Abstract Acute myeloid leukemia (AML) is an aggressive blood malignancy with a dismal 5-year survival rate below 30%. Dysregulation of mRNA translation is a hallmark and a driver of tumorigenesis, including leukemogenesis. However, the precise contributions of translation factors to AML pathogenesis and their potential as therapeutic targets remain poorly understood. Here, we identify eukaryotic translation initiation factor 4A1 (eIF4A1) as a promising vulnerability of AML; genetic depletion or pharmacological inhibition of eIF4A1 markedly suppresses AML initiation and progression via reprogramming amino acid metabolism. Through unbiased multi-omics analysis, we identified eIF4A1 as the most highly expressed translation factor in AML. Notably, eIF4A1 expression was significantly elevated in AML cells and patient samples compared to healthy controls. eIF4A1 knockout (KO) dramatically inhibited AML cell proliferation, suppressed mitochondrial respiration, and reduced global translation intensity in vitro and substantially delayed AML progression in vivo. While eIF4A1 is traditionally studied within the cap-binding eIF4F complex, our other findings uncover a novel eIF4F complex-independent mechanism. BioID-MS assays, coupled with the validation of PLA assays and co-IP assays, revealed the robust RNA independent proximity of eIF4A1 and mRNA stabilizer Y-box binding protein 1 (YB-1). Integrative RNA-seq and proteomics demonstrated phosphoglycerate dehydrogenase (PHGDH) as a functionally essential target of eIF4A1. Moreover, metabolic profiling combined with isotope tracing (13C) orthogonally confirmed the crucial role of eIF4A1 in rewiring de novo serine metabolism, in which PHGDH serves as the rate-limiting enzyme. Gene specific CLIP-qPCR verified the direct binding of both eIF4A1 and YB-1 to PHGDH mRNA. Furthermore, the KO of either eIF4A1 or YB-1 accelerated PHGDH mRNA decay. Collectively, these findings suggest an eIF4F-independent mechanism of eIF4A1: eIF4A1 cooperates with YB-1, stabilized PHGDH mRNA and reprogrammed amino acid metabolism in AML. Zotatifin, an FDA-approved eIF4A1 inhibitor, administered intraperitoneally (0.5 mg/kg; twice weekly for five weeks), dramatically reduced the leukemia burden and significantly prolonged survival of AML mouse models in vivo (immunodeficient xenograft model: 63 vs. 150 days median survival for PBS vs. Zotatifin, P = 0.0006; immunocompetent bone marrow transplantation model: 40 vs. 75 days, P = 0.001). Moreover, Zotatifin demonstrated strong synergistic activity with the YB-1 inhibitor SU056 in eradicating AML both in vitro and in vivo (P < 0.0001), primarily by disrupting amino acid biosynthesis. Overall, our findings identify eIF4A1 as a key regulator of AML pathogenesis and metabolic homeostasis. Targeting eIF4A1, particularly with Zotatifin, represents a promising therapeutic strategy for AML. Citation Format: Xiaoxu Zhang, Honghai Zhang, Lei Dong, Alexandra Huang, Xueer Wang, Lili Ren, Hongjie Bi, Seán O’Leary, Rui Su. Pharmacological inhibition of eIF4A1 suppresses leukemogenesis via specifically rewiring amino acid biosynthesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4037.

