怀尔通过PLIN3的脱乙酰化诱导脂吞噬促进癌症的脱铁和化疗敏感性
Huaier induces lipophagy to promote ferroptosis and chemosensitivity via de-acetylation of PLIN3 in triple-negative breast cancer.
摘要(中文译文)
槐耳是一种传统中药蘑菇，我们既往研究已显示其具有抗肿瘤特性。然而，其在三阴性乳腺癌（TNBC）中调节多柔比星（DOX）敏感性的作用及潜在机制尚不清楚。本研究探讨了槐耳是否能增强TNBC细胞对DOX的敏感性，并探索了涉及脂噬和铁死亡的相关分子机制。通过体外细胞活力及集落形成实验评估槐耳联合DOX的治疗潜力，并在体内异种移植模型中加以验证。通过定量ROS、MDA和GSH，以及BODIPY和Lyso-Tracker染色来表征铁死亡和脂噬。利用乙酰化谱分析、LC-MS、共免疫沉淀（co-IP）和邻近连接实验（PLA）剖析潜在机制。槐耳通过触发脂噬和铁死亡，在体外和体内均显著增强TNBC细胞对DOX的敏感性。乙酰化谱分析显示，槐耳选择性去乙酰化Perilipin 3（PLIN3）第65位赖氨酸（K65），这介导了槐耳对TNBC脂噬、铁死亡和DOX敏感性的调节作用。机制上，槐耳上调组蛋白去乙酰化酶3（HDAC3）以去乙酰化PLIN3 K65。我们的数据还显示，PLIN3 K65去乙酰化增加了PLIN3介导的ATG16L1募集，促进脂噬和铁死亡，最终提高TNBC细胞的化疗敏感性。本研究表明，槐耳通过去乙酰化PLIN3并随后诱导脂噬和铁死亡来增强DOX敏感性。这些结果表明，槐耳可能作为一种有前景的辅助治疗方法，以增强TNBC的化疗疗效。
Abstract
Huaier, a traditional Chinese medicinal mushroom, has been shown to have anti-tumor properties in our previous studies. However, its role and underlying mechanisms in regulating doxorubicin (DOX) sensitivity in triple-negative breast cancer (TNBC) remain unclear. This study investigated whether Huaier could potentiate TNBC cell susceptibility to DOX and explored the associated molecular mechanisms involving lipophagy and ferroptosis. The therapeutic potential of Huaier in combination with DOX was evaluated using in vitro cell viability and colony formation assays and validated in xenograft models in vivo. Ferroptosis and lipophagy were characterized by quantifying ROS, MDA, and GSH, as well as by staining with BODIPY and Lyso-Tracker. Underlying mechanisms were dissected using acetylation spectrum profiling, LC-MS, co-immunoprecipitation (co-IP), and proximity ligation assays (PLA). Huaier significantly enhances TNBC cell sensitivity to DOX both in vitro and in vivo by triggering lipophagy and ferroptosis. Acetylation spectrum profiling revealed that Huaier selectively deacetylates Perilipin 3 (PLIN3) at lysine 65 (K65), which was responsible for Huaier's regulatory effects on TNBC lipophagy, ferroptosis, and DOX sensitivity. Mechanistically, Huaier upregulated histone deacetylase 3 (HDAC3) to de-acetylate PLIN3 at K65. Our data also showed that deacetylation of PLIN3 at K65 increased PLIN3-mediated recruitment of ATG16L1, promoting lipophagy and ferroptosis, and ultimately improving chemo-sensitivity in TNBC cells. This study showed that Huaier enhanced DOX sensitivity by deacetylating PLIN3 and subsequently induction of lipophagy and ferroptosis. These results indicate that Huaier may serve as a promising adjuvant therapeutic approach to augment chemotherapy efficacy in TNBC.
如何引用
AMA
Tingting Ma, Tong Niu, Yaming Li, Qifeng Yang. Huaier induces lipophagy to promote ferroptosis and chemosensitivity via de-acetylation of PLIN3 in triple-negative breast cancer.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158559.
APA
Tingting Ma, Tong Niu, Yaming Li, Qifeng Yang (2026). Huaier induces lipophagy to promote ferroptosis and chemosensitivity via de-acetylation of PLIN3 in triple-negative breast cancer.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158559
GB/T 7714
Tingting Ma, Tong Niu, Yaming Li, Qifeng Yang. Huaier induces lipophagy to promote ferroptosis and chemosensitivity via de-acetylation of PLIN3 in triple-negative breast cancer.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158559.
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