Protein myristoylation, catalyzed by N-myristoyltransferases (NMT1 and NMT2), is a key co- and posttranslational modification involved in cellular signaling, yet its role in ferroptosis remains poorly defined. Here, we developed a novel myristoylproteomics workflow leveraging click chemistry to comprehensively profile N-myristoylated proteins within NSCLC cells. We found that NMT1 and NMT2 expression positively correlates with ferroptosis sensitivity. Genetic or pharmacological inhibition of NMT attenuated ferroptosis, whereas their overexpression enhanced it. Using our optimized quantitative myristoylproteomics platform, we identified GLIPR2 as a novel myristoylated protein with elevated modification levels in ferroptosis-sensitive cells. Functional studies confirmed that GLIPR2 promotes ferroptosis, and this pro-ferroptotic activity of GLIPR2 requires its N-myristoylation, as a myristoylation-deficient mutant (G2A) failed to restore ferroptosis sensitivity. Our work establishes a robust proteomic methodology for mapping protein myristoylation and uncovers the NMT1/ NMT2-GLIPR2 axis as a pivotal regulator of ferroptosis. These findings propose new therapeutic strategies for NSCLC.

Dynamic changes occurring in the lung microbiota can impact the initiation, progression, and prognosis of lung cancer (LC). Consequently, the development of suitable intratumoral microbiota analysis methods is crucial. Although matrix‐assisted laser desorption/ionization mass spectrometry (MALDI MS) involves straightforward operations and provides precise results, the “direct smear method” limits the identification of bacterial subspecies. Furthermore, the issue of inadequate quantification with MALDI MS renders it unsuitable for direct analysis of intratumoral bacteria. To address these challenges, a novel ionic liquid in this study is employed, called norharmane conjugated to 2,5‐dihydroxybenzoic acid (Nor@DHB) for the direct detection of intratumoral bacteria using MALDI MS. Because gram‐negative bacteria are dominant within cancer cells, lipid A is selected as the chemical fingerprint for bacterial identification. The results demonstrated that using Nor@DHB can enhance the lipid A signal by an order of magnitude and achieved a good linear relationship within a concentration range of 0.01–80 ng mL −1 . Here, this method is successfully applied to the direct analysis of lipid A in actual clinical samples. Subsequent machine learning and nomogram models further confirmed the correlation between characteristic lipid A ions and LC patient clinicopathological features, which are further validated through both in vitro and in vivo experiments.

Intestinal homeostasis is tightly regulated by the reciprocal interaction between the gut epithelium and adjacent mesenchyme. The Hippo pathway is intimately associated with intestinal epithelial homeostasis and regeneration; however, its role in postnatal gut mesenchyme remains poorly defined. Here, we find that removal of the core Hippo kinases Lats1/2 or activation of YAP in adult intestinal smooth muscle layers has largely no effect; however, Hippo-YAP signaling in the niche-forming Gli1+ mesenchymal cells plays intrinsic roles in regulating intestinal homeostasis. We find that Lats1/2 deletion drives robust mesenchymal over-proliferation, and YAP activation in Gli1+ pericryptal cells disrupts the intestinal epithelial-mesenchymal crosstalk via promoting Wnt ligand production. We show that YAP is upregulated in the stroma during dextran sodium sulfate (DSS)-induced injury, and mesenchymal YAP activation facilitates intestinal epithelial regeneration. Altogether, our data suggest an important role for mesenchymal Hippo-YAP signaling in the stem cell niche during intestinal homeostasis and pathogenesis.

Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEADs. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2 , recently identified in human spindle cell rhabdomyosarcoma. We demonstrate that in contrast to VGLL2 and TEAD1 the fusion proteins are potent activators of TEAD-dependent transcription, and the function of these fusion proteins does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase EP300 to control TEAD-mediated transcriptional and epigenetic landscapes. We show that small-molecule EP300 inhibition can suppress fusion protein-induced oncogenic transformation both in vitro and in vivo in mouse models. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL , TEAD , or NCOA translocations.

