Objective Artificial intelligence-based magnetic resonance imaging (MRI) analysis has shown promising potential in predicting the response to intravenous glucocorticoid (IVGC) treatment in thyroid eye disease (TED). We aimed to explore a novel model for multimodal feature fusion based on MRI data to enhance predictive effectiveness. Methods We enrolled a total of 147 TED patients who underwent IVGC treatment. Pre-treatment orbital T2-weighted image was obtained for each subject, and individual segmentation of four extraocular muscles (EOMs) was performed. Radiomics analysis using different combinations of muscles as region of interests (ROIs) and machine learning algorithms were employed. Furthermore, we proposed a Residual Dynamic Integration Network (RDINet), which integrated image features extracted by convolutional neural network (ResNet-50), radiomics features, and clinical features using a dynamic mapping module. Results Combining medial rectus (MR) and lateral rectus (LR) in the modeling exhibited marginally improved performance than using all four EOMs in radiomics analysis (AUC = 0.8981 vs. 0.8796). ResNet-50 models based on MR + LR and four EOMs yielded AUC values of 0.9074 and 0.8889, respectively. RDINet achieved AUC values of 0.9213 and 0.9028 for the above two ROI strategies, which increased to 0.9537 and 0.9259 after integrating clinical features into modeling. Conclusion The focused combination of MR and LR in radiomics and deep learning analysis outperformed the inclusion of four EOMs for IVGC response prediction in TED patients. The proposed RDINet realizes effective multimodal feature fusion of TED, which serves as a potent dynamic mapping model for treatment response prediction.

Retinoblastoma (RB) represents the most common primary intraocular malignancy in childhood and stands as a paradigm for translating molecular oncology into precision clinical management. This review synthesizes the comprehensive evolution in the understanding and treatment of RB. First, we deconstruct the intricate oncogenic circuitry that extends far beyond Knudson's classic "two-hit" RB1 inactivation model, describing non-classical MYCN-driven pathogenesis, multi-layered epigenetic reprogramming (including chromatin, RNA and histone changes), and distinct histological subtypes with defined clinical correlates, such as the favorable-prognosis cavitary RB. Single-cell genomics has elucidated the cellular origin from cone precursor cells and intratumoral heterogeneity. Risk stratification has been refined through well-defined classification systems, from the therapy-guiding International Intraocular Retinoblastoma Classification (IIRC) to the comprehensive American Joint Committee on Cancer Tumor-Node-metastasis (AJCC TNM) staging. Furthermore, the diagnostic paradigm has advanced from conventional anatomical imaging to liquid biopsies, enabling non-invasive molecular staging and monitoring via tumor-derived cell-free DNA analysis. Concurrently, the therapeutic landscape has undergone a radical shift, moving from enucleation and external-beam radiotherapy to an era dominated by local sight-preserving strategies. We provide a critical synthesis of the evidence for intravenous chemotherapy and the transformative role of super-selective intra-arterial chemotherapy (IAC), and describe essential randomized controlled trials, technical innovations, and optimized drug regimens. Finally, we explore emerging targeted molecular therapies and future directions. By integrating cutting-edge molecular insights with robust, high-level clinical evidence, this review offers the framework for achieving patient and eye survival as well as vision preservation in children with Retinoblastoma.

ABSTRACT Autoimmune thyroid diseases (AITD) are systemic conditions frequently associated with neurological manifestations, yet the underlying neural and immunological mechanisms remain unclear. This study focuses on thyroid eye disease (TED), a representative AITD, to provide a deeper insight into its neural mechanism. We first combined resting‐state functional magnetic resonance imaging (rs‐fMRI) data from a retrospective cohort of 116 TED patients with transcriptomic data from the Allen Human Brain Atlas. The analysis of rs‐fMRI data demonstrated significant alterations in frontal, parietal, subcortical, and brainstem regions in TED. By integrating rs‐fMRI data with regional transcriptomic profiles derived from the postmortem Allen Human Brain Atlas, enabling region‐level transcriptional inference, we revealed enriched pathways related to synaptic signaling, neurovascular regulation, and immune activation. Tissue and cellular level enrichment further showed close association with the cortex and neurons. Key neuroimaging findings identified in the retrospective cohort were subsequently validated in an independent prospective cohort of TED patients and healthy controls (TED: 39; HC: 42) using paired rs‐fMRI and peripheral blood RNA sequencing data, which identified significant associations between immune cell infiltration and neural activity patterns. Collectively, these findings delineate coordinated brain–immune associations in TED and generate hypotheses regarding neuroimmune interactions in AITD.

