Next-generation HER2-targeted therapies including tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) improve survival of HER2-positive cancer patients. However, mechanisms of primary and acquired resistance remain unclear. Here, we reported that primary HER2-specific targeted therapy (tucatinib) resistant or sensitive breast cancers derived from clinical trial patients exhibited differential protein profiles. Prolonged tucatinib exposure induced autophagy pathway enrichment in HER2-positive breast cancer cells. Integrated high-throughput analyses identified A-kinase anchoring protein (AKAP)13 as a critical molecule involved in both primary and acquired resistance and an independent predictor of poor prognosis. Silencing of AKAP13 significantly diminished novel HER2-targeted therapies resistance. Mechanistically, AKAP13 inhibits autophagosome formation by suppressing the expression of ULK1, a kinase essential for autophagy initiation. ULK1 transcription is driven by GLI1, which binds to the ULK1 promoter via its arginine-592 residue. We further elucidated that the RhoGEF domain of AKAP13 activates RhoA, which subsequently triggers the activation of PKA anchored to AKAP13. The activated PKA then inhibits the nuclear translocation of GLI1, thereby repressing its transcriptional activity on ULK1. In vivo and in vitro experiments demonstrated the synergistic efficacy of tucatinib and AKAP13 inhibitor A13. In the validation phase, organoids were constructed using tissue obtained via puncture from patients resistant to trastuzumab deruxtecan, confirming upregulation of AKAP13 and A13-mediated reversal of resistance to novel HER2-targeted therapies. Collectively, these findings highlight the role of AKAP13 in drug resistance and propose A13 as a promising therapeutic strategy for HER2-positive breast cancer. Model diagram of this study and proposed molecular mechanisms.

Microglia migrate from the yolk sac and populate the developing brain. How microglia expand rapidly to meet the microglial demand in fast-expanding human fetal brains remains uncharted. Using thick sections in 5-22-gestational week (gw) brains and super-resolution scanning, we identified a large proliferative microglial aggregate (2.129 mm(2)) near the lateral ganglionic eminence (>12.5 gw), expanding in Down's syndrome (DS) (4.767 mm(2)) and Edwards syndrome (ES) (3.437 mm(2)) fetal brains. Ki67(+) microglia within the aggregates accounted for 26.65% (DS: 38.9%; ES: 46.3%) compared with 6.32% (DS: 6.01%; ES: 5.2%) in scattered microglia. This aggregate region contained a distinct microglial population characterized by the absence of phagocytic structures and complex processes, high CSF-1R expression, abundant IL-34(+) cells, and some SPP1(+) bipolar microglia. We termed this structure the secondary microglial formation center (SMFC). Chimeric microglia-human cortical organoids recapitulated the SMFC in an IL-34- and CSF-1R-dependent manner, indicating that the human SMFC may compensate for the microglial shortage during the fastest expansion period.

Huntingtin (HTT) is a naturally aggregating protein that causes Huntington’s disease (HD) when its polyglutamine (polyQ) tract exceeds 38 repeats. Despite its importance, the biology of HTT aggregates remains poorly defined. Utilizing high-resolution imaging of HD family-derived cells, we have redefined polyQ assemblies—formerly viewed as pathogenic aggregates—as dynamic structures resembling knitted-fabric patches. These assemblies encircle the Golgi apparatus, integrating ribbons and stacks to form a functional polyQ assembly-Golgi complex and attaching clathrin vesicles. Mechanistically, we show that the fragmentation of polyQ assemblies is dynamically coupled with mitotic Golgi fragmentation and that treatment with the ARF inhibitor Brefeldin A splits and fragments the complex. The presence of mutant HTT (mHTT) ’crisps’ these assemblies and complexes, altering their response to nutrient deprivation and autophagy enhancers but not to antisense oligonucleotide (ASO) therapy. The polyQ assembly in HD cells also reduces the scaffolding capacity of the Golgi apparatus, clathrin vesicles, and ARF1, impairing Golgi functions. Our results demonstrate that mHTT disrupts the homeostatic dynamics of the polyQ assembly-Golgi complex, inducing a ’Golgipathy’ by crippling Golgi structure and function.