Introduction:The cryopreservation of semen from the Inner Mongolia cashmere goat, a valuable dual-purpose breed in China, results in a sharp decline in sperm motility, hindering genetic improvement and germplasm propagation. This study aimed to investigate the protective effects and underlying mechanisms of skim milk as a supplement in a cryopreservation extender. Methods:Skim milk was added stepwise (2%-3.6%) to an egg yolk-soy lecithin basal extender, with 2.8% identified as the optimal concentration. Tandem mass tag (TMT) quantitative proteomics, coupled with parallel reaction monitoring (PRM) validation, was employed to analyze the proteomic profiles of post-thaw sperm and elucidate homeostatic mechanisms related to sperm membrane stability. Results:The addition of 2.8% skim milk significantly increased post-thaw sperm motility to 68.23%, reduced ultrastructural abnormalities, elevated acrosomal integrity by 18.7%, and decreased lipid peroxidation by 29% (P < 0.05). Proteomic analysis identified 32 differentially expressed proteins. Gene Ontology (GO) enrichment revealed significant involvement in processes related to purine ribonucleoside triphosphate metabolism and transmembrane transporter activity. KEGG pathway analysis indicated predominant enrichment in energy metabolism and signal transduction pathways. PRM validation confirmed that proteins NDUFA8, PGAM2, ACTL7A, PRXL2B, ATP6V0C, and LELP1 exhibited expression patterns consistent with the proteomic data, serving as core biomarkers for skim milk-mediated membrane stabilization. Discussion:This study provides the first proteomic-level evidence that skim milk enhances the cryotolerance of Inner Mongolia cashmere goat spermatozoa. The mechanism involves the modulation of an energy-membrane protein network, which stabilizes sperm membranes during cryopreservation. The identified proteins establish molecular biomarkers for optimizing semen cryopreservation protocols in this breed.

Metastatic breast cancer remains a critical clinical challenge with limited therapeutic options, severe tumor metastasis and unsatisfactory single-treatment efficacy, and it is urgent to develop targeted and synergistic therapeutic strategies to improve anti-tumor outcomes. In this study, we developed a novel tumor-targeted nanomedicine (MFSE) based on exosome-modified mesoporous polydopamine (MPDA) loaded with saikosaponin D (SSd) and ferric ions (Fe3+) to achieve synergistic photothermal and drug therapies for improved anti-tumor efficacy. The internal pore size of MPDA matched the structural characteristics of SSd molecules, facilitating efficient loading and controlled release of SSd and preventing drug degradation. Importantly, Fe3+ doping enhanced the photothermal conversion efficiency by 38.68% compared with that of undoped MPDA. Owing to the homing effect of exosomes, MFSE exhibited superior cellular internalization and tumor accumulation. Upon 808 nm laser irradiation, the released SSd combined with the photothermal effect of MPDA to exert a synergistic anti-tumor effect, which effectively eliminated tumor cells, elicited immune responses, and significantly suppressed primary tumors, distant tumors, and lung metastases. Meanwhile, the MFSE-based therapeutic strategy displayed no obvious adverse effects and excellent biocompatibility in vivo. Overall, this study established a reliable and effective paradigm for the rational design of exosome-integrated nanoplatforms for precise targeting and synergistic therapy against metastatic breast cancer.

Cuproptosis, a newly discovered form of copper-driven regulated cell death, has been shown to be closely related to ovarian function. However, whether the oocyte dysfunction, decreased ovulation efficiency, and cumulus cell aging caused by copper overload or imbalance are associated with regulatory pathways related to cuproptosis remains unclear. In this study, the expression profiles of genes related to cuproptosis in cumulus cells were comprehensively analyzed through transcriptome sequencing and metabolome analysis, and key genes and pathways that affect oocyte maturation were identified in response to elesclomol and CuSO4 treatment. Transcriptome analysis of cumulus cells revealed the differential expression of genes involved in key biological processes, such as cellular senescence (AKT3, MORC3, RBL1, etc.), gap junctions (GJA1, GNAI1, GJB3, etc.), steroid biosynthesis (FDX1, HSD17B7, CYP1A1, etc.), and cell cycle regulation (CDK2, CCNB2, MAPK7, etc.). Metabolomic analysis revealed significant changes in the levels of malic acid, PS (18:3(10,12,15)-OH(9)/14:0), and PA (21:0/LTE4), among other compounds. Subsequent Smart-seq analysis of oocytes revealed that after cuproptosis was induced in cumulus cells, oocyte maturation was disrupted, which affected genes associated with cellular senescence (TGFB2, SIRT1, CHEK2, etc.), oocyte meiosis (FBXO5, CCNB3, PLK1, etc.), and DNA methylation (PPM1D, DNMT3B, KMT2A, etc.). These findings provide deeper theoretical support for the key genes and biological processes involved in cumulus cell regulation and oocyte maturation, further clarifying the regulatory mechanisms of cuproptosis in the field of reproduction.