Lactate was once regarded merely as a byproduct of glycolysis, but is now recognized as a multifunctional metabolite that coordinates energy redistribution, intercellular communication, receptor-mediated signaling, and epigenetic regulation. In the retina, these functions are especially consequential because visual processing depends on a highly specialized and energetically demanding tissue, characterized by steep oxygen gradients, a dual vascular supply, and tightly integrated metabolic crosstalk among photoreceptors (PCs), Müller glia, the retinal pigment epithelium, vascular cells, and retinal ganglion cells. In this review, we synthesize current advances in lactate signaling and lactylation in the retina, and examine how their dysregulation contributes to neovascularization, inflammation, and neurodegeneration in disorders including diabetic retinopathy, age-related macular degeneration, autoimmune uveitis and glaucoma. Drawing from these metabolic insights, therapeutic interventions targeting lactate signaling and lactylation are discussed as potential approaches to mitigate retinal abnormalities. Collectively, this review highlights the central importance of lactate signaling and lactylation in retinal physiology and pathology, and provides a conceptual framework for developing metabolic interventions aimed at restoring retinal lactate homeostasis.

Melanoma, a malignant tumour originating from melanin-producing melanocytes, poses a significant threat to human health, including cutaneous melanoma and uveal melanoma (UM). Although surgical resection remains a primary treatment modality, radiotherapy has emerged as another therapeutic option, particularly for UM. Nevertheless, the adverse effects induced by radiotherapy are considerably pronounced. In this study, we identified WT-161, a selective histone deacetylase 6 (HDAC6) inhibitor, as a potent radiosensitizer for melanoma therapy through high-throughput drug screening. Mechanistically, inhibition of HDAC6 disrupted its interaction with DNA damage repair proteins (DDB2 and DEK) and suppressed gene expression in the DNA damage repair pathway, leading to the accumulation of irradiation-induced DNA damage and tumour regression. Our findings establish HDAC6 as a predictive biomarker for radiation response in melanoma and demonstrate that pharmacological inhibition of HDAC6 with WT-161 could expand the clinical utility of radiotherapy in patients with UM.

MYCN amplification is a recurrent, high-risk molecular hallmark across diverse tumors, most notably neuroectodermal malignancies. Although MYCN-driven tumors uniformly exhibit robust intrinsic resistance to ferroptosis, the mechanistic link between MYCN and the ferroptotic pathway remains undefined. Here, we charted the genomic and epigenomic landscape of neuroectodermal tumors by combining single-cell RNA-seq, spatial transcriptomics (ST), CUT&Tag, and deep-coverage mass spectrometry proteomics. This integrative atlas identified UBE2C as a spatially resolved, MYCN-controlled driver gene. MYCN occupies the UBE2C promoter and potently transactivates its transcription, thereby accelerating tumor progression in vitro and in vivo. Re-expression of UBE2C fully rescued the proliferative arrest triggered by MYCN depletion, confirming its essential function downstream of MYCN. Proteomic interrogation of the UBE2C interactome further revealed that the tumor suppressor TFRC is a previously unknown ubiquitination substrate of UBE2C. Mechanistically, the polyubiquitination and proteasomal degradation of TFRC by UBE2C reduces iron influx and effectively shields cancer cells from ferroptosis. Clinically, genetic silencing of UBE2C induces ferroptosis and sensitizes tumor cells to the ferroptosis inducer erastin, revealing a therapeutically exploitable vulnerability in MYCN-amplified malignancies. Our study reveals a previously unrecognized MYCN-UBE2C-TFRC-ferroptosis regulatory axis that drives neuroectodermal tumor growth. These findings establish a mechanistic rationale for combining UBE2C silencing and ferroptosis induction as a precision therapeutic strategy against MYCN-amplified tumors.

磷酸化聚合物因其能够模拟天然骨细胞外基质的理化特性与生物学功能, 构建具有成骨诱导性的仿生微环境, 在骨再生领域受到广泛关注. 本研究以生物相容性良好、 可促进成骨的可降解聚癸二酸甘油酯(PGS)为骨架, 设计并合成了一系列磷含量可调的磷酸化聚酯衍生物(PGS-Ps). 实验结果表明, 磷修饰程度适中的PGS-P4可显著促进大鼠骨髓间充质干细胞的成骨分化, 上调碱性磷酸酶和骨唾液蛋白的mRNA表达水平, 有效增强骨钙素蛋白及Runt相关转录因子2的蛋白表达. 该工作为磷酸化生物活性材料的设计与开发提供了参考, 为骨修复提供了新材料.

