Fig. 3: CYP51A1-mediated regulation of diverse regulated cell death pathways.
From: CYP51A1 in health and disease: from sterol metabolism to regulated cell death
A In CD8⁺ T cell apoptosis, DUSP18 of CRC activates the USF1–SREBF2 axis, inducing cholesterol biosynthetic enzymes including CYP51A1. Elevated lanosterol suppresses T cell activation and promotes apoptosis. B In ferroptosis, CD40 ligand (CD40LG) from bone marrow stromal cells activates CD40 on multiple myeloma (MM) cells, increasing intracellular iron and lanosterol, and lanosterol promotes ROS accumulation, enhancing ferroptotic cell death. Furthermore, the ferroptosis inhibitory function of CYP51A1 is independent of lanosterol in HEK293T cells. C In alkaliptosis, the small molecule JTC801 impairs lysosomal acidification by inhibiting V-ATPase, resulting in cholesterol accumulation in the ER and upregulation of CYP51A1. This process facilitates the degradation of lanosterol, restores TMEM175-mediated proton efflux, and protects against alkaliptosis. D In pyroptosis, lipopolysaccharide (LPS)-induced type I interferons (IFNA1 and IFNB1) activate IFNAR1/2 signaling, leading to histone deacetylation at the CYP51A1 promoter and repression of its expression. Lanosterol accumulation alters membrane fluidity and suppresses STAT1/STAT2 activity, alleviating pyroptotic sensitivity.