Chinese indigenous goat breeds exhibit rich genetic diversity and a long history of domestication, endowing these native populations with superior traits in environmental adaptation, forage utilization, and disease resistance. The identification of selection signatures through comparative genomic analysis could facilitate the understanding of breed differentiation and enables the discovery of functionally important genes. Using whole-genome sequencing data (23.87× Average coverage), we assessed genetic variation, population stratification, runs of homozygosity (ROH), and selection signatures in two Chinese goat breeds: Inner Mongolia cashmere goats (IMCGs, n = 200) and Zhongwei goats (ZWGs, n = 200). The results showed that the two goat breeds exhibited distinct separation in the phylogenetic tree and the Principal component analysis (PCA) and the IMCG population exhibited a faster LD decay rate. A total of 11,484 and 7240 ROH fragments were detected in ZWGs and IMCGs respectively by homozygosity analysis of all chromosomes. Subsequently, the investigation of regions of homozygosity (ROH) was performed utilizing the PLINK software. In ZWGs and IMCGs, there were 5 and 14 genomic regions with high frequency of ROH island (ROHi) respectively, leading to the identification of 77 genes, containing 10 shared genes. Taking Fst (screening for population differentiation sites), π-Ratio (reflecting genetic diversity differences), and XP-CLR (detecting cross-population selection sweeps) as the core methods, cross-screening for strong selection signal regions; Tajima’s D is used to verify whether the candidate regions deviate from neutral evolution (to exclude genetic drift interference), and finally results to obtain 10 (ROHi) and 38 (Fst, π-Ratio, XP-CLR) shared candidate genes. Among these candidate genes are related to carcass and muscle development (CTNNA1, BIRC6, SIL1, BMPER, CACNA2D1, DGKB, MED13), fat deposition (BMPER, MAP3K3, PDGFD, FREBF2), growth and body size (DCHS2, GALNTL6, PDGFD, SHROOM3), cashmere (NBEA, TGFBR3, GALNTL6), reproduction (BRIC6, CDH23) and environmental adaptation (NBEA, CNGB3) of goats. Among them, PDGFD and TGFBR3 genes showed highly significant differentiation and haplotype patterns between the two groups. These results provide suggestive evidence that PDGFD and TGFBR3 genes may play an important role in the differentiation of goat body size and cashmere characteristics, which is worth further investigation. In summary, we conducted a genome-wide exploration of goats from two regions in China. Our analysis of the population structure, genetic diversity and selection signature of these two groups revealed several selection regions and candidate genes that could influence goat important traits and characteristics through various selection signal analysis methods. The findings of this study provide a basis for further conservation and utilization of goat resources and offer valuable materials for genetic improvement of goats.

Abnormal accumulation of oncometabolite fumarate drives susceptibility in fumarate hydratase-deficient renal cell carcinoma (FH-dRCC), but the precise mechanisms remain not fully understood. In this study, we demonstrate that high fumarate levels impair activation of ATR-CHK1 signaling in response to replication stress and DNA damage. Mechanistically, fumarate modifies RPA1, an essential factor for ATR-CHK1 activation through succination, a post-translational modification. Succination of RPA1 occurs mainly at cysteine residues 481 and 486, which reduces its binding affinity for single-stranded DNA (ssDNA). RPA1 succination leads to deficient recruitment of TOPBP1 to ssDNA, resulting in attenuated CHK1 activation and defective cell cycle arrest in response to DNA damage. Succinated RPA1 compromises homologous recombination-mediated DNA repair. Our findings establish that fumarate-induced succination of RPA1 impairs DNA repair and cell cycle control, promoting genomic instability in FH-dRCC. This work reveals a novel mechanism by which oncometabolites contribute to genomic instability.

Through natural and artificial selection, goats develop distinct hair phenotypes driven by genomic variations, such as structural variations (SVs). The fatty acid desaturase (FADS) family plays an important role in hair follicle (HF) growth, yet its molecular mechanisms remain unclear. In this study, we construct a goat graph-based pangenome containing 99,792 non-redundant presence-absence variations (PAVs) from 16 goat breeds. Using this pangenome, we identify 15,866 allelic variants of PAVs with distinct dominant frequencies (dPAVs) from the resequencing data of 300 goats. Among them, 1290 dPAVs regulate the expression of 772 corresponding genes in cashmere goats (CGs) with different hair types over 12 months. We identify an expanded FADS2P1 gene family with two intact copies and one truncated copy within segmental duplications. An intron deletion in the truncated FADS2P1 copy shows population-specific distribution patterns among goats with cashmere traits. All FADS2P1 copies are significantly upregulated in short-hair CGs, and their expression levels are negatively correlated with oleic acid (OA) levels. Functional validation in FADS2P1 knock-in mice indicates a slower hair growth rate and reduced HF numbers. These findings demonstrate that SV-driven FADS2P1 expression regulates HF development and growth through OA metabolism, providing insights into how PAVs influence complex phenotypes.