BACKGROUND:Hereditary hearing loss is one of the most common disabling disorders in children and lacks effective pharmacological treatments. Recent breakthroughs in OTOF gene therapy clinical trials necessitate standardized frameworks to guide emerging therapies. This study aims to establish the first international consensus on the clinical application of gene therapy for hereditary hearing loss. METHODS:A modified Delphi process was conducted from March 2024 to March 2025, involving 46 multidisciplinary experts from several countries across otology, genetics, audiology, gene therapy, and hearing rehabilitation. After a systematic literature review, as well as integration of research and clinical expertise and experience, three iterative voting rounds (two anonymous surveys and one online consensus meeting) were performed. Statements required ≥75% agreement for inclusion. FINDINGS:From 9,093 publications, 69 were used to draft and support the consensus statements. A total of 30 statements relevant to six domains achieved consensus on gene therapy for hereditary hearing loss, including ethical review (1 statement), patient selection criteria (12 statements), diagnosis and preoperative evaluation (9 statements), gene therapy drug delivery (4 statements), follow-up (3 statements), and post-treatment auditory and speech rehabilitation (1 statement). CONCLUSIONS:This consensus provides the first globally endorsed framework for gene therapy in hereditary hearing loss. It standardizes clinical trial design and patient management, accelerating translation from research to practice while ensuring safety. The guidelines are immediately applicable to OTOF-related hearing loss and adaptable to other genetic forms. FUNDING:This work was supported by the National Natural Science Foundation of China, the German Research Foundation (DFG) via the Cluster of Excellence, and others.

Recent breakthroughs in gene therapy for autosomal recessive deafness 9 (DFNB9) caused by OTOF mutations have transformed treatment paradigms for hereditary hearing loss (HHL). To date, eight clinical trials targeting DFNB9 have been registered in 51 centers across eight countries, demonstrating the rapid progress of gene therapy in auditory medicine. These pioneering studies establish the framework for the clinical translation of gene therapy targeting HHL. This review synthesizes progress in OTOF-related clinical trials, highlighting translational foci such as inner ear drug delivery, trial design, safety assessments, and auditory restoration outcomes. Key challenges in optimizing future therapeutic strategies - including addressing anatomical constraints, refining patient selection criteria, and standardizing outcome measures - are critically examined.

Background: Ferroptosis plays a vital role in cancer development and treatment. The relationship between ferroptosis-related genes and breast cancer prognosis, as well as immunotherapy outcomes, remains unknown. Objectives: To evaluate the prognostic value of ferroptosis-related genes in breast cancer. Methods: We conducted differential expressions and prognostic analysis for ferroptosis-related genes on public databases and breast cancer patients in our center and analyzed their predictive value for immunotherapy of breast cancer patients. Results: We identified prognostic ferroptosis-related genes, constructed a nomogram, and validated key genes using patient data from our center. We also investigated ferroptosis-related genes significantly associated with immune infiltration and identified FTH1 as a promising biomarker for triple-negative breast cancer immunotherapy. Conclusion: Ferroptosis-related genes had potential prognostic value and predictive value for breast cancer immunotherapy.

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Gene therapy has made significant progress in the treatment of hereditary hearing loss. However, most research has focused on deafness-related genes that are primarily expressed in hair cells with less attention given to multisite-expressed deafness genes. MPZL2, the second leading cause of mild-to-moderate hereditary deafness, is widely expressed in different inner ear cells. We generated a mouse model with a deletion in the Mpzl2 gene, which displayed moderate and slowly progressive hearing loss, mimicking the phenotype of individuals with DFNB111. We developed a gene replacement therapy system mediated by AAV-ie for efficient transduction in various types of cochlear cells. AAV-ie-Mpzl2 administration significantly lowered the auditory brainstem response and distortion product otoacoustic emission thresholds of Mpzl2-/- mice for at least seven months. AAV-ie-Mpzl2 delivery restored the structural integrity in both outer hair cells and Deiters cells. This study suggests the potential of gene therapy for MPZL2-related deafness and provides a proof of concept for gene therapy targeting other deafness-related genes that are expressed in different cell populations in the cochlea.

