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Received — 13 September 2026 ⏭

NBR1-Mediated Autophagic Degradation of YTHDF1 Curtails <em>FDX1</em> Translation to Drive Concurrent Multikinase Inhibitor Resistance and Cuproptosis Tolerance

✇(Multiomics OR Omics) AND (Lung OR gastric OR Hepatocellular)
By: Weikai Wang · Xin Jiang · Xiaona Chen · Kaiyu Liang · Miaoqin Chen · Kaizhong Lu · Qi Wei · Yuchen Wu · Liyuan Zhu · Yuan Chen · Tianlun Hou · Jingfeng Luo · Chentao Li · Xian Wang · Hongchuan Jin · Lifeng Feng
12 September 2026 at 18:00

Cancer Commun (Lond). 2026 Sep 11;46:0048. doi: 10.34133/cancomm.0048. eCollection 2026.

ABSTRACT

Background: Cancer cells frequently acquire adaptive resistance to targeted therapies; however, strategies capable of concurrently overcoming treatment tolerance and reactivating cell death pathways are currently lacking. Here, we investigated the dual role of ferredoxin 1 (FDX1) in modulating both multikinase inhibitor (MKI) sensitivity and cuproptosis susceptibility in hepatocellular carcinoma (HCC), and sought to develop a therapeutic approach for reversing resistance. Methods: HCC models, both in vitro and in vivo, were employed to investigate the role of FDX1 in MKI resistance and cuproptosis evasion. Polysome profiling, SunTag translation reporters, CRISPR-Cas9 mutagenesis, and mass spectrometry were employed to delineate the underlying mechanisms. A codelivery nanoliposome system was engineered and tested in orthotopic HCC models. Results: Prolonged exposure to MKIs led to the down-regulation of FDX1 protein levels, resulting in MKI resistance and cuproptosis tolerance in HCC both in vitro and in vivo. Mechanistically, we found that MKIs inactivated protein kinase B (PKB, also known as AKT)-mechanistic target of rapamycin (mTOR) signaling, thereby suppressing the SET and MYND domain-containing protein 2 (SMYD2)-mediated methylation of YTH domain family protein 1 (YTHDF1) at lysine 515 (K515). Hypomethylated YTHDF1 was degraded via next to BRCA1 gene 1 protein (NBR1)-dependent autophagy, leading to the repression of N6-methyladenosine modification-dependent translation of FDX1 mRNA. FDX1 deficiency drove MKI resistance by reactivating AKT survival signaling while impairing cuproptosis through reduced divalent copper ions (Cu2+) to monovalent copper ions (Cu+) conversion and the loss of protein lipoylation. Additionally, restoring FDX1 expression through NBR1 knockdown or YTHDF1 overexpression overcame MKI resistance and resensitized HCC cells to cuproptosis. Finally, a nanoliposomal system, super cuproptosis detonator liposome, designed for the codelivery of NBR1 small interfering RNA, a copper ionophore, and sorafenib restored FDX1-dependent cuproptosis and exhibited marked anti-HCC efficacy, suppressing HCC growth in vivo. Conclusions: MKIs suppressed SMYD2-mediated YTHDF1 methylation at K515 via the inactivation of AKT-mTOR signaling. This led to the inhibition of FDX1 translation, resulting in AKT signaling reactivation and protein lipoylation impairment, effects that contributed to both MKI resistance and cuproptosis tolerance in HCC. Overcoming MKI resistance and resensitizing cells to cuproptosis by targeting NBR1-mediated YTHDF1 degradation using a nanoliposomal codelivery system represents a promising strategy for HCC treatment.

PMID:42729649 | PMC:PMC13562797 | DOI:10.34133/cancomm.0048

Received — 14 March 2026 ⏭

MAPK14/SLC7A11/GPX4 axis dysregulation drives podocyte ferroptosis via mediating glycerophospholipid metabolism

✇Cell Death Discovery nature.com science feeds
By: Shi Qiu · Dandan Xie · Sifan Guo · Zhibo Wang · Ying Cai · Xian Wang · Zhencai Hu · Shiwei Wang · Chunsheng Lin · Hong Yao · Qiang Yang · Yu Guan · Qiqi Zhao · Songqi Tang · Wenjie Sun · Yiqiang Xie · Aihua Zhang
11 March 2026 at 08:00

Cell Death Discovery, Published online: 11 March 2026; doi:10.1038/s41420-026-02990-7

MAPK14/SLC7A11/GPX4 axis dysregulation drives podocyte ferroptosis via mediating glycerophospholipid metabolism
Received — 11 March 2026 ⏭