Hair type diversity in Inner Mongolia cashmere goats is an economically important trait that directly affects cashmere quality and production. Based on hair length, hair types of cashmere goat are classified as long (> 22 cm), short (< 13 cm), and intermediate (13-22 cm). However, reciprocal transcriptomic and lipidomic mechanisms accounting for these differences remain largely unclear. In this study, we integrated transcriptomic and lipidomic data of skin from long and short hair cashmere goats. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules significantly associated with hair type. WGCNA analysis of the combined transcriptome and lipidome data identified 43 co-expression modules. We observed the blue module significantly correlated with hair types, including 116 differentially expressed mRNAs, 193 lncRNAs, 66 circRNAs, 3 microRNAs, and 62 lipid compounds. FGF21 expression remained consistently higher in long hair cashmere goats than in short hair cashmere goats at three critical time points of hair follicle growth by qRT-PCR. Chi-miR-143-3p exhibited significantly elevated expression exclusively in long-haired goats during March. Based on interactions among candidate molecules, a regulatory network associated with hair types was constructed. Specifically, circ_1073 and circ_5535 competitively bound to chi-miR-143-3p, while chi-miR-143-3p directly targeted XLOC_003612 and indirectly regulated FGF21, subsequently influencing lipid compounds like stearic acid and palmitic acid. This multi-omics analysis highlights a novel regulatory axis associated with hair type variation in Inner Mongolia cashmere goats, further elucidating the underlying molecular interactions governing hair type. These findings provide new insights into transcriptomic and lipidomic mechanisms shaping hair type diversity.

R-loops are three-stranded nucleic acid structures consisting of a DNA-RNA hybrid strand and a displaced single-stranded DNA, and represent pervasive chromatin structural features in eukaryotic cells. Although it has long been considered that the RNA substrates of R-loops are linear RNAs, emerging evidence has demonstrated that circular RNAs (circRNAs), a class of covalently closed single-stranded RNAs generated via back-splicing, can also hybridize with genomic DNA to form R-loops. These circRNA-derived R-loops are termed ciR-loops herein. Owing to the exceptional stability of circRNAs relative to their linear counterparts, ciR-loops are more difficult to resolve than those derived from linear RNAs. Consequently, the accumulation of unscheduled or deleterious ciR-loops can more readily interfere with gene transcription and replication, posing greater threats to genomic and transcriptomic integrity. Given that functions and regulatory mechanisms of ciR-loops have gained increasing attention in the field of RNA biology and gene expression, particularly over the past 3 years, a timely and comprehensive review is urgently needed. However, the molecular mechanisms underlying ciR-loop metabolism and hot spots of investigations about ciR-loop-mediated chromatin regulation are yet to be summarized. Here, we provide a systematic review of recent advances in ciR-loop biology, focusing on the diverse mechanisms of their formation and resolution, as well as their molecular and physiological functions.

Investigating the impact of drugs on cancer cell metabolism is pivotal for advancing cancer therapeutics. The involved metabolites encompass intricate inorganic small molecules with short lifespans (e.g., ROS, RNS) and biomolecules such as amino acids. This necessitates high sensitivity and high throughput analytical methods. Herein, a novel integrated method combining electrochemical mass spectrometry (MS) with transcriptomics was established to investigate the modulation of NO metabolism by saikosaponin D (SsD) in breast cancer cells. Metal-organic frameworks decorated on fluorine-doped tin oxide with the outstanding features of sensitivity and renewability were made and served as an electrochemical sensor for in situ NO release detection, while MS identified NO-related metabolites and transcriptomics examined changes in gene expression following SsD treatment. Combined electrochemical and high-resolution MS data revealed a decrease in arginine and NO levels and an increase in ornithine, implicating changes in the arginine-proline metabolic pathway. Transcriptomics analysis further demonstrated that SsD treatment altered gene expression within this pathway. These findings clarify how SsD affects breast cancer metabolism, revealing a novel and efficient method for assessing drug efficacy through the perspective of NO metabolism.

