前列腺癌（PCa）耐药是目前癌症治疗面临的挑战之一，亟需探索新的治疗策略。雄激素受体（AR）及其信号通路是驱动PCa发生发展的核心因素，临床上常采用雄激素剥夺疗法（ADT）单用或联合AR信号抑制剂（ARSI）抑制PCa进展，但多数患者最终会对ADT产生耐药并进展至转移性去势抵抗性前列腺癌（mCRPC）阶段。近年研究表明，AR与铁死亡存在密切的相互调控作用，抑制AR表达可以增强PCa细胞的铁死亡敏感性，并部分逆转ADT耐药。铁死亡作为一种铁依赖的、以脂质过氧化累积为特征的调节性死亡方式，近年来已成为癌症治疗的重要方向。系统梳理AR与铁死亡相关的最新研究进展，重点阐述AR调节的抗铁死亡关键分子机制，系统总结具有调控AR-铁死亡轴功能的天然产物（如Sinularin、Rhytidone C）在逆转PCa耐药中的应用潜力，为攻克PCa耐药提供新思路与潜在治疗策略。AR-铁死亡轴为破解PCa耐药提供了全新分子靶点，天然产物靶向该轴的治疗范式具有重要的临床意义。

Prostate cancer (PCa) drug resistance is one of the major challenges in cancer treatment, and there is an urgent need to explore new therapeutic strategies. The androgen receptor (AR) and its signaling pathway are the core factors driving the occurrence and development of PCa. Clinically, androgen deprivation therapy (ADT) alone or in combination with androgen receptor signaling inhibitors (ARSI) is often used to inhibit the progression of PCa. However, most patients eventually develop resistance to ADT and progress to the metastatic castration-resistant prostate cancer (mCRPC) stage. Recent studies have shown that AR and ferroptosis have a close mutual regulatory relationship. Inhibiting AR expression can enhance the ferroptosis sensitivity of PCa cells and partially reverse ADT resistance. Ferroptosis, as an iron-dependent, regulated form of cell death characterized by the accumulation of lipid peroxidation, has become an important direction in cancer treatment in recent years. This paper systematically reviews the latest research progress related to AR and ferroptosis, focuses on elaborating the key molecular mechanisms of AR-regulated anti-ferroptosis, and systematically summarizes the application potential of natural products (such as Sinularin and Rhytidone C) that regulate the ARferroptosis axis in reversing PCa resistance. The AR-ferroptosis axis provides a new molecular target for overcoming PCa resistance, and the therapeutic paradigm of targeting this axis with natural products has important clinical significance.

R979.1

辽宁省中医药多学科交叉创新团队项目（LNZYYCXTD-JCCX-002）；国家自然科学基金资助项目（82204793）