The global epidemic of myopia constitutes a growing public health concern worldwide. Myopia development is characterized by pathological scleral remodeling through fibroblast-myofibroblast transdifferentiation (FMT) and extracellular matrix (ECM) degradation. Since myopia is progressive, the development of sustainable and safe preventive interventions is imperative. While mitochondrial dynamics critically regulate fibrotic processes in other organs, their role in scleral homeostasis has remained unexplored. Here, we identify pathological mitochondrial fragmentation, caused by increased mitochondrial fission, as a key driver of myopia progression. Using two mammalian animal models, we demonstrate that both genetic and pharmacological enhancement of mitochondrial fission (inducing mitochondrial fragmentation) exacerbates collagen loss and accelerates axial elongation, whereas genetic and pharmacological inhibition of mitochondrial fission prevents collagen degradation and attenuates myopia progression. Hypoxia-induced FMT in cultured human scleral fibroblasts (HSFs) requires activation of mitochondrial fission, revealing overproduction of reactive oxygen species (ROS) as the downstream effector on HSFs and in both animal models. Our multilevel analyses identify the mitochondrial fission-ROS axis as a key pathway linking scleral hypoxia to ECM remodeling. Lycopene, a naturally occurring carotenoid antioxidant, significantly attenuated scleral ROS levels and was found suitable for long-term application, highlighting its potential as a therapeutic agent for myopia control. Collectively, these findings have identified a therapeutic target and agent for controlling myopia progression.

PURPOSE. Uveal melanoma (UM), the most prevalent primary intraocular cancer in adults, is defined by salient histopathological diversity. Spindle and epithelioid cells constitute its two dominant pathological lineages, yet the latter foreshadows aggressive behavior and shortened survival. This study aimed to explore the molecular and metabolic underpinnings of UM pathology using regionally resolved proteomics. METHODS. Formalin-fixed, paraffin-embedded tumors from four patients-two spindle cell and two epithelioid-were histologically stratified via hematoxylin and eosin staining and subsequently interrogated by regionally resolved proteomics across eight precisely mapped regions. Immunofluorescence corroborated the shifts in melanocyte lineage markers. To translate these tissue-level signatures into functional biology, spindle-like 92.1 and epithelioid Mel290 cell lines were subjected to quantitative RT-PCR and Seahorse metabolic profiling, quantifying oxidative-phosphorylation (OXPHOS) gene expression and mitochondrial respiration. RESULTS. Proteomic profiling of microdissected tissue uncovered a selective collapse of the melanocytic differentiation program within epithelioid foci. Endothelin receptor type B, the receptor required for melanocyte stem cell fate, and the lineage-defining calciumbinding protein S100B were both sharply repressed in epithelioid samples, with S100B registering the single largest drop across the entire dataset. Immunofluorescence corroborated this signature, revealing concomitant loss of microphthalmia-associated transcription factor and premelanosome protein, further attesting to the dedifferentiated state of epithelioid cells. Simultaneously, the same regions exhibited a striking surge in OXPHOS machinery. Concordantly, Mel290 epithelioid cells displayed elevated transcription of OXPHOS genes and a markedly higher basal and maximal oxygen consumption rate compared with the spindle-like 92.1 line, aligning tissue-level proteomic shifts with cellautonomous metabolic rewiring. CONCLUSIONS. Our findings reveal a distinct proteomic signature in epithelioid UM characterized by dedifferentiation and enhanced mitochondrial respiration. This study provides the first regionally resolved proteomic landscape of UM pathology and suggests that the epithelioid transformation may reflect a shift toward a dedifferentiated, metabolically active tumor state.