Abstract “Golden Hook” beans turn purple to different degrees due to the different compositions and contents of flavonoids during storage. At the same time, quality losses due to softening or pathogen invasion, and the deteriorations of flavor associated with carbohydrate metabolism occur. To reveal the effect of nitric oxide (NO) generated from sodium nitroprusside (SNP) on the postharvest quality of “Golden Hook” beans, we used metabolome, transcriptome, and assay for transposase‐accessible chromatin with high‐throughput sequencing approaches to compare beans at the time of treatment with untreated and SNP‐treated beans stored at 8°C for 12 days. The results showed that NO induced the expression of CERK1, FLS2, JAZ, and MYC2, stimulated the expression of polyphenol oxidase, CAT, and l‐ascorbate oxidase, the accumulation of flavonoids, and the synthesis of lignin in the antioxidant system, improving the ability of beans to resist stress while maintaining the balance of reactive oxygen species. High expressions of F3′H, FLS, INV, SUS, BCAT, and the accumulation of 6‐C‐methylquercetin‐3‐O‐rutinoside were associated with the maintenance of the fresh purplish red appearance of the beans in the SNP‐12d group, without loss of flavor. SNP treatment downregulated the transcription factors blimp‐1, OBP1, COG1, and AT1G6957 associated with bean senescence. These results provide insight into the postharvest quality control of “Golden Hook” beans.

Cowpea ( Vigna unguiculata (L.) Walp) is prone to water loss and shriveling after harvest. Sodium nitroprusside (SNP) as a generator of nitric oxide acts as a senescence retarding agent. In this study, the influence of SNP on cowpea senescence during storage at 15 degrees C for 8 d has been investigated. SNP treatment (0.3 mM) decreased the mass loss and maintained the hardness, total chlorophyll, and vitamin C content of the cowpeas. SNP suppressed the expression of the genes involved in ethylene signaling ( SAM1 , ETR2 , ERFs ), cell wall disassembly ( PE2 , PL5 , PG ), and the lignin synthesis genes ( 4CL , CCR , and CAD ), while inducing the expression of defense and resistance -related genes ( KCS , ABCG , BAK1 , PR -4 , and CpPR3 ). The major differentially accumulated metabolites in SNP -treated cowpeas were flavonoids, phenolic acids, and alkaloids. SNP -induced differentially expressed proteins that are involved in lignification (4CL, CAD, and POD), texture -related processes (PL5, PE, and EG), and disease resistance (PBSI, PR1, and SCP). Overall, the study revealed that SNP -generated NO suppressed ethylene signaling, inhibited lignin accumulation, regulated wax, suberin, and cuticle biosynthesis, and enhanced defense processes, resulting in higher -quality cowpeas than those of the untreated controls.

Bitter melon fruit is susceptible to yellowing, softening, and rotting under room-temperature storage conditions, resulting in reduced commercial value. Nitric oxide (NO) is an important signaling molecule and plays a crucial role in regulating the fruit postharvest quality. In this study, we investigated the effects of NO treatment on changes in sensory and firmness of bitter melon fruit during postharvest storage. Moreover, transcriptomic, metabolomic, and proteomic analyses were performed to elucidate the regulatory mechanisms through which NO treatment delays the ripening and senescence of bitter melon fruit. Our results show that differentially expressed genes (DEGs) were involved in fruit texture (CSLE, β-Gal, and PME), plant hormone signal transduction (ACS, JAR4, and AUX28), and fruit flavor and aroma (SUS2, LOX, and GDH2). In addition, proteins differentially abundant were associated with fruit texture (PLY, PME, and PGA) and plant hormone signal transduction (PBL15, JAR1, and PYL9). Moreover, NO significantly increased the abundance of key enzymes involved in the phenylpropanoid biosynthetic pathway, thus enhancing the disease resistance and alleviating softening of bitter melon fruit. Finally, differential metabolites mainly included phenolic acids, terpenoids, and flavonoids. These results provide a theoretical basis for further studies on the physiological changes associated with postharvest ripening and senescence of bitter melon fruit.