Haematopoietic stem cells (HSCs) represent a well-established system for studying stem cell maintenance. While RNA regulators have been reported in HSCs, a systematic characterization and how they define transcript fate remains outstanding. Here we profile RNA characteristics of HSC-essential genes and uncover a notable feature in both human and mouse: they have extended 3' untranslated regions specifically enriched with AU-rich elements (AREs). These AREs are crucial for the expression of HSC genes, primarily through NAT10, which stabilizes their mRNAs. Notably, Nat10 deficiency markedly disrupts HSCs self-renewal and long-term reconstitution capacity. Mechanistically, NAT10 recruits ribosomes to the 3' untranslated region AREs of HSC-essential mRNAs, sheltering them from degradation-an effect independent of NAT10's ac4C catalytic activity. Moreover, NAT10 dysregulations were associated with multiple human haematological malignancies. Collectively, our findings uncover a specific mechanism of RNA turnover control mediated by specific RNA ARE motifs and identify a non-catalytic role of NAT10 in maintaining HSC homeostasis.

Background: Copy number variation (CNV) is an important class of structural variations (SVs) that contribute to phenotypic diversity and environmental adaptation in animals. However, large-scale population-level analyses of CNVs in goats remain limited. This study aimed to comprehensively characterize CNVs and explore their potential roles in economically important traits in Chinese goat populations. Methods: Whole-genome resequencing data from 151 individuals representing 17 Chinese goat breeds were analyzed. CNV regions (CNVRs) were identified across the genome, followed by gene annotation, functional enrichment analysis, and population differentiation analysis based on VST. Results: A total of 5636 CNVRs were identified from 151 individuals of 17 goat breeds, including 1365 duplication CNVRs, 4241 deletion CNVRs, and 30 both CNVRs. These CNVRs collectively spanned 2.38% of the goat genome. A total of 912 protein-coding genes overlapped with these CNVRs. After Bonferroni correction, GO enrichment analysis showed that these genes were significantly enriched in terms related to transmembrane transport, cell projection, ion binding, and ATP binding. Population differentiation analysis identified several CNVR-associated candidate genes with potential relevance to production or adaptive traits, including ABCC4, APOL3, EXOC3L4, ERG, B4GALT1, and FTH. Conclusions: This study provides a comprehensive CNVR map of Chinese goat populations and offers insights into the genetic basis of economically important traits, contributing to future genetic improvement and breeding strategies in goats.

Economic traits in livestock and poultry arise from the intricate interplay between genetic inheritance and environmental factors, mediated largely by epigenetic regulation. Histone modifications, particularly methylation and acetylation, serve as fundamental epigenetic mechanisms that dynamically remodel chromatin architecture and regulate gene expression in response to developmental and environmental cues. By bridging the gap between static DNA sequences and complex phenotypes, these dynamic marks offer a novel perspective for elucidating trait formation. This review examines the regulatory roles of histone modifications in shaping key economic traits, focusing on skeletal muscle development, fat deposition, and reproductive performance. Furthermore, we highlight two prospective strategies for integrating histone modification data into modern breeding programs: utilizing comprehensive epigenomic maps as novel biomarkers for precision selection, and implementing targeted nutritional regimens to program early phenotypic development. Despite substantial mechanistic advances, critical challenges persist, including high detection costs, inherent tissue specificity, and the necessity to validate transgenerational stability. Looking forward, the integration of multi-omics approaches is anticipated to propel animal breeding beyond traditional genomic selection toward an era of precise epigenomic design.

