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. 2021 Dec 23;14(1):48. doi: 10.3390/cancers14010048

Figure 1.

Figure 1

Programmed cell death pathways initiated by TNF and FAS: (A) The TNF–TNFR1 cascade simultaneously activates proapoptotic and antiapoptotic signals, and diverse signaling complexes are formed. Complex I, composed by the adaptor protein TRADD, the receptor RIPK1, and the E3 ligase TRAF2, enables the recruitment of the inhibitor NF-ƙB kinase complex, comprising IKKα/β and NEMO. Subsequently, the inhibitor of NF-ƙB (IƙBα) is ubiquitinated and NF-ƙB translocates to the nucleus, promoting the expression of survival and antiapoptotic genes such as Bcl2 and c-FLIP. (B) In the FAS/TRAIL-mediated apoptotic pathway, binding of FASL/TRAIL to their cognate receptors results in FAS clustering and binding to FADD. TRADD dissociates from complex I and associates with FADD to form complex IIa, which triggers caspase-8 activation and, consequently, apoptosis. Complex IIb, or ripoptosome, is highly dependent on RIPK1 activity, and represents an alternative death complex that induces apoptosis through direct activation of caspase-8. (C) In contrast, caspase-8 can be inhibited under certain physiological or pharmacological conditions, promoting the shift from the ripoptosome-induced apoptosis to necroptosis, a form of programmed necrosis via complex IIc or necrosome. RIPK3 mediates the phosphorylation of MLKL, resulting in its conformational change and oligomerization. This allows MLKL to bind to plasma membrane lipids and form a pore that leads to cell lysis. Release of cellular components (cytokines, chemokines and DAMPs) perpetuates liver inflammation and fibrogenesis in a pro-tumoral microenvironment, thus promoting HCC development. Abbreviations: Bcl2, B-cell lymphoma 2; Casp-3, caspase-3; c-FLIP, cellular FLICE-like inhibitory protein; DAMPs, damage-associated molecular patterns; FAS, FS-7-associated surface antigen; FADD, FAS-associated death domain protein; FASR, FAS receptor; FASL, FAS ligand; MLKL, mixed lineage kinase domain-like protein; NF-ƙB, nuclear factor kappa-light-chain-enhancer of activated B cells; RIPK1, serine/threonine-protein kinase 1; TNF, tumor necrosis factor; TRADD, TNFRSF1A-associated via death domain; TRAF2, receptor-associated factor; TRAIL, Targeting TNF-related apoptosis-inducing ligand. Created with BioRender.com.