背景与目的 铁死亡是一种以铁依赖方式由脂质过氧化物过度积累引起的调节性细胞死亡,近年来发现铁死亡抵抗与肺腺癌(lung adenocarcinoma,LUAD)发生发展有关.细胞内抗氧化系统是抗铁死亡所必需的.本研究旨在探讨细胞外系统是否以及如何使LUAD细胞对铁死亡失去敏感性.方法 在本研究中,使用已建立的人肺成纤维细胞(MRC-5、WI38)、人肺腺癌细胞(H1650、PC9、H1975、H358、A549和H1299细胞系)、LUAD肿瘤及相匹配的癌旁正常组织、健康个体及LUAD患者的血浆,应用免疫组化和免疫印迹方法分析蛋白表达,实时荧光定量PCR(quantitative reverse transcription-PCR,qPCR)法分析mRNA表达.通过测定细胞活力、细胞死亡和脂质活性氧(reactive oxygen species,ROS)生成评估细胞对铁死亡的反应.通过透射电镜观察外泌体,用点击化学法配合共聚焦显微镜检测花生四烯酸(arachidonic acid,AA)的定位.采用RNA pull down、RNA免疫沉淀(RNA immunoprecipitation,RIP)、光激活核糖核酸苷增强交联和免疫沉淀(photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation,CAR-CLIP)等方法检测RNA和蛋白质之间的相互作用.用蛋白质组学方法来分析RNA调控蛋白,用代谢组学方法分析代谢物.细胞源性异种移植物(cell derived xenograft,CDX)模型、患者源性异种移植物(patient-derived xenograft,PDX)模型、细胞植入肺内LUAD小鼠模型和来自LUAD患者的血浆/组织标本被用于分子机制的验证.结果 LUAD患者血浆外泌体特异地降低了脂质过氧化,使LUAD细胞对铁死亡敏感性下降.可能的机制是在LUAD中,外泌体circRNA_101093(cir93)中维持了细胞内cir93的升高,调节AA,一种对铁死亡相关的质膜过氧化增加至关重要的多不饱和脂肪酸.对具体机制而言,cir93与脂肪酸结合蛋白3(acid-binding protein 3,FABP3)相互作用增加其表达,后者转运AA并促进其与牛磺酸的反应.因此,总体AA被降低,而N-花生四烯酰基牛磺酸(N-arachidonoyl taurine,NAT;AA和牛磺酸的产物)被诱导产生.值得注意的是,NAT在抑制AA合并到质膜中的作用也被揭示.在临床前的体内模型中,减少外泌体提高了以铁死亡为基础疗法的疗效.结论 外泌体和cir93是抑制LUAD细胞铁死亡敏感性的关键,阻断外泌体可能有助于未来LUAD的治疗.

Protein modifications have significant effects on tumorigenesis. N-Myristoylation is one of the most important lipidation modifications, and N-myristoyltransferase 1 (NMT1) is the main enzyme required for this process. However, the mechanism underlying how NMT1 modulates tumorigenesis remains largely unclear. Here, we found that NMT1 sustains cell adhesion and suppresses tumor cell migration. Intracellular adhesion molecule 1 (ICAM-1) was a potential functional downstream effector of NMT1, and its N-terminus could be N-myristoylated. NMT1 prevented ubiquitination and proteasome degradation of ICAM-1 by inhibiting Ub E3 ligase F-box protein 4, which prolonged the half-life of ICAM-1 protein. Correlations between NMT1 and ICAM-1 were observed in liver and lung cancers, which were associated with metastasis and overall survival. Therefore, carefully designed strategies focusing on NMT1 and its downstream effectors might be helpful to treat tumors.

N6-Methyladenosine (m6A) RNA modification, methylation at the N6 position of adenosine, plays critical roles in tumorigenesis. m6A readers recognize m6A modifications and thus act as key executors for the biological consequences of RNA methylation. However, knowledge about the regulatory mechanism(s) of m6A readers is extremely limited. In this study, RN7SK was identified as a small nuclear RNA that interacts with m6A readers. m6A readers recognized and facilitated secondary structure formation of m6A-modified RN7SK, which in turn prevented m6A reader mRNA degradation from exonucleases. Thus, a positive feedback circuit between RN7SK and m6A readers is established in tumor cells. From findings on the interaction with RN7SK, new m6A readers, such as EWS RNA binding protein 1 (EWSR1) and KH RNA binding domain containing, signal transduction-associated 1 (KHDRBS1), were identified and shown to boost Wnt/b-catenin signaling and tumorigenesis by suppressing translation of Cullin1 (CUL1). Moreover, several Food and Drug Administrationapproved small molecules were demonstrated to reduce RN7SK expression and inhibit tumorigenesis. Together, these findings reveal a common regulatory mechanism of m6A readers and indicate that targeting RN7SK has strong potential for tumor treatment.