Purpose:We previously found that scleral hypoxia led to a cascade involving glycolysis-lactate-histone H3 lysine 18 lactylation (H3K18la), which contributes to myopia. Since Cut&Tag identified Postn as a primary H3K18la-enriched extracellular matrix (ECM) gene, which encodes the periostin (Postn) protein, this study aimed to investigate whether Postn drives myopia by modulating scleral ECM remodeling. Methods:H3K18la enrichment at the Postn promoter was validated via CUT&Tag-quantitative PCR. Scleral Postn levels were assessed via reverse-transcription quantitative PCR (RT-qPCR) and immunoblotting during form deprivation myopia (FDM) in mice. Gain- or loss-of-function experiments were conducted to evaluate the role of scleral Postn in normal refractive development or FDM. Mechanisms were explored in FDM mice and human scleral fibroblasts (HSFs) using immunoblotting, co-immunoprecipitation, gene manipulation, and recombinant human POSTN (rhPOSTN) protein treatment. Results:H3K18la enrichment in the Postn promoter region and Postn mRNA and protein levels were increased during myopia. In HSFs, POSTN knockdown inhibited the hypoxia- or lactate-induced rise in fibroblast-to-myofibroblast transdifferentiation (FMT) and rescued type I collagen decline. Scleral Postn overexpression induced myopia in mice, while its knockdown attenuated FDM development. Mechanistically, Postn binds to integrin αvβ3 and αvβ5 receptors to activate the AKT signaling pathway, driving FMT and suppressing type I collagen. Conclusions:Scleral Postn contributes to myopia by promoting FMT in the sclera.

PURPOSE:This study aims to investigate retinal structure and vessel density (VD) alterations in the macular and optic nerve head (ONH) regions of patients with dysthyroid optic neuropathy (DON), and to assess their correlation with visual function. METHODS:A total of 133 thyroid eye disease (TED) patients (63 with DON and 70 without DON) and 24 healthy controls were enrolled. Retinal structural and vascular parameters were quantified using optical coherence tomography angiography (OCTA) in the macular (6 × 6 mm) and ONH (4 × 4 mm) regions. Visual function in TED patients was assessed by best corrected visual acuity (BCVA), visual field (VF), and visual evoked potentials. The diagnostic performance of OCTA parameters for identifying DON was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS:Compared with the non-DON patients, those with DON exhibited significantly decreased retinal VD in both macular and ONH regions, accompanied by thinner macular retina. The most pronounced changes were observed in macular whole retinal layer (WRL) and superficial retinal layer VD (P < 0.001). Both retinal VD and thickness correlated positively with BCVA and VF mean deviation. Furthermore, the macular WRL-VD demonstrated the highest diagnostic performance for DON (AUC = 0.833) and the combination parameters further improved accuracy (AUC = 0.861). CONCLUSIONS:OCTA reveals retinal microvascular and structural alterations in DON and may serve as a simple, precise, and noninvasive tool for early detection and clinical management to prevent irreversible visual loss.

Chemoresistance remains a significant challenge in cancer treatment, substantially limiting therapeutic efficacy. Cuproptosis is copper-induced cell death driven by mitochondrial protein aggregation and metabolic dysfunction. However, the involvement of cuproptosis in chemoresistance remains enigmatic. This study reveals that epigenetic remodeling augments mitochondrial respiration, thereby sensitizing cells to elesclomol-induced cuproptosis in cisplatin-resistant uveal melanoma (UM). First, we established cisplatin-resistant UM cell lines, which were validated in vitro and in vivo. A multi-omics analysis, including transcriptomics, metabolomics, and histone acetylation profiling (H3K9Ac/H3K27Ac CUT&Tag), revealed an upregulation of mitochondrial respiration and downregulation of glycolysis in cisplatin-resistant cells due to changes in histone acetylation. This metabolic reprogramming was associated with increased sensitivity to elesclomol-mediated cuproptosis, characterized by the diminishment of Fe–S cluster proteins and DLAT aggregation. Our research further delineated that the absence of FDX1 not only mitigated the sensitivity of chemoresistant UM cells to elesclomol but also attenuated copper-induced cell death, thereby substantiating the pivotal role of cuproptosis in this context. Therapeutically, employing zebrafish models, orthotopic xenografts, and patient-derived xenografts (PDXs), we confirmed the therapeutic efficacy of elesclomol in overcoming chemoresistance. Collectively, our study highlights a novel avenue for the development of a combinatorial therapeutic approach employing cisplatin and elesclomol to improve chemotherapy outcomes.

