T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with poor clinical outcome. Poricoic acid A (PAA) is the main chemical constituent on the surface layer of the mushroom Poria cocos, and exerts protective effects against various diseases. In the study, its effects on T-ALL progression were investigated both in vitro and in vivo. Our results showed that PAA strongly reduced the cell viability of T-ALL cell lines, and induced cell G2 cycle arrest and apoptosis in vitro. Mitochondrial dysfunction was also elevated by PAA, along with enhanced cellular reactive oxygen species (ROS) production. Importantly, PAA-suppressed cell viability and -triggered apoptosis were ROS-dependent. Additionally, autophagy was significantly induced by PAA in T-ALL cells through regulating AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and LC3 signaling pathways. PAA treatments also provoked ferroptosis in T-ALL cells with reduced glutathione (GSH) levels and elevated malonaldehyde (MDA) contents. Suppressing autophagy and ferroptosis almost abrogated the capacity of PAA to restrain T-ALL proliferation and growth. The effects of PAA to suppress T-ALL tumor growth were also confirmed in vivo with undetectable toxicity. Therefore, the present study highlighted the potential of PAA for T-ALL treatment mainly through inducing autophagic cell death and ferroptosis.

T 细胞急性淋巴细胞白血病 (T-ALL) 是一种侵袭性癌症，临床结果较差。茯苓酸A（PAA）是茯苓表层的主要化学成分，对各种疾病具有保护作用。在这项研究中，在体外和体内研究了它对 T-ALL 进展的影响。我们的研究结果表明，PAA 强烈降低了 T-ALL 细胞系的细胞活力，并在体外诱导细胞 G2 周期停滞和细胞凋亡. PAA 也提高了线粒体功能障碍，同时增强了细胞活性氧 (ROS) 的产生。重要的是，PAA 抑制的细胞活力和触发的细胞凋亡是 ROS 依赖性的。此外，通过调节 AMP 活化蛋白激酶 (AMPK)/哺乳动物雷帕霉素靶蛋白 (mTOR) 和 LC3 信号通路，PAA 在 T-ALL 细胞中显着诱导自噬。PAA 处理还引起了 T-ALL 细胞的铁死亡，谷胱甘肽 (GSH) 水平降低，丙二醛 (MDA) 含量升高。抑制自噬和铁死亡几乎消除了 PAA 抑制 T-ALL 增殖和生长的能力。PAA 抑制 T-ALL 肿瘤生长的作用也在体内得到证实具有无法检测的毒性。因此，本研究强调了 PAA 主要通过诱导自噬细胞死亡和铁死亡来治疗 T-ALL 的潜力。