Several physiological changes occur during fruit storage, which include the regulation of genes, metabolisms and transcription factors. In this study, we compared 'JF308' (a normal tomato cultivar) and 'YS006' (a storable tomato cultivar) to determine the difference in accumulated metabolites, gene expression, and accessible chromatin regions through metabolome, transcriptome, and ATAC-seq analysis. A total of 1006 metabolites were identified in two cultivars. During storage time, sugars, alcohols and flavonoids were found to be more abundant in 'YS006' compared to 'JF308' on day 7, 14, and 21, respectively. Differentially expressed genes, which involved in starch and sucrose biosynthesis were observed higher in 'YS006'. 'YS006' had lower expression levels of CesA (cellulose synthase), PL (pectate lyase), EXPA (expansin) and XTH (xyglucan endoglutransglucosylase/hydrolase) than 'JF308'. The results showed that phenylpropanoid pathway, carbohydrate metabolism and cell wall metabolism play important roles in prolonging the shelf life of tomato (Solanum lycopersicum) fruit. The ATAC-seq analysis revealed that the most significantly up-regulated transcription factors during storage were TCP 2,3,4,5, and 24 in 'YS006' compared to 'JF308' on day 21. This information on the molecular regulatory mechanisms and metabolic pathways of post-harvest quality changes in tomato fruit provides a theoretical foundation for slowing post-harvest decay and loss, and has theoretical importance and application value in breeding for longer shelf life cultivars.

Background Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Patient prognosis is poor, and the existing therapeutic strategies for LUAD are far from satisfactory. Recently, targeting N6-methyladenosine (m 6 A) modification of RNA has been suggested as a potential strategy to impede tumor progression. However, the roles of m 6 A modification in LUAD tumorigenesis is unknown. Methods Global m 6 A levels and expressions of m 6 A writers, erasers and readers were evaluated by RNA methylation assay, dot blot, immunoblotting, immunohistochemistry and ELISA in human LUAD, mouse models and cell lines. Cell viability, 3D-spheroid generation, in vivo LUAD formation, experiments in cell- and patient-derived xenograft mice and survival analysis were conducted to explore the impact of m 6 A on LUAD. The RNA-protein interactions, translation, putative m 6 A sites and glycolysis were explored in the investigation of the mechanism underlying how m 6 A stimulates tumorigenesis. Results The elevation of global m 6 A level in most human LUAD specimens resulted from the combined upregulation of m 6 A writer methyltransferase 3 (METTL3) and downregulation of eraser alkB homolog 5 (ALKBH5). Elevated global m 6 A level was associated with a poor overall survival in LUAD patients. Reducing m 6 A levels by knocking out METTL3 and overexpressing ALKBH5 suppressed 3D-spheroid generation in LUAD cells and intra-pulmonary tumor formation in mice. Mechanistically, m 6 A-dependent stimulation of glycolysis and tumorigenesis occurred via enolase 1 (ENO1). ENO1 mRNA was m 6 A methylated at 359 A, which facilitated it’s binding with the m 6 A reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) and resulted in enhanced translation of ENO1. ENO1 positively correlated with METTL3 and global m 6 A levels, and negatively correlated with ALKBH5 in human LUAD. In addition, m 6 A-dependent elevation of ENO1 was associated with LUAD progression. In preclinical models, tumors with a higher global m 6 A level showed a more sensitive response to the inhibition of pan-methylation, glycolysis and ENO activity in LUAD. Conclusions The m 6 A-dependent stimulation of glycolysis and tumorigenesis in LUAD is at least partially orchestrated by the upregulation of METTL3, downregulation of ALKBH5, and stimulation of YTHDF1-mediated ENO1 translation. Blocking this mechanism may represent a potential treatment strategy for m 6 A-dependent LUAD.