Background The Inner Mongolian cashmere goat is a major Chinese goat breed that can be categorized into longhaired, short-haired, and intermediate-haired types on the basis of hair characteristics. Previous research by our team revealed that genes influencing different hair types are enriched primarily in KEGG pathways such as lipid metabolism. However, the effects of lipid compounds on cashmere goat hair types remain unclear. Results In this study, skin tissue samples were collected from the scapular region of long-haired and short-haired Inner Mongolian cashmere goats during the anagen (September), catagen (December), and telogen (March) phases of the hair follicle growth cycle, followed by lipidomics analysis. A total of 359 lipid compounds were found to be differentially expressed between the hair types. KEGG enrichment analysis revealed that the biosynthesis of unsaturated fatty acids and sphingolipid metabolism were the most significantly enriched pathways. Weighted gene co-expression network analysis (WGCNA) of the lipidomics dataset identified 11 modules, among which the pink module showed the strongest association with hair types, which contained a large number of triglyceride lipids. Further screening identified 31 lipid compositions associated with hair type variation, including arecoline, linoleyl carnitine, spermine, arachidic acid, and several triglycerides. Several of these lipid compounds were significantly correlated with hair growth related genes such as FGF5, FGF22, CTNNAL1, and LSAMP. Conclusions These findings suggest that skin lipid compounds contribute to hair types regulation in Inner Mongolian cashmere goats and provide new insights into the mechanisms of hair growth in cashmere goats.

How maternal nutrition influences neonatal immune development and imprinting through breastfeeding remains largely unclear. We report that maternal supplementation with trans-vaccenic acid (TVA), the predominant naturally occurring trans-fatty acid in human breast milk, promoted neonatal T cell development in mice. Neonates fed by mothers on a TVA-enriched diet showed an expanded naïve cluster of differentiation 4 (CD4+) T cell population and enhanced adaptive immunity against infection. TVA reprogrammed neonatal naïve CD4+ T cells through a G protein-coupled receptor-CCCTC-binding factor axis and promoted T helper cells (Th1)-skewing by cooperating with the transcription factor TBX21. Early-life exposure to maternal TVA via breastfeeding supported long-lasting antiviral immunity in adulthood. Our findings establish the multifaceted benefits of maternal nutrition and breastfeeding via TVA in promoting infant immune homeostasis and protective immunity.

Transfer RNA (tRNA) modifications play a critical role in regulating codon-specific mRNA translation and enabling tumor cell adaptation. The RNA methyltransferase METTL1 installs N7-methylguanosine (m⁷G) modifications on tRNAs, thereby shaping codon usage and translational output. However, the function and mechanistic contribution of the METTL1-tRNA axis in pancreatic ductal adenocarcinoma (PDAC) remain poorly defined. Here, we show that METTL1 is overexpressed in PDAC tissues and that elevated METTL1 expression is associated with poor patient survival. Genetic ablation of METTL1 markedly suppresses PDAC cell proliferation, migration, and tumor growth in vitro and in vivo. Mechanistically, METTL1 loss selectively reduces m⁷G-modified valine tRNAs - particularly, Val-AAC, Val-CAC, and Val-TAC - leading to impaired translation of valine-enriched oxidative phosphorylation transcripts. As a consequence, METTL1 deficiency disrupts mitochondrial respiration and energy production in PDAC cells. Consistent with this model, valine tRNA levels are elevated in PDAC tissues, and their selective depletion phenocopies METTL1 loss by impairing mitochondrial bioenergetics and tumor cell fitness. Thus, the METTL1-valine tRNA axis promotes PDAC progression through codon-dependent translational control of mitochondrial electron transport chain and oxidative metabolism. Together, our findings identify a METTL1-tRNA-mitochondrial signaling axis as a previously unrecognized metabolic vulnerability and a promising therapeutic target in pancreatic cancer.

