Residue Y362 is crucial for FLIP to impart catalytic activity to pro-caspase-8 to suppress necroptosis.

The pro-form of caspase-8 prevents necroptosis by functioning in a proteolytically active complex with its catalytic-dead homolog, FLICE (FADD [Fas-associated death domain]-like interleukin 1β-converting enzyme)-like inhibitory protein long-form (FLIP). However, how FLIP imparts caspase-8 the catalytic activity to suppress necroptosis remains elusive. Here, we show that the protease-like domain of FLIP is essential for the activity of the caspase-8-FLIP heterodimer in blocking necroptosis.

Induction of IL-6Rα by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma.

Sorafenib and its derivative regorafenib are the first- and second-line targeted drugs for advanced HCC, respectively. Although both drugs improve overall survival, drug resistance remains the major barrier to their full efficacy. Thus, strategies to enhance sorafenib and regorafenib efficacy against HCC are solely needed.