotting assay was used to analyze protein expression. Cell viability, proliferation, senescence, apoptosis, ferroptosis, and inflammation were assessed using cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine assay, SA-β-gal staining, flow cytometry, fluorometric assay, colorimetric method, and enzyme-linked immunosorbent assay. The association among PCSK9, WTAP, and IGF2BP2 was analyzed using RNA immunoprecipitation assay and dual-luciferase reporter assay. WTAP expression was upregulated in AAA and angiotensin II (Ang II)-induced human aortic smooth muscle cells (HASMCs). Ang II treatment inhibited HASMC proliferation and induced senescence, apoptosis, ferroptosis, and NLRP3 inflammasome-mediated inflammation. However, these effects were mitigated by WTAP knockdown. In addition, PCSK9 expression was increased in AAA, and WTAP stabilized PCSK9 mRNA expression in an IGF2BP2-dependent manner. Moreover, WTAP overexpression promoted senescence, apoptosis, ferroptosis, and inflammation by regulating PCSK9 in Ang II-induced HASMCs. WTAP silencing protected HASMCs from Ang II-induced senescence, apoptosis, ferroptosis, and inflammation by regulating PCSK9, suggesting a potential therapeutic target for AAA treatment.