More Bang for the Buck: Process Reward Modeling with Entropy-Driven Uncertainty

✇cs.AI, q-bio.NC updates on arXiv.org
By: Lang Cao · Renhong Chen · Yingtian Zou · Chao Peng · Huacong Xu · Yuxian Wang · Wu Ning · Qian Chen · Mofan Peng · Zijie Chen · Peishuo Su · Yitong Li
10 March 2026 at 12:00
arXiv:2503.22233v4 Announce Type: replace-cross Abstract: We introduce the Entropy-Driven Uncertainty Process Reward Model (EDU-PRM), a novel entropy-driven training framework for process reward modeling that enables dynamic, uncertainty-aligned segmentation of complex reasoning steps, eliminating the need for costly manual step annotations. Unlike previous Process Reward Models (PRMs) that rely on static partitioning and human labeling, EDU-PRM automatically anchors step boundaries at tokens with high predictive entropy, effectively capturing intrinsic logical transitions and facilitating efficient exploration of diverse reasoning paths. On the ProcessBench benchmark, EDU-PRM outperforms strong public PRM baselines, such as Math-Shepherd PRM and Omega PRM, and EDU-PRM achieves comparable results with SOTA models while only using 1.5% training data. Furthermore, by leveraging our proposed EDU sampling strategy, we observe accuracy boosts from 64.7% to 67.3% for generative reasoning tasks, accompanied by a reduction of 32% in token usage. These findings underscore the potential of EDU-PRM as a scalable and annotation-efficient paradigm for process supervision in mathematical reasoning, paving the way for more efficient and robust approaches to complex mathematical problem solving.
Received — 5 March 2026 ⏭

Benchmarking MLLM-based Web Understanding: Reasoning, Robustness and Safety

✇cs.AI, q-bio.NC updates on arXiv.org
By: Junliang Liu · Jingyu Xiao · Wenxin Tang · Zhixian Wang · Zipeng Xie · Wenxuan Wang · Minrui Zhang · Shuanghe Yu
5 March 2026 at 13:00
arXiv:2509.21782v2 Announce Type: replace Abstract: Multimodal large language models (MLLMs) are increasingly deployed as the core reasoning engine for web-facing systems, powering GUI agents and front-end automation that must interpret page structure, select actionable widgets, and execute multi-step interactions reliably. However, existing benchmarks largely emphasize visual perception or UI code generation, showing insufficient evaluation on the reasoning, robustness and safety capability required for end-to-end web applications. To bridge the gap, we introduce a comprehensive web understanding benchmark, named WebRRSBench, that jointly evaluates Reasoning, Robustness, and Safety across eight tasks, such as position relationship reasoning, color robustness, and safety critical detection, etc. The benchmark is constructed from 729 websites and contains 3799 QA pairs that probe multi-step inference over page structure, text, widgets, and safety-critical interactions. To ensure reliable measurement, we adopt standardized prompts, a protocolized and deterministic evaluation pipeline, and multi-stage quality control combining automatic checks with targeted human verification. We evaluate 11 MLLMs on WebRRSBench. The results reveal significant gaps: models still struggle with compositional and cross-element reasoning over realistic layouts, show limited robustness when facing perturbations in user interfaces and content such as layout rearrangements or visual style shifts, and are rather conservative in recognizing and avoiding safety critical or irreversible actions. Our code and appendix are available at https: //github.com/annoy-worker/WebRSSBench.
Received — 25 February 2026 ⏭

A Very Big Video Reasoning Suite

✇cs.AI, q-bio.NC updates on arXiv.org
By: Maijunxian Wang, Ruisi Wang, Juyi Lin, Ran Ji, Thadd\"aus Wiedemer, Qingying Gao, Dezhi Luo, Yaoyao Qian, Lianyu Huang, Zelong Hong, Jiahui Ge, Qianli Ma, Hang He, Yifan Zhou, Lingzi Guo, Lantao Mei, Jiachen Li, Hanwen Xing, Tianqi Zhao, Fengyuan Yu, Weihang Xiao, Yizheng Jiao, Jianheng Hou, Danyang Zhang, Pengcheng Xu, Boyang Zhong, Zehong Zhao, Gaoyun Fang, John Kitaoka, Yile Xu, Hua Xu, Kenton Blacutt, Tin Nguyen, Siyuan Song, Haoran Sun, Shaoyue Wen, Linyang He, Runming Wang, Yanzhi Wang, Mengyue Yang, Ziqiao Ma, Rapha\"el Milli\`ere, Freda Shi, Nuno Vasconcelos, Daniel Khashabi, Alan Yuille, Yilun Du, Ziming Liu, Bo Li, Dahua Lin, Ziwei Liu, Vikash Kumar, Yijiang Li, Lei Yang, Zhongang Cai, Hokin Deng
24 February 2026 at 13:00
arXiv:2602.20159v1 Announce Type: cross Abstract: Rapid progress in video models has largely focused on visual quality, leaving their reasoning capabilities underexplored. Video reasoning grounds intelligence in spatiotemporally consistent visual environments that go beyond what text can naturally capture, enabling intuitive reasoning over spatiotemporal structure such as continuity, interaction, and causality. However, systematically studying video reasoning and its scaling behavior is hindered by the lack of large-scale training data. To address this gap, we introduce the Very Big Video Reasoning (VBVR) Dataset, an unprecedentedly large-scale resource spanning 200 curated reasoning tasks following a principled taxonomy and over one million video clips, approximately three orders of magnitude larger than existing datasets. We further present VBVR-Bench, a verifiable evaluation framework that moves beyond model-based judging by incorporating rule-based, human-aligned scorers, enabling reproducible and interpretable diagnosis of video reasoning capabilities. Leveraging the VBVR suite, we conduct one of the first large-scale scaling studies of video reasoning and observe early signs of emergent generalization to unseen reasoning tasks. Together, VBVR lays a foundation for the next stage of research in generalizable video reasoning. The data, benchmark toolkit, and models are publicly available at https://video-reason.com/ .
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