BACKGROUND:Resistance to ferroptosis, a regulated cell death caused by iron-dependent excessive accumulation of lipid peroxides, has recently been linked to lung adenocarcinoma (LUAD). Intracellular antioxidant systems are required for protection against ferroptosis. The purpose of the present study was to investigate whether and how extracellular system desensitizes LUAD cells to ferroptosis.METHODS:Established human lung fibroblasts MRC-5, WI38, and human LUAD H1650, PC9, H1975, H358, A549, and H1299 cell lines, tumor and matched normal adjacent tissues of LUAD, and plasma from healthy individuals and LUAD patients were used in this study. Immunohistochemistry and immunoblotting were used to analyze protein expression, and quantitative reverse transcription-PCR was used to analyze mRNA expression. Cell viability, cell death, and the lipid reactive oxygen species generation were measured to evaluate the responses to ferroptosis. Exosomes were observed using transmission electron microscope. The localization of arachidonic acid (AA) was detected using click chemistry labeling followed by confocal microscopy. Interactions between RNAs and proteins were detected using RNA pull-down, RNA immunoprecipitation and photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation methods. Proteomic analysis was used to investigate RNA-regulated proteins, and metabolomic analysis was performed to analyze metabolites. Cell-derived xenograft, patient-derived xenograft, cell-implanted intrapulmonary LUAD mouse models and plasma/tissue specimens from LUAD patients were used to validate the molecular mechanism.RESULTS:Plasma exosome from LUAD patients specifically reduced lipid peroxidation and desensitized LUAD cells to ferroptosis. A potential explanation is that exosomal circRNA_101093 (cir93) maintained an elevation in intracellular cir93 in LUAD to modulate AA, a poly-unsaturated fatty acid critical for ferroptosis-associated increased peroxidation in the plasma membrane. Mechanistically, cir93 interacted with and increased fatty acid-binding protein 3 (FABP3), which transported AA and facilitated its reaction with taurine. Thus, global AA was reduced, whereas N-arachidonoyl taurine (NAT, the product of AA and taurine) was induced. Notably, the role of NAT in suppressing AA incorporation into the plasma membrane was also revealed. In pre-clinical in vivo models, reducing exosome improved ferroptosis-based treatment.CONCLUSION:Exosome and cir93 are essential for desensitizing LUAD cells to ferroptosis, and blocking exosome may be helpful for future LUAD treatment.

Circulating microRNAs (miRNAs) can be used as noninvasive biomarkers and are also found circulating in body fluids such as blood. Dysregulated miRNA expression is associated with many diseases, including non-small cell lung cancer (NSCLC), and the miRNA assay is helpful in cancer diagnosis, prognosis, and monitoring. In this work, a versatile electrochemical biosensing system is developed for miRNA detection by DNAzyme-cleavage cycling amplification and hybridization chain reaction (HCR) amplification. With cleavage by Mn2+ targeted DNAzyme, DNA-walker can move along the predesigned DNA tracks and contribute to the transduction and enhancement of signals. For the electrochemical process, the formation of multiple G-quadruplex-incorporated long double-stranded DNA (dsDNA/G-quadruplex) structures is triggered through HCR amplification. The introduction of G-quadruplex allows sensitive measurement of miRNA down to 5.68 fM with good specificity. Furthermore, by profiling miRNA in the NSCLC cohort, this designed strategy shows high efficiency (area under the curve (AUC) of 0.879 using receiver operating characteristic (ROC) analysis) with the sensitivity of 80.0% for NSCLC early diagnosis (stage I). For the discrimination of NSCLC and benign disease, the assay displays an AUC of 0.907, superior to six clinically-acceptable protein tumor markers. Therefore, this platform holds promise in clinical application toward NSCLC diagnosis and prognosis.

Ripening is the last, irreversible developmental stage during which fruit become palatable, thus promoting seed dispersal by frugivory. In Alisa Craig fruit, mRNAs with increasing m5C levels, such as STPK and WRKY 40, were identified as being involved in response to biotic and abiotic stresses. Furthermore, two mRNAs involved in cell wall metabolism, PG and EXP-B1, also presented increased m5C levels. In the Nr mutant, several m5C-modified mRNAs involved in fruit ripening, including those encoding WRKY and MADS-box proteins, were found. Targets of long non-coding RNAs and circular RNAs with different m5C sites were also found; these targets included 2-alkenal reductase, soluble starch synthase 1, WRKY, MADS-box, and F-box/ketch-repeat protein SKIP11. A combined analysis of changes in 5mC methylation and mRNA revealed many differentially expressed genes with differentially methylated regions encoding transcription factors and key enzymes related to ethylene biosynthesis and signal transduction; these included ERF084, EIN3, AP2/ERF, ACO5, ACS7, EIN3/4, EBF1, MADS-box, AP2/ERF, and ETR1. Taken together, our findings contribute to the global understanding of the mechanisms underlying fruit ripening, thereby providing new information for both fruit and post-harvest behavior.