PURPOSE:To evaluate the safety and effectiveness of eye-preserving therapies in patients with American Joint Committee on Cancer (AJCC) eighth edition cT3c retinoblastoma presenting with neovascular glaucoma (NVG) without buphthalmos (defined as early cT3c), focusing on overall survival and eye preservation. DESIGN:Retrospective, single-center cohort study. PARTICIPANTS:132 patients diagnosed with early cT3c retinoblastoma from May 2014 through October 2024. METHODS:The patients were divided into primary enucleation (50 patients) and primary eye-preserving groups (82 patients). They were followed up for survival status and ocular outcomes. MAIN OUTCOMES MEASURES:Overall survival, high-risk pathological features, globe salvage and vision preservation. RESULTS:After a median follow-up of 52.9 months, one death occurred in each group, and overall survival did not differ significantly between the primary eye-preserving and primary enucleation groups (log-rank test, P = 0.775). Eye-preserving therapies were associated with a lower incidence of high-risk pathological features (odds ratio [OR], 0.21; P = 0.003), with attenuated severity of both choroidal (OR, 0.25; P = 0.002) and optic nerve invasion (OR, 0.23; P = 0.008). The globe salvage rate was 49.4% (41/83) in the primary eye-preserving group. And among these preserved eyes, 46.3% (19/41) regained light projection or better after receiving eye-preserving therapies. Importantly, presenting intraocular pressure (IOP) ≥32 mmHg (hazard ratio [HR], 2.37; P = 0.010) and corneal edema (HR, 2.86; P = 0.007) were high risk factors for globe salvage failure. Compared with intravenous chemotherapy (IVC) alone, application of intra-arterial chemotherapy (IAC; HR, 0.13; P = 0.001) alone and combined IVC-IAC regimens (HR, 0.15; P = 0.001) demonstrated a significantly association with better globe salvage outcomes. Additionally, cryotherapy (HR, 0.14; P < 0.001) was identified as an independent protective factor for overall globe salvage. CONCLUSION:Primary eye-preserving therapies can secure high rates of globe salvage with partial visual function in patients with early cT3c retinoblastoma, without jeopardizing patient survival. However, eyes exhibiting corneal edema or IOP ≥32 mmHg demonstrate markedly inferior salvage outcomes, the treatment strategy for such patients must therefore be cautiously individualized.

Uveal melanoma (UM) is a rare yet aggressive malignancy with a high propensity for distant metastasis and poor response to systemic therapies, including immunotherapies. Although recent single-cell studies have uncovered pronounced intratumoral heterogeneity and an immunosuppressive tumor microenvironment, the tumor-intrinsic metabolic programs that drive immune escape remain poorly defined. Here, we performed single-cell RNA sequencing on primary UM specimens to generate a high-resolution atlas of tumor and immune cell states. We identified a redox-optimized melanoma subpopulation under heavy metabolic-proteostatic demand, characterized by intensive protein secretory activity and elevated antioxidant defenses. This adaptive state is required to sustain the robust secretion of the matricellular protein SPP1, which suppressed the proliferation and function of CD8+ T cells through CD44 engagement. Disruption of redox equilibrium by enhancing reactive oxygen species (ROS) via a mitochondria-targeted oxidative phosphorylation inhibitor triggered endoplasmic reticulum stress and downregulated SPP1 expression, thereby defining a direct metabolic-immune regulatory axis. Together, our findings reveal a previously unrecognized ROS-SPP1-CD44 axis that links tumor redox homeostasis to immune evasion, providing mechanistic insight into the immune-resistant phenotype of UM and suggesting potential therapeutic vulnerabilities within the metabolic-immune crosstalk.

Thyroid eye disease (TED) is a disfiguring and potentially sight-threatening autoimmune orbital disorder. Intravenous glucocorticoid (IVGC) is the current first-line treatment for active, moderate-to-severe TED but its efficacy in reducing proptosis and diplopia is limited and inconsistent, with high relapse rates. In recent years, inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) have emerged as a novel therapeutic class for TED. Clinical studies have demonstrated that IGF-1R inhibitors can significantly reduce proptosis and improve overall disease activity in patients with active, moderate-to-severe TED. Although both therapies are available, no head-to-head clinical trial has directly compared IGF-1R inhibitors with IVGC. Therefore, this study aims to evaluate the efficacy and safety of an IGF-1R inhibitor compared with IVGC pulse therapy on proptosis in patients with active TED. This is a multicenter, randomized, open-label, active-controlled phase 4 trial. Adults with active moderate-to-severe TED and baseline proptosis ≥ 16 mm in the study eye will be enrolled. Participants will be randomized 1:1 to receive either intravenous teprotumumab N01 (10 mg/kg initial dose on day 1, followed by 20 mg/kg at weeks 3, 6, 9, and 12) or IVGC pulse therapy (methylprednisolone 500 mg on day 1 and from week 1 to week 5, followed by 250 mg from week 6 to week 11). After completing the 12-week treatment period, participants will enter an extended treatment and observation phase. The primary outcome measure is the proportion of participants who achieve a ≥ 2-mm reduction in proptosis in the study eye at week 15. Key secondary outcome measures include the change from baseline in proptosis and the overall responder rate in the study eye at week 15. This study plans to enroll approximately 92 participants with active TED. This trial is the first head-to-head clinical study comparing an IGF-1R (Insulin-like growth factor-1 receptor) inhibitor with IVGC. It aims to address the limitations of IVGC, including its uncertain efficacy on proptosis and diplopia, by utilizing a targeted approach to provide more comprehensive clinical evidence for TED treatment. ClinicalTrials.gov identifier, NCT07265258 (RESTORE-4).

