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MITF-SCD1 Lipid Metabolic Axis Prevents Ouabain-Induced Spiral Ganglion Neuron Ferroptosis and Hearing Loss

Ouabain triggers cochlear spiral ganglion neuron (SGN) ferroptosis and hearing loss via SCD1 downregulation. MITF directly activates Scd1 transcription, and the MITF–SCD1 axis mitigates SGN ferroptosis and hearing impairment in ototoxic ouabain and cisplatin models, revealing a lipid metabolic vulnerability and therapeutic target for sensorineural hearing loss.

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma

Cell Rep Med. 2026 Mar 30:102708. doi: 10.1016/j.xcrm.2026.102708. Online ahead of print.

ABSTRACT

Intratumor heterogeneity (ITH) undermines transcriptome-based stratification in intrahepatic cholangiocarcinoma (iCCA). Here, we integrate multi-omics data from multi-region, single-region, and single-cell RNA sequencing cohorts to systematically characterize gene expression ITH. We uncover that immune and stromal heterogeneity are primary drivers of ITH, leading to misclassification of a median 27.8% of tumors by existing subtyping systems. To overcome this, we identify a low-intratumor-heterogeneity/high-intertumor-variability (LIHV) gene set and develop an ITH-insensitive classification system defining five subgroups: inflammatory (SI), metabolic (SII), atypical (SIII-1), immune-silent (SIII-2), and neurodegenerative (SIII-3). These subgroups exhibit distinct clinical outcomes, molecular features, immune landscapes, and therapeutic vulnerabilities. GPRC5A and VTCN1 serve as robust immunohistochemical biomarkers for SI and SIII tumors, while serum CEA and CA19-9 identify inflammatory iCCA. Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA. Collectively, our study provides a robust molecular framework and actionable therapeutic strategies for iCCA.

PMID:41916296 | DOI:10.1016/j.xcrm.2026.102708

Improving Visual Object Tracking through Visual Prompting

arXiv:2409.18901v2 Announce Type: replace-cross Abstract: Learning a discriminative model that distinguishes the specified target from surrounding distractors across frames is essential for generic object tracking (GOT). Dynamic adaptation of target representation against distractors remains challenging because prevailing trackers exhibit limited discriminative capability. To address this issue, we present a new visual prompting mechanism for generic object tracking, termed PiVOT. PiVOT introduces mechanisms that leverage the pretrained foundation model (CLIP) to automatically generate and refine visual prompts online, thereby enabling the tracker to suppress distractors through contrastive guidance. To transfer contrastive knowledge from the foundation model to the tracker, PiVOT automatically propagates this knowledge online and dynamically generates and updates visual prompts. Specifically, it proposes a prompt initialization mechanism that produces an initial visual prompt highlighting potential target locations. The foundation model is then used to refine the prompt based on appearance similarities between candidate objects and reference templates across potential targets. After refinement, the visual prompt better highlights potential target locations and reduces irrelevant prompt information. With the proposed prompting mechanism, the tracker can generate instance-aware feature maps guided by the visual prompts, which are incrementally and automatically updated during tracking, thereby effectively suppressing distractors. Extensive experiments across multiple benchmarks indicate that PiVOT, with the proposed prompting mechanism, can suppress distracting objects and improve tracking performance.

GOT-Edit: Geometry-Aware Generic Object Tracking via Online Model Editing

arXiv:2602.08550v2 Announce Type: replace-cross Abstract: Human perception for effective object tracking in a 2D video stream arises from the implicit use of prior 3D knowledge combined with semantic reasoning. In contrast, most generic object tracking (GOT) methods primarily rely on 2D features of the target and its surroundings while neglecting 3D geometric cues, which makes them susceptible to partial occlusion, distractors, and variations in geometry and appearance. To address this limitation, we introduce GOT-Edit, an online cross-modality model editing approach that integrates geometry-aware cues into a generic object tracker from a 2D video stream. Our approach leverages features from a pre-trained Visual Geometry Grounded Transformer to enable geometric cue inference from only a few 2D images. To tackle the challenge of seamlessly combining geometry and semantics, GOT-Edit performs online model editing with null-space constrained updates that incorporate geometric information while preserving semantic discrimination, yielding consistently better performance across diverse scenarios. Extensive experiments on multiple GOT benchmarks demonstrate that GOT-Edit achieves superior robustness and accuracy, particularly under occlusion and clutter, establishing a new paradigm for combining 2D semantics with 3D geometric reasoning for generic object tracking.

GOT-JEPA: Generic Object Tracking with Model Adaptation and Occlusion Handling using Joint-Embedding Predictive Architecture

arXiv:2602.14771v1 Announce Type: cross Abstract: The human visual system tracks objects by integrating current observations with previously observed information, adapting to target and scene changes, and reasoning about occlusion at fine granularity. In contrast, recent generic object trackers are often optimized for training targets, which limits robustness and generalization in unseen scenarios, and their occlusion reasoning remains coarse, lacking detailed modeling of occlusion patterns. To address these limitations in generalization and occlusion perception, we propose GOT-JEPA, a model-predictive pretraining framework that extends JEPA from predicting image features to predicting tracking models. Given identical historical information, a teacher predictor generates pseudo-tracking models from a clean current frame, and a student predictor learns to predict the same pseudo-tracking models from a corrupted version of the current frame. This design provides stable pseudo supervision and explicitly trains the predictor to produce reliable tracking models under occlusions, distractors, and other adverse observations, improving generalization to dynamic environments. Building on GOT-JEPA, we further propose OccuSolver to enhance occlusion perception for object tracking. OccuSolver adapts a point-centric point tracker for object-aware visibility estimation and detailed occlusion-pattern capture. Conditioned on object priors iteratively generated by the tracker, OccuSolver incrementally refines visibility states, strengthens occlusion handling, and produces higher-quality reference labels that progressively improve subsequent model predictions. Extensive evaluations on seven benchmarks show that our method effectively enhances tracker generalization and robustness.
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