Adeno-associated viral (AAV) vectors are increasingly used as vehicles for gene delivery to treat hearing loss. However, lack of specificity of the transgene expression may lead to overexpression of the transgene in nontarget tissues. In this study, we evaluated the expression efficiency and specificity of transgene delivered by AAV-PHP.eB under the inner ear sensory cell-specific Myo15 promoter. Compared with the ubiquitous CAG promoter, the Myo15 promoter initiates efficient expression of the GFP fluorescence reporter in hair cells, while minimizing non-specific expression in other cell types of the inner ear and CNS. Furthermore, using the Myo15 promoter, we constructed an AAV-mediated therapeutic system with the coding sequence of OTOF gene. After inner ear injection, we observed apparent hearing recovery in Otof-/- mice, highly efficient expression of exogenous otoferlin, and significant improvement in the exocytosis function of inner hair cells. Overall, our results indicate that gene therapy mediated by the hair cell-specific Myo15 promoter has potential clinical application for the treatment of autosomal recessive deafness and yet for other hereditary hearing loss related to dysfunction of hair cells.

A prevalent recessive mutation (c.2485C>T, p.Q829X) within the OTOF gene leads to profound prelingual hearing loss. Here we show that in Otof mice harbouring a mutation (c.2482C>T, p.Q828X) homozygous to human OTOF that faithfully mimics the hearing-loss phenotype, a base editor (consisting of the deaminase ABE7.10max and the Cas9 variant SpCas9-NG) packaged in adeno-associated viruses and injected into the inner ear of the mice via the round-window membrane effectively corrected the pathogenic mutation, with no apparent off-target effects. The treatment restored the levels of the otoferlin protein in 88

Fewer than 5% glioblastoma (GBM) patients survive over five years and are termed long-term survivors (LTS), yet their molecular background is unclear. The present cohort included 72 isocitrate dehydrogenase (IDH)-wildtype GBM patients, consisting of 35 LTS and 37 short-term survivors (STS), and we employed whole exome sequencing, RNA-seq and DNA methylation array to delineate this largest LTS cohort to date. Although LTS and STS demonstrated analogous clinical characters and classical GBM biomarkers, CASC5 (P = 0.002) and SPEN (P = 0.013) mutations were enriched in LTS, whereas gene-to-gene fusions were concentrated in STS (P = 0.007). Importantly, LTS exhibited higher tumor mutation burden (P < 0.001) and copy number (CN) increase (P = 0.013), but lower mutant-allele tumor heterogeneity score (P < 0.001) and CN decrease (P = 0.026). Additionally, LTS demonstrated hypermethylated genome (P < 0.001) relative to STS. Differentially expressed and methylated genes both enriched in olfactory transduction. Further, analysis of the tumor microenvironment revealed higher infiltration of M1 macrophages (P = 0.043), B cells (P = 0.016), class-switched memory B cells (P = 0.002), central memory CD4+ T cells (P = 0.031) and CD4+ Th1 cells (P = 0.005) in LTS. We also separately analyzed a subset of patients who were methylation class-defined GBM, contributing 70.8% of the entire cohort, and obtained similar results relative to prior analyses. Finally, we demonstrated that LTS and STS could be distinguished using a subset of molecular features. Taken together, the present study delineated unique molecular attributes of LTS GBM.

Huntington's disease (HD), an incurable neurodegenerative disease, is caused by polyglutamine (polyQ) expansion in Huntingtin (HTT) protein. Despite HTTs naturally aggregating, huge variations of HTTs in visualizing methods make it unpredictable. Using 64 nm resolution scanning in the fibroblasts, induced neurons, organoids from an HD family, and human brain tissues, we revealed massive/long polyQ aggregates of HTTs formed by paralleled and interfused spindles that preferentially include flat Golgi stacks/ribbons/vesicles and disassembled in the mitotic and stressed cells with fragmented Golgi, brefeldin A (BFA) treatment and postfixation, and fragmented Golgi in the mitotic and stressed cells but not in BFA-treated cells binds to small HTTs. The disassembling of HTTs aggregates degraded HTTs. PolyQ aggregates with mutant HTT (mHTT)include a flat Golgi stack with a deformed surface, fragment easier in starvation, attach fewer Golgi/clathrin + vesicles and ARF1 than polyQ assemblies without mHTT in fibroblasts or striatal/cortical neurons, and cause intranuclear inclusion bodies in striatal neurons. ScRNA data of striatal GABAergic neurons reveal impaired Golgi- or vesicle-related activities. Collectively, polyQ aggregates of HTTs are a stable form and highly organized scaffold and mold for flat Golgi stacks/ribbons/vesicles, and the existence of mHTT in polyQ assemblies reduced ARF-related activities and impaired Golgi in striatal/cortical neurons. ### Competing Interest Statement The authors have declared no competing interest.

