(1) Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Surgical resection, tumor ablation, and liver transplantation are curative treatments indicated for early-stage HCC. The management of intermediate and advanced stages of pathology is based on the use of systemic therapies which often show important side effects. Vitamin E-derivative tocotrienols (TTs) play antitumoral properties in different tumors. Here, we analyzed the activity of delta-TT (δ-TT) on HCC human cell lines. (2) We analyzed the ability of δ-TT to trigger apoptosis, to induce oxidative stress, autophagy, and mitophagy in HepG2 cell line. We evaluated the correlation between the activation of autophagy with the ability of δ-TT to induce cell death. (3) The data obtained demonstrate that δ-TT exerts an antiproliferative and proapoptotic effect in HCC cells. Furthermore, δ-TT induces the release of mitochondrial ROS and causes a structural and functional alteration of the mitochondria compatible with a fission process. Finally, δ-TT triggers selective autophagy process removing dysfunctional mitochondria. Inhibition of autophagy reversed the cytotoxic action of δ-TT. (4) Our results demonstrate that δ-TT through the activation of autophagy could represent a potential new approach in the treatment of advanced HCC.
(1) 肝细胞癌（HCC）是原发性肝癌的主要类型。手术切除、肿瘤消融和肝移植是针对早期HCC的根治性治疗方法。中晚期HCC的治疗主要依赖全身性疗法，但这些疗法常伴随显著的副作用。维生素E衍生物生育三烯酚（TTs）在多种肿瘤中表现出抗肿瘤特性。本研究分析了δ-生育三烯酚（δ-TT）对人HCC细胞系的作用。(2) 我们检测了δ-TT在HepG2细胞系中诱导细胞凋亡、氧化应激、自噬及线粒体自噬的能力，并评估了自噬激活与δ-TT诱导细胞死亡之间的相关性。(3) 研究数据显示，δ-TT对HCC细胞具有抗增殖和促凋亡作用。此外，δ-TT能诱导线粒体活性氧释放，并引起线粒体结构和功能改变，这一过程与线粒体分裂现象相符。最终，δ-TT通过启动选择性自噬过程清除功能失调的线粒体。抑制自噬可逆转δ-TT的细胞毒性作用。(4) 我们的研究结果表明，δ-TT通过激活自噬可能成为治疗晚期HCC的潜在新策略。
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