铁下垂中的翻译后修饰网络：协调肝细胞癌的防御、耐药性和治疗机会

摘要(中文译文)

肝细胞癌（HCC）仍然是癌症相关死亡的主要原因之一，其治疗效果因耐药性而受到严重限制。铁死亡是一种由脂质过氧化驱动的铁依赖性细胞死亡形式，已成为一种关键的肿瘤抑制机制，鉴于肝脏在铁稳态中的核心作用，其与HCC尤为相关。尽管关注度日益增加，但目前仍缺乏对翻译后修饰（PTMs）如何协调调控所有主要防御系统中的铁死亡易感性，以及这种调控逻辑在耐药过程中如何被利用的系统性研究。本综述围绕四个相互关联的主题来填补这一空白。我们首先剖析HCC中的三大铁死亡防御系统——system Xc-GSH-GPX4轴、ACSL4-LPCAT3-PUFA过氧化级联反应以及FSP1/CoQ10-DHODH平行通路——揭示每个节点均受组合性“PTMs密码”调控，涉及泛素化、磷酸化、乙酰化和脂质修饰，共同决定铁死亡阈值。随后我们刻画铁代谢重编程的特征，展示TFRC↑/FTH1↑/FPN1↓三联模式如何营造富铁微环境，使肿瘤细胞易于发生铁死亡执行，同时通过PTM依赖性机制激活促生存通路。一个核心焦点是铁死亡逃逸作为索拉非尼、仑伐替尼、免疫治疗和放疗耐药的统一机制。我们揭示，尽管分子多样性显著，耐药机制均汇聚于通过多层PTMs输入强化铁死亡防御——从NRF2驱动的转录和SLC7A11/GPX4稳定化，到近期发现的代谢物敏感性修饰包括乳酸化、ISG化和O-GlcNAc糖基化。本文对新兴治疗策略进行了批判性评估，包括天然产物、纳米技术平台以及靶向泛素-蛋白酶体系统的合理药物组合。我们的综合分析凸显了三个关键见解：（i）铁死亡易感性由多种同时存在的PTMs的组合状态决定，而非任何单一修饰；（ii）代谢物敏感性PTMs作为分子密码，将耐药细胞改变的代谢状态直接与铁死亡逃逸联系起来；（iii）耐药进化过程中PTMs部署的时间层级决定了治疗窗口的收窄，为最佳干预时机提供依据。最后，我们识别了关键的知识空白，并提出了将PTMs-铁死亡关联转化为HCC患者临床获益的未来方向。

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with therapeutic efficacy severely limited by drug resistance. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a critical tumor-suppressive mechanism with particular relevance to HCC given the liver's central role in iron homeostasis. Despite growing interest, a systematic examination of how post-translational modifications (PTMs) coordinately regulate ferroptotic susceptibility across all major defense systems and how this regulatory logic is exploited during drug resistance has been lacking. This review addresses this gap across four interconnected themes. We first dissect the three major ferroptosis defense systems in HCC-the system Xc-GSH-GPX4 axis, the ACSL4-LPCAT3-PUFA peroxidation cascade, and the FSP1/CoQ10-DHODH parallel pathways-revealing that each node is governed by a combinatorial "PTMs code" involving ubiquitination, phosphorylation, acetylation, and lipid modifications that collectively determine the ferroptotic threshold. We then characterize iron metabolism reprogramming, demonstrating how the TFRC↑/FTH1↑/FPN1↓ triad creates an iron-rich milieu that primes tumor cells for ferroptotic execution while engaging pro-survival pathways through PTM-dependent mechanisms. A central focus is ferroptosis evasion as a unifying mechanism underlying resistance to sorafenib, lenvatinib, immunotherapy, and radiotherapy. We reveal that despite remarkable molecular diversity, resistance mechanisms converge on reinforcement of ferroptosis defense through multi-layered PTMs inputs-from NRF2-driven transcription and SLC7A11/GPX4 stabilization to recently discovered metabolite-sensitive modifications including lactylation, ISGylation, and O-GlcNAcylation. Emerging therapeutic strategies, including natural products, nanotechnology-based platforms, and rational drug combinations targeting the ubiquitin-proteasome system, are critically evaluated. Our synthesis highlights three key insights: (i) ferroptotic susceptibility is determined by the combinatorial state of multiple concurrent PTMs rather than any single modification; (ii) metabolite-sensitive PTMs serve as a molecular code linking the altered metabolic state of resistant cells directly to ferroptosis evasion; and (iii) the temporal hierarchy of PTMs deployment during resistance evolution defines a narrowing therapeutic window informing optimal intervention timing. Finally, we identify critical knowledge gaps and propose future directions for translating the PTMs-ferroptosis nexus into clinical benefit for HCC patients.

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