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SIRT3 deacetylates STEAP4 to modulate cuproptosis sensitivity via mitochondrial metabolic reprogramming in HBV-related HCC

Cell Death Differ. 2026 Mar 16. doi: 10.1038/s41418-026-01713-w. Online ahead of print.

ABSTRACT

Hepatitis B virus (HBV) infection remains a leading etiological driver of hepatocellular carcinoma (HCC). Cuproptosis is a recently defined copper-dependent form of regulated cell death that selectively eliminates mitochondria-dependent cells; whether HBV rewires this vulnerability remains unknown. Here we unveil a novel HBV X protein (HBx)-driven mechanism of cuproptosis evasion. Integrative analysis of clinical specimens, HBx-transgenic (HBx-Tg) mice, and multi-omics datasets revealed marked downregulation of STEAP4 (six-transmembrane epithelial antigen of prostate 4), a metalloreductase essential for cuproptosis sensitivity, in HBV-positive HCC. Mechanistically, HBx attenuates sirtuin 3 (SIRT3), impairing deacetylation of STEAP4 at lysine 404 and abolishing its mitochondrial targeting. Consequently, cells switch from the tricarboxylic acid (TCA) cycle respiration to glycolysis, reducing sensitivity to the copper ionophore elesclomol (ES). Restoring STEAP4 expression or pharmacological activation of SIRT3 with honokiol (HKL) re-instated mitochondrial STEAP4 localization and re-sensitized HBV-related HCC cells to cuproptosis; combination with ES produced synergistic tumor suppression in vitro and in orthotopic models. Collectively, our findings establish the SIRT3-STEAP4 axis as a novel regulator of cuproptosis resistance in HBV-related HCC. HBx-mediated repression of SIRT3 disrupts STEAP4 deacetylation and mitochondrial targeting, fostering metabolic reprogramming and evasion of copper-induced cell death. The results provide a pre-clinical rationale for copper-directed combination strategies in HBV-associated HCC.

PMID:41840161 | DOI:10.1038/s41418-026-01713-w

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A Geometrically-Grounded Drive for MDL-Based Optimization in Deep Learning

arXiv:2603.12304v1 Announce Type: cross Abstract: This paper introduces a novel optimization framework that fundamentally integrates the Minimum Description Length (MDL) principle into the training dynamics of deep neural networks. Moving beyond its conventional role as a model selection criterion, we reformulate MDL as an active, adaptive driving force within the optimization process itself. The core of our method is a geometrically-grounded cognitive manifold whose evolution is governed by a \textit{coupled Ricci flow}, enriched with a novel \textit{MDL Drive} term derived from first principles. This drive, modulated by the task-loss gradient, creates a seamless harmony between data fidelity and model simplification, actively compressing the internal representation during training. We establish a comprehensive theoretical foundation, proving key properties including the monotonic decrease of description length (Theorem~\ref{thm:convergence}), a finite number of topological phase transitions via a geometric surgery protocol (Theorems~\ref{thm:surgery}, \ref{thm:ultimate_fate}), and the emergence of universal critical behavior (Theorem~\ref{thm:universality}). Furthermore, we provide a practical, computationally efficient algorithm with $O(N \log N)$ per-iteration complexity (Theorem~\ref{thm:complexity}), alongside guarantees for numerical stability (Theorem~\ref{thm:stability}) and exponential convergence under convexity assumptions (Theorem~\ref{thm:convergence_rate}). Empirical validation on synthetic regression and classification tasks confirms the theoretical predictions, demonstrating the algorithm's efficacy in achieving robust generalization and autonomous model simplification. This work provides a principled path toward more autonomous, generalizable, and interpretable AI systems by unifying geometric deep learning with information-theoretic principles.
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HCP-DCNet: A Hierarchical Causal Primitive Dynamic Composition Network for Self-Improving Causal Understanding

arXiv:2603.12305v1 Announce Type: cross Abstract: The ability to understand and reason about cause and effect -- encompassing interventions, counterfactuals, and underlying mechanisms -- is a cornerstone of robust artificial intelligence. While deep learning excels at pattern recognition, it fundamentally lacks a model of causality, making systems brittle under distribution shifts and unable to answer ``what-if'' questions. This paper introduces the \emph{Hierarchical Causal Primitive Dynamic Composition Network (HCP-DCNet)}, a unified framework that bridges continuous physical dynamics with discrete symbolic causal inference. Departing from monolithic representations, HCP-DCNet decomposes causal scenes into reusable, typed \emph{causal primitives} organized into four abstraction layers: physical, functional, event, and rule. A dual-channel routing network dynamically composes these primitives into task-specific, fully differentiable \emph{Causal Execution Graphs (CEGs)}. Crucially, the system employs a \emph{causal-intervention-driven meta-evolution} strategy, enabling autonomous self-improvement through a constrained Markov decision process. We establish rigorous theoretical guarantees, including type-safe composition, routing convergence, and universal approximation of causal dynamics. Extensive experiments across simulated physical and social environments demonstrate that HCP-DCNet significantly outperforms state-of-the-art baselines in causal discovery, counterfactual reasoning, and compositional generalization. This work provides a principled, scalable, and interpretable architecture for building AI systems with human-like causal abstraction and continual self-refinement capabilities.
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