Core Insights - Lung cancer is the most prevalent cancer globally, with 2.48 million new cases and 1.8 million deaths annually, primarily due to non-small cell lung cancer (NSCLC) which accounts for over 85% of cases [2] - The recent study published by a team from Sun Yat-sen University identifies LIC1 as a new therapeutic target for NSCLC and highlights the potential of DAA as an autophagy-inducing agent for treatment [3][7] Group 1: Research Findings - The research isolated a small molecule, DAA, from endophytic fungi of Euphorbiaceae plants, which effectively induces autophagic cell death in NSCLC cells [3][5] - DAA shows significant anti-tumor efficacy in NSCLC and enhances sensitivity to anti-PD-1 immunotherapy while exhibiting low toxicity to normal lung fibroblasts [5] - LIC1 was identified as the direct target of DAA, which is overexpressed in NSCLC tumors and associated with poor prognosis [5] Group 2: Mechanism of Action - DAA disrupts the interaction between LIC1 and the stress response effector RuvBL1, enhancing the integrated stress response mediated by the GCN2-eIF2α-ATF4 signaling axis, ultimately promoting autophagic cell death [5]

Core Viewpoint - The research reveals the critical role of endocytosis in cysteine-deprivation-induced ferroptosis, challenging previous understandings of lysosomal inhibitor mechanisms and suggesting different execution pathways for ferroptosis [3][7]. Group 1: Key Findings - Lysosomal inhibitors can independently suppress cysteine-deprivation-induced (CDI) ferroptosis, regardless of autophagy [5]. - Endocytosis is essential for CDI ferroptosis but is not required for ferroptosis induced by GPX4 depletion [5]. - Endocytic defects reduce intracellular iron levels and prevent CDI ferroptosis [5]. Group 2: Mechanisms and Implications - Transferrin's clathrin-mediated endocytosis (CME) is crucial for driving CDI ferroptosis [4][5]. - Inhibition of lysosomal proteolytic activity does not prevent ferroptosis, while disrupting endosomal acidification and removing endocytic protein AP2M1 can block ferroptosis [4]. - Supplementing iron through ammonium iron citrate, independent of endocytosis, can restore CDI ferroptosis in cells with endocytic defects [4].