Pathogenic mutant huntingtin (mHTT) infiltrates the adult Huntington’s disease (HD) brain and impairs fetal corticogenesis. However, most HD animal models rarely recapitulate neuroanatomical alterations in adult HD and developing brains. Thus, the human cortical organoid (hCO) is an alternative approach to decode mHTT pathogenesis precisely during human corticogenesis. Here, we replicated the altered corticogenesis in the HD fetal brain using HD patient-derived hCOs. Our HD-hCOs had pathological phenotypes, including deficient junctional complexes in the neural tubes, delayed postmitotic neuronal maturation, dysregulated fate specification of cortical neuron subtypes, and abnormalities in early HD subcortical projections during corticogenesis, revealing a causal link between impaired progenitor cells and chaotic cortical neuronal layering in the HD brain. We identified novel long, oriented, and enriched polyQ assemblies of HTTs that hold large flat Golgi stacks and scaffold clathrin+ vesicles in the neural tubes of hCOs. Flat Golgi stacks conjugated polyQ assemblies by ADP-ribosylation factor 1 (ARF1). Inhibiting ARF1 activation with Brefeldin A (BFA) disassociated polyQ assemblies from Golgi. PolyQ assembles with mHTT scaffolded fewer ARF1 and formed shorter polyQ assembles with fewer and shorter Golgi and clathrin vesicles in neural tubes of HD-hCOs compared with those in hCOs. Inhibiting the activation of ARF1 by BFA in healthy hCOs replicated impaired junctional complexes in the neural tubes. Together, endogenous polyQ assemblies with mHTT reduced the Golgi recruiting ARF1 in the neuroepithelium, impaired the Golgi structure and activities, and altered the corticogenesis in HD-hCO.

Yolk sac-derived microglia migrate and populate the brain during development, constituting 10−15% of the total brain cells. The human brain is the largest and most complex brain with the highest cognitive capacity among all species. Therefore, the limitations of rodent brain studies in interpreting the human brain are evident. By co-immunostaining microglia in 50 µm fetal brain sections from 7.5 to 16 gestational weeks (gw) and combining high-resolution scanning, we identified a highly proliferative microglia aggregate (0.108−2.129 mm2) that expanded in Down’s Syndrome fetal brain (4.168 mm2) and was located near the ganglion eminence, in which Ki67+ microglia accounted for 23.4% of total microglia compared to 6.3% in other brain regions. The microglia in the aggregates lack phagocytic bulbs, membrane ruffles, and long/branching processes compared to microglia in other brain regions. Introducing human microglia into cortical organoids, but not macrophages, replicated proliferative microglial aggregates on the brain organoid surface and sufficiently penetrated deeper regions of the cortical organoids. Penetrating microglia display phagocytic capacity, enhance immunity, and accelerate the maturation of brain organoids. The large proliferative microglial aggregate may be a unique secondary microglial formation center in the human fetal brain to compensate for the enormous microglial demands during brain expansion.### Competing Interest StatementThe authors have declared no competing interest.

Background Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. Methods This single -arm, single -centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF , and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. Findings Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 x 10 11 vector genomes [vg] and five received 15 x 10 12 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 05-40 kHz. In the participant who received the 9 x 10 11 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 15 x 10 12 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. Interpretation AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9.

BACKGROUND:Immune checkpoint inhibitors (ICIs) shed new light on triple-negative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens.METHODS:Databases, including The Cancer Genome Atlas, Gene Ontology Resource, University of California Santa Cruz Genome Browser, and Pubmed, were used to screen epigenetic modulators, regulators for CD8+ T cells, and transcriptional regulators of programmed cell death-ligand 1 (PD-L1). Human peripheral blood mononuclear cell (Hu-PBMC) reconstruction mice were adopted for xenograft transplantation. Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed. RNA-sequencing, Western blotting, qPCR and immunohistochemistry were used to assess gene expression. Coculture assays were performed to evaluate the regulation of TNBC cells on T cells. Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility.RESULTS:The epigenetic modulator AT-rich interaction domain 1A (ARID1A) gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients. Low ARID1A expression in TNBC, causing an immunosuppressive microenvironment, promoted AIR and inhibited CD8+ T cell infiltration and activity through upregulating PD-L1. However, ARID1A did not directly regulate PD-L1 expression. We found that ARID1A directly bound the promoter of nucleophosmin 1 (NPM1) and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression, further activating PD-L1 transcription. In Hu-PBMC mice, atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity. In CTR20191353, ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients.CONCLUSIONS:In AIR epigenetics, low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis, leading to poor outcome but sensitivity to ICI treatment.

