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HKDC1-Mediated Polyamine Rewiring Drives Lenvatinib Resistance and Immune Escape in Hepatocellular Carcinoma

Clin Mol Hepatol. 2026 Mar 11. doi: 10.3350/cmh.2025.1269. Online ahead of print.

ABSTRACT

BACKGROUND/AIMS: Lenvatinib resistance and immune exclusion limit outcomes in HCC. We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and PD-1 blockade.

METHODS: We established LS/LR HCC models and employed multi-omics (proteomics/RNA-seq), ChIP, luciferase, and RIP assays to map HKDC1 regulation. Tumor immunity was profiled by scRNA-seq, mIHC, and flow cytometry. SPD + lenvatinib efficacy was tested in cell lines, patient-derived organoids/xenografts. Tested therapy effect in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion; and analyzed a postoperative cohort (n = 40) treated with lenvatinib + PD-1.

RESULTS: HKDC1, upregulated in LR HCC, was transcriptionally activated by USF1 and promoted SMS-mediated polyamine rewiring. This impaired CD8⁺ T-cell metabolism, reversible by HKDC1 knockdown or spermidine (SPD). SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib + aPD-1.

CONCLUSIONS: A USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and support polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.

PMID:41812646 | DOI:10.3350/cmh.2025.1269

OmniVideoBench: Towards Audio-Visual Understanding Evaluation for Omni MLLMs

arXiv:2510.10689v2 Announce Type: replace Abstract: Recent advances in multimodal large language models (MLLMs) have demonstrated substantial potential in video understanding. However, existing benchmarks fail to comprehensively evaluate synergistic reasoning capabilities across audio and visual modalities, often neglecting either one of the modalities or integrating them in a logically inconsistent manner. To bridge this gap, we introduce OmniVideoBench, a large-scale and rigorously designed benchmark dedicated to assessing synergistic audio-visual understanding, with a strong emphasis on modality complementarity and logical consistency. Specifically, OmniVideoBench comprises 1000 high-quality question-answer(QA) pairs, each annotated with step-by-step reasoning traces, derived from 628 diverse videos ranging from several seconds to 30 minutes, and manually verified to guarantee complete correctness and uniqueness. Moreover, OmniVideoBench encompasses 13 carefully designed question types, covering temporal reasoning, spatial localization, counting, causal inference, summarization, and beyond, thereby capturing the essential challenges of video understanding. Evaluation of multiple MLLMs on OmniVideoBench reveals a pronounced gap between model performance and human reasoning, with open-source models lagging significantly behind their closed-source counterparts, underscoring the inherent difficulty of genuine audio-visual reasoning. We will release OmniVideoBench to foster the development of MLLMs with stronger and more generalizable reasoning capabilities.

Training Multimodal Large Reasoning Models Needs Better Thoughts: A Three-Stage Framework for Long Chain-of-Thought Synthesis and Selection

arXiv:2512.18956v2 Announce Type: replace Abstract: Large Reasoning Models (LRMs) have demonstrated remarkable performance on complex reasoning tasks through long Chain-of-Thought (CoT) reasoning. Extending these successes to multimodal reasoning remains challenging due to the increased complexity of integrating diverse input modalities and the scarcity of high-quality long CoT training data. Existing multimodal datasets and CoT synthesis methods still suffer from limited reasoning depth, modality conversion errors, and rigid generation pipelines, hindering model performance and stability. To this end, in this paper, we propose SynSelect, a novel three-stage Synthesis-Selection framework for generating high-quality long CoT data tailored to multimodal reasoning tasks. Specifically, SynSelect first leverages multiple heterogeneous multimodal LRMs to produce diverse candidate CoTs, and then applies both instance and batch level selection to filter high-quality CoTs that can effectively enhance the model's reasoning capabilities. Extensive experiments on multiple multimodal benchmarks demonstrate that models supervised fine-tuned on SynSelect-generated data significantly outperform baselines and achieve further improvements after reinforcement learning post-training. Our results validate SynSelect as an effective approach for advancing multimodal LRMs reasoning capabilities.
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