肝癌是全世界主要的癌症死因之一。Sorafenib (蕾莎瓦®)為一種多激酶抑制劑，被許可做為肝癌病人的第一線藥物；然而，癌細胞產生的抗藥性減弱sorafenib的療效。由於對sorafenib阻抗的肝癌也對於細胞凋亡產生阻抗，所以探尋其它調控型細胞死亡是非常重要。鐵依賴型細胞死亡為一新穎的鐵依賴型非凋亡的調控型細胞死亡，已被報導可有效殺死多種癌症部位的藥物阻抗細胞。鐵依賴型死亡具有以下特徵：脂質過氧化修復功能受損、產生氧化還原活躍的鐵離子、以及多元不飽和脂肪酸的氧化。透過整合型生物資訊分析，我們發現鐵依賴型死亡參與肝癌細胞對sorafenib的阻抗，以及發現穀胱苷肽過氧化酶4 (GPX4) 為癌症的良好預後指標；此外， sorafenib阻抗的人類肝癌細胞株Huh7 (Huh7R) 相對Huh7具有較少的GPX4表現、異常的鐵恆定，以及較高的ACSL4表現，且對於GPX4抑制劑1S,3R-RSL3 (RSL3) 所誘導的鐵依賴型死亡更敏感。而且，添加細胞自噬抑制劑Bafilomycin A1可緩解在Huh7R中抑制GPX4所造成的鐵依賴型死亡。機轉層面而言，鐵蛋白藉由溶酶體降解提供具細胞利用性的鐵增強抑制GPX4所誘導的鐵依賴型死亡。總結而言，本研究證明抑制GPX4所誘導的鐵依賴型死亡是個有潛力用於對抗sorafenib阻抗肝癌的策略。

Hepatocellular carcinoma (HCC) has been one of the leading causes of cancer death worldwide. Sorafenib (NEXAVAR®), a multikinase inhibitor, has been approved as a first-line systemic therapeutic for patients with HCC; however, its efficacy is compromised by the chemoresistance of the tumor cells. Since sorafenib resistant HCC are defective in apoptotic cell death, exploiting alternative regulated cell death is of paramount. Ferroptosis, a novel iron-dependent nonapoptotic regulated cell death, which possesses characteristics of impaired lipid peroxide repair, redox active iron, and the oxidation of polyunsaturated fatty acids has been reported to effectively kill the drug resistant cancer cells from broad range of origins. In the present study, by using integrative bioinformatics analysis, ferroptosis was found to be involved in the modulation of sorafenib resistant HCC cells. We found that glutathione peroxidase 4 (GPX4) is a favorable prognostic factor in cancer survival via analyzing public database; furthermore, sorafenib resistant human HCC Huh7 cell line (Huh7R) having lower expression of GPX4, dysregulated iron homeostasis, and higher expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) showed higher sensitivity to the ferroptosis induction exerted by 1S,3R-RSL3 (RSL3) which is a GPX4 inhibitor compared to the parental Huh7 cells. Besides, the GPX4-inactivation-induced ferroptosis in Huh7R could be attenuated by lysosomal blocker Bafilomycin A1. Mechanistically, lysosomal degradation of ferritin may confer sensitivity to GPX4-inactivation-induced ferroptosis by providing accessible iron as evidenced by western blotting. In conclusion, we provided evidence for the first time that GPX4-inactivation-induced ferroptosis is a promising strategy to tackle with sorafenib resistant HCC.

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