MECHANISMS OF DEOXYSPHINGANINE CYTOTOXICITY IN LYMPHOMA CELLS

Deoxysphingolipids (dSLs) are atypical sphingolipids that accumulate in several pathological settings, yet their impact on hematologic malignancies is poorly understood. Here, we investigate the pathways and mechanisms of deoxysphinganine (dSA) cytotoxicity in lymphoma cells and its potential as a therapeutic agent. dSA exhibited markedly greater cytotoxicity than canonical sphingoid bases in lymphoma cell lines, yet induced only cytostatic effects in normal human T cells, indicating a therapeutically exploitable window. Inhibition of ceramide synthase blocked the generation of deoxy(dihydro)ceramides, prevented mitochondrial depolarization, caspase activation, ER stress, and DNA damage, establishing CerS-dependent deoxysphingolipids as essential mediators of dSA-induced death. Mechanistically, dSA engaged a mitochondrial apoptotic pathway, with DNA damage occurring downstream of mitochondrial permeabilization and caspase activation, while PERK-driven ER stress occurred in parallel and was dispensable for cytotoxicity. Subtype-specific engagement of ER stress and DNA damage further suggests that dSL signaling is shaped by lineage context. The differential sensitivity between malignant lymphoid cells and normal T cells, together with the central role of CerS-derived deoxy(dihydro)ceramides, highlights deoxysphingolipid metabolism as a druggable vulnerability in lymphoma. These findings support further exploration of dSA-based strategies and targeted modulation of dSL synthesis as a novel therapeutic avenue for non-solid hematologic malignancies.