PurposeUbiquitin-conjugating enzymes E2S (UBE2S) and E2C (UBE2C), which mediate the biological process of ubiquitination, have been widely reported in various cancers. Numb, the cell fate determinant and tumor suppressor, was also involved in ubiquitination and proteasomal degradation. However, the interaction between UBE2S/UBE2C and Numb and their roles in the clinical outcome of breast cancer (BC) are not widely elucidated.MethodsOncomine, Cancer Cell Line Encyclopedia (CCLE), the Human Protein Atlas (HPA) database, qRT-PCR, and Western blot analyses were utilized to analyze UBE2S/UBE2C and Numb expression in various cancer types and their respective normal controls, breast cancer tissues, and breast cancer cell lines. The expression of UBE2S, UBE2C, and Numb in BC patients with different ER, PR, and HER2 status, grades, stages, and survival status was compared. By Kaplan–Meier plotter, we further evaluated the prognostic value of UBE2S, UBE2C, and Numb in BC patients. We also explored the potential regulatory mechanisms underlying UBE2S/UBE2C and Numb through overexpression and knockdown experiments in BC cell lines and performed growth and colony formation assays to assess cell malignancy.ResultsIn this study, we showed that UBE2S and UBE2C were overexpressed while Numb was downregulated in BC, and in BC of higher grade, stage, and poor survival. Compared to hormone receptor negative (HR−) BC cell lines or tissues, HR+ BC demonstrated lower UBE2S/UBE2C and higher Numb, corresponding to better survival. We also showed that increased UBE2S/UBE2C and reduced Numb predicted poor prognosis in BC patients, as well as in ER+ BC patients. In BC cell lines, UBE2S/UBE2C overexpression decreased the level of Numb and enhanced cell malignancy, while knocking down UBE2S/UBE2C demonstrated the opposite effects.ConclusionUBE2S and UBE2C downregulated Numb and enhanced BC malignancy. The combination of UBE2S/UBE2C and Numb could potentially serve as novel biomarkers for BC.

Mutations to the OTOF gene are among the most common reasons for auditory neuropathy. Although cochlear implants are often effective in restoring sound transduction, there are currently no biological treatments for individuals with variants of OTOF . Previous studies have reported the rescue of hearing in DFNB9 mice using OTOF gene replacement although the efficacy needs improvement. Here, we developed a novel dual-AAV-mediated gene therapy system based on the principles of protein trans-splicing, and we show that this system can reverse bilateral deafness in Otof –/– mice after a single unilateral injection. The system effectively expressed exogenous mouse or human otoferlin after injection on postnatal day 0–2. Human otoferlin restored hearing to near wild-type levels for at least 6 months and restored the release of synaptic vesicles in inner hair cells. Our study not only provides a preferential clinical strategy for the treatment of OTOF -related auditory neuropathies, but also describes a route of development for other large-gene therapies and protein engineering techniques.

Heterogeneity represents a pivotal factor in the therapeutic failure of triple-negative breast cancer (TNBC). In this study, we retrospectively collected and analysed clinical and pathological data from 258 patients diagnosed with TNBC at the Fudan University Cancer Hospital. Our findings show that low ARID1A expression is an independent prognostic indicator for poor overall survival (OS) and recurrence-free survival (RFS) in TNBC patients. Mechanistically, both nuclear and cytoplasmic protein analyses and immunofluorescent localisation assays confirm that ARID1A recruits the Hippo pathway effector YAP into the nucleus in human triple-negative breast cancer cells. Subsequently, we designed a YAP truncator plasmid and confirmed through co-immunoprecipitation that ARID1A can competitively bind to the WW domain of YAP, forming an ARID1A/YAP complex. Moreover, the downregulation of ARID1A promoted migration and invasion in both human triple-negative breast cancer cells and xenograft models through the Hippo/YAP signalling axis. Collectively, these findings demonstrate that ARID1A orchestrates the molecular network of YAP/EMT pathways to affect the heterogeneity in TNBC.