Abstract Background Ferroptosis, a form of regulated cell death, is an important topic in the field of cancer research. However, the signalling pathways and factors that sensitise tumour cells to ferroptosis remain elusive. Methods We determined the level of ferroptosis in cells by measuring cell death and lipid reactive oxygen species (ROS) production. The expression of RB1‐inducible coiled‐coil 1 (RB1CC1) and related proteins was analyzed by immunoblotting and immunohistochemistry. Immunofluorescence was used to determine the subcellular localization of RB1CC1. We investigated the mechanism of RB1CC1 nuclear translocation by constructing a series of RB1CC1 variants. To examine the ferroptosis‐ and RB1CC1‐dependent transcriptional program in tumour cells, chromatin immunoprecipitation sequencing was performed. To assess the effect of c‐Jun N‐terminal kinase (JNK) agonists on strenthening imidazole ketone erastin (IKE) therapy, we constructed cell‐derived xenograft mouse models. Mouse models of hepatocellular carcinoma to elucidate the importance of Rb1cc1 in IKE‐based therapy of liver tumourigenesis. Results RB1CC1 is upregulated by lipid ROS and that nuclear translocation of phosphorylation of RB1CC1 at Ser537 was essential for sensitising ferroptosis in tumour cells. Upon ferroptosis induction, nuclear RB1CC1 sharing forkhead box (FOX)‐binding motifs recruits elongator acetyltransferase complex subunit 3 (ELP3) to strengthen H4K12Ac histone modifications within enhancers linked to ferroptosis. This also stimulated transcription of ferroptosis‐associated genes, such as coiled‐coil–helix–coiled‐coil–helix domain containing 3 (CHCHD3), which enhanced mitochondrial function to elevate mitochondrial ROS early following induction of ferroptosis. FDA‐approved JNK activators reinforced RB1CC1 nuclear translocation and sensitised cells to ferroptosis, which strongly suggested that JNK is upstream of RB1CC1. Nuclear localisation of RB1CC1 correlated with lipid peroxidation in clinical lung cancer specimens. Rb1cc1 was essential for ferroptosis agonists to suppress liver tumourigenesis in mice. Conclusions Our findings indicate that RB1CC1‐associated signalling sensitises tumour cells to ferroptosis and that targeting RB1CC1 may be beneficial for tumour treatment.

The biological functions of N6-methyladenosine (m6A) RNA methylation are mainly dependent on the reader; however, its role in lung tumorigenesis remains unclear. Here, we have demonstrated that the m6A reader YT521-B homology domain containing 2 (YTHDC2) is frequently suppressed in lung adenocarcinoma (LUAD). Downregulation of YTHDC2 was associated with poor clinical outcome of LUAD. YTHDC2 decreased tumorigenesis in a spontaneous LUAD mouse model. Moreover, YTHDC2 exhibited antitumor activity in human LUAD cells. Mechanistically, YTHDC2, via its m6A-recognizing YTH domain, suppressed cystine uptake and blocked the downstream antioxidant program. Administration of cystine downstream antioxidants to pulmonary YTHDC2-overexpressing mice rescued lung tumorigenesis. Furthermore, solute carrier 7A11 (SLC7A11), the catalytic subunit of system XC−, was identified to be the direct target of YTHDC2. YTHDC2 destabilized SLC7A11 mRNA in an m6A-dependent manner because YTHDC2 preferentially bound to m6A-modified SLC7A11 mRNA and thereafter promoted its decay. Clinically, a large proportion of acinar LUAD subtype cases exhibited simultaneous YTHDC2 downregulation and SLC7A11 elevation. Patient-derived xenograft (PDX) mouse models generated from acinar LUAD showed sensitivity to system XC− inhibitors. Collectively, the promotion of cystine uptake via the suppression of YTHDC2 is critical for LUAD tumorigenesis, and blocking this process may benefit future treatment.