Schematic representation of the proposed mechanism of action. By binding to and inhibiting PIKfyve function, apilimod blocks the formation of PI(3,5)P2 (1). Apilimod mediated-TFEB dephosphorylation promotes TFEB nuclear translocation and transcription of its target gene, CLCN7 (2). In addition to CLCN7, OSTM1 and SNX10 are 2 other key genes upregulated with apilimod treatment. Both CLCN7 and OSTM1 encode anion exchange transporters of pivotal importance for lysosome homeostasis, whereas SNX10 plays an important role in regulating endolysosomal trafficking (3). Apilimod-mediated impairment of lysosomal homeostasis (upregulation of CLCN7, OSTM1) in the setting of endolysosomal membrane traffic dysfunction (upregulation of SNX10) may induce tumor cell stress, ultimately leading to lymphoma cell death. LC3, light chain 3; TFEB-p, transcription factor EB-phosphorylated; TLR9, Toll-like receptor 9; V-ATPase, vacuolar-type H⁺ ATPase. Professional illustration by Somersault18:24.