BCR-ABL1-independent resistance remains a major challenge in chronic myeloid leukemia (CML). These resistant cells exhibit elevated basal reactive oxygen species (ROS), which creates a therapeutic vulnerability. We show that berberine (BBR) acts as a natural molecular glue degrader of Hypoxia-Inducible Factor 1 Alpha (HIF1α) to exploit this vulnerability. BBR directly binds HIF1α at E816, stabilizing its interaction with the E3 ubiquitin ligase TRIM28, which subsequently promotes K48-linked ubiquitination of HIF1α. HIF1α degradation transcriptionally suppresses PDE4D, leading to cyclic AMP (cAMP) accumulation and activation of the xCT axis, depleting glutathione. BBR also induces metallothionein-mediated metal ion dyshomeostasis by upregulating MT1X, MT2A, and SLC30A8 mRNA levels, sequestering Cu2+/Zn2+ and inhibiting SOD1. These effects synergistically upregulate ROS to trigger ferroptosis, overcoming BCR-ABL1-independent resistance in vivo and in vitro. Thus, our findings identify an oxidative stress vulnerability in BCR-ABL1-independent resistant cells and show that BBR, a natural molecular glue degrader, exploits this vulnerability through HIF1α ubiquitination and degradation. This leads to elevated ROS that subsequently triggers ferroptosis, thereby offering a new therapeutic strategy against BCR-ABL1-independent resistance.

Abstract Background: Immune checkpoint inhibitors (ICIs) have significantly improved therapeutic outcomes in colorectal cancer (CRC), particularly for metastatic tumors with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR). While patients with metastatic CRC have a median overall survival of only 21 months, MSI-H/dMMR patients treated with ICIs can achieve durable responses and even long-term survival. However, the vast majority are microsatellite-stable (MSS) and remain profoundly resistant to immunotherapy, underscoring a critical unmet clinical need. Therefore, elucidating and overcoming the mechanisms that drive immune resistance is essential to broaden the therapeutic benefit of immunotherapy. Methods: We investigated the role of the RNA acetyltransferase NAT10, responsible for N4-acetylcytidine (ac4C) modification, in mediating immune escape in CRC. MYC-mediated transcriptional regulation and NAT10-dependent mRNA stabilization were analyzed. The stability of autophagy-related transcripts and MHC class I expression was assessed. The effects of NAT10 inhibition, achieved through genetic knockdown or pharmacological Remodelin treatment, on immune cell infiltration and response to immune checkpoint blockade were evaluated. Results: NAT10 was found to be significantly upregulated in CRC across multiple cohorts, with higher expression in MSS tumors compared to MSI-H tumors (p<0.01-0.001). Elevated NAT10 expression correlated with immune-cold phenotypes, poorer predicted immunotherapy response, and was negatively associated with T-cell activation genes (p<0.01). NAT10 positively regulated autophagy-lysosome genes, including BECN1, ATG3, and ATG5, through direct ac4C modification, enhancing their mRNA stability (p<0.05). NAT10 knockout reduced autophagic flux (p<0.001), increased MHC-I expression (p<0.01), and promoted infiltration and activation of CD8+ and CD4+ T cells, leading to enhanced tumor cytotoxicity and suppressed tumor growth, effects that were abrogated by CD8 depletion. A combination of NAT10 knockout with anti-PD-1 therapy resulted in 80% complete tumor regression. MYC was identified as an upstream activator of NAT10, with MYC mRNA itself modified by ac4C. MYC deletion reduced NAT10 expression, global ac4C levels, and autophagy. Remodelin synergized with anti-PD-1 treatment, underscoring NAT10 as a druggable epitranscriptomic-autophagy checkpoint. Conclusion: Our findings reveal a novel NAT10-MYC-autophagy axis that drives MHC-I degradation and orchestrates tumor immune evasion and resistance to immunotherapy in CRC. Targeting NAT10 represents a promising therapeutic strategy to overcome immune resistance and enhance the efficacy of immunotherapy in CRC. Citation Format: Junyong Weng, Tianchen Xiong, Zilan Ye, Zezhi Shan, Rui Su, Jianhua Yu, Michael A. Caligiuri, Xinxiang Li, Ajay Goel. NAT10-MYC loop induces MHC-I loss through autophagy to promote immune evasion and immunotherapy resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6745.

Distinct coat morphological differences are widely observed in Inner Mongolian cashmere goats, and individuals can be classified into different hair types based on coarse-hair length. These different hair types directly affect cashmere fiber length, quality, and production efficiency. To elucidate the molecular basis underlying hair type differentiation, we performed whole-transcriptome sequencing of skin tissues from Long hair type cashmere goat (LHG) and Short hair type cashmere goat (SHG) at three key stages of the secondary hair follicle cycle (September, December, and March). High-quality sequencing data were obtained from both strand-specific and small RNA libraries (Q30 > 91.8