Rb1cc1, also known as FIP200, is an essential macroautophagy/autophagy protein [2]. It is a subunit of the ULK1 complex in more complex eukaryotes and is proposed to be a functional homolog of the Atg17 and Atg11 scaffolding proteins in yeast [3]. Rb1cc1 plays important roles in a variety of biological and disease processes through its canonical autophagy-dependent and-independent functions, and is involved in pathways such as autophagy initiation, autophagosome formation, and mitophagy [2,3,4,5].

In tumour cells, Rb1cc1 is upregulated by lipid ROS, and its nuclear translocation and phosphorylation at Ser537 are essential for sensitising ferroptosis. Nuclear Rb1cc1 recruits ELP3 to enhance H4K12Ac histone modifications within enhancers related to ferroptosis, stimulating the transcription of ferroptosis-associated genes and enhancing mitochondrial function to elevate mitochondrial ROS early during ferroptosis induction. Also, Rb1cc1 was essential for ferroptosis agonists to suppress liver tumourigenesis in mice [1]. Moreover, in the context of TNF-induced cell death, Rb1cc1, along with ATG9A and TAX1BP1, acts as a component of a cell-death checkpoint to prevent TNF cytotoxicity, which is crucial in preventing inflammatory skin disease [6].

In conclusion, Rb1cc1 is crucial for autophagy-related biological functions. Its role in tumour cell ferroptosis and TNF-induced cell-death checkpoints, as revealed by in vivo studies including mouse models, provides important insights into potential therapeutic strategies for cancer and inflammatory skin diseases.