We introduce OrbitCT-1K, an orbital computed tomography (CT) dataset comprising 1,000 orbits from 500 volumetric scans, each annotated with 10 clinically relevant binary radiological findings: orbital fracture, proptosis, orbital mass, periorbital soft tissue thickening, globe rupture, postoperative ocular change, lens abnormality, suspected nasolacrimal duct obstruction, optic nerve abnormality, and lacrimal gland abnormality. These expert-validated labels were designed to cover a spectrum from common to relatively rare but vision- or life-threatening orbital and adnexal radiological findings that are routinely used for clinical decision-making. Each orbit was independently annotated by two board-certified radiologists, achieving 98.91% overall agreement; remaining disagreements were adjudicated by a senior orbital radiology expert. OrbitCT-1K addresses the critical shortage of standardized orbital imaging repositories and establishes a reproducible benchmark for multi-label orbit-level classification and related tasks. It is expected to facilitate the development and evaluation of artificial intelligence (AI) models for orbital disease detection, triage, and decision support in both clinical and research settings.

BACKGROUND/AIMS:Diabetic retinopathy (DR) is a major ocular complication of diabetes mellitus. While artificial intelligence (AI)-based DR screening tools have gained widespread adoption, most research focuses on comparing AI performance with human, with limited attention to AI's role as assistants. This study evaluates the impact of AI-assisted decision-making on DR diagnosis and grading based on colour fundus photographs (CFP) and ultra-widefield fundus (UWF) images. METHODS:A total of 224 retinal images were analysed by 21 ophthalmologists and primary care physicians (PCPs) in China. Participants independently diagnosed and graded DR based on CFP and UWF images. After a 1-week interval, they repeated the task with AI assistance. Diagnosis accuracy was compared with a gold standard before and after AI assistance. Incremental costs and accuracy improvements were assessed using generalized estimating equations (GEE) models. RESULTS:AI assistance significantly improved DR diagnosis accuracy for both CFP and UWF images. For CFP, accuracy increased from 79.90% to 85.68% for PCPs, 81.19% to 88.69% for ophthalmic residents and 81.41% to 88.05% for ophthalmic attendings. Similar improvements were observed for UWF, with accuracy rising from 83.62% to 89.66% for residents and from 81.31% to 88.98% for attendings. GEE analysis revealed an incremental cost of 4.79 units and an accuracy improvement of 0.35 units with AI assistance. CONCLUSION:AI assistance shows potential in improving the accuracy of DR diagnosis and grading. Despite the associated costs, AI enables ophthalmologists to achieve superior diagnosis, facilitating earlier DR detection and treatment.

Research on cholesterol and its metabolic pathways has catalyzed the development of anticancer drugs targeting cholesterol synthesis. However, the cholesterol metabolic state in melanoma remains poorly characterized. In this study, we found that total cholesterol levels and the expression of acetyl-CoA acetyltransferase 2 (ACAT2), a key cholesterogenic enzyme, were significantly elevated in melanoma cells. ACAT2-mediated de novo cholesterol synthesis promoted melanoma growth both in vitro and in vivo. Furthermore, we identified that the transcription factor SOX10, which is critical for melanocyte development, was specifically highly expressed in melanoma and directly upregulated ACAT2 expression, thereby promoting cholesterol synthesis and tumor proliferation. Mechanistically, SOX10 transcriptionally activated ACAT2 expression by interacting with TAF15. This SOX10-TAF15 complex subsequently enhanced ACAT2 protein levels, stimulated cholesterol synthesis, suppressed apoptosis, and ultimately drove melanoma proliferation. Our findings reveal that the SOX10-TAF15-ACAT2 axis is a key regulator of cholesterol synthesis and melanoma proliferation, presenting a promising therapeutic target.