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. 2021 Oct 21;12(11):977. doi: 10.1038/s41419-021-04262-x

Fig. 1. FASN and the cell death decision circuitry controlled by the BCL-2 family.

Fig. 1

We envisioned that the functional interaction between FASN-catalyzed endogenous fatty acid biogenesis and the BCL-2 family interaction network that controls the mitochondrial pathway of apoptosis might be the basis for the differential sensitivity to FASN inhibitors (FASNis). The BCL-2 family can be divided into three classes, namely the pro-apoptotic BAX/BAK proteins, the proapoptotic BH3-only proteins, and the pro-survival proteins, the latter inhibiting the activity of the pro-apoptotic BCL-2 family members. Although historically those BH3-only proteins able to directly activate BAX/BAK have been termed either “activators” and those targeting pro-survival proteins to indirectly activate BAX/BAK have been called “sensitizers”, this strict categorization is no longer appropriate as some “sensitizers” can exhibit direct activation functions under certain circumstances. Thus, BH3-only proteins can be better distinguished by their ability to either directly bind and “activate” BAX/BAK or indirectly “derepress” pro-survival proteins (via hindering the ability of pro-survival proteins to sequester BH3-only proteins to stop them activating BAX/BAK or impeding the ability of pro-survival proteins to bind to activated BAX/BAK and prevent their homo-oligomerization). BAX/BAK activation ultimately controls mitochondrial outer membrane permeabilization (MOMP), which precedes the release of mitochondria-stored cytochrome c (Cyt c) into the cytosol to promote apoptosome formation, subsequent activation of effector caspases, and apoptosis. The balanced interactions within the BCL-2 family involving activation of BH3-only proteins and inhibition by pro-survival proteins lastly sets how close a cell is to the threshold or apoptosis, a property called “mitochondrial priming”. Lack or low levels of activating/de-repressing events upon exposure to FASNis might lead to a resistant or unprimed state. When FASN blockade drives a high mitochondrial priming, cancer cells might acquire a primed-for-death state in which they ensure their survival by becoming “addicted” to anti-apoptotic proteins sequestering pro-apoptotic members. Created with BioRender.com.