PTDSS2 (phosphatidylserine synthase 2) catalyzes a base-exchange reaction converting phosphatidylethanolamine (PE) into phosphatidylserine (PS), but does not act on phosphatidylcholine 1. The enzyme preferentially utilizes diacyl PE over PE plasmalogen and shows selectivity for docosahexaenoic acid at the sn-2 position [UniProt annotation]. PTDSS2 functions as part of a critical phospholipid interconversion system regulating cellular PS levels 2. Dysregulation of PTDSS2 has significant disease implications. In breast cancer, elevated PTDSS2 expression combined with low ATP11B promotes externalization of nonapoptotic PS on the cell membrane, creating an immunosuppressive microenvironment that enhances metastasis through myeloid-derived suppressor cell accumulation and reduced cytotoxic T cell activity 3. PTDSS2 is implicated in hepatocellular carcinoma progression as a component of a metabolism-related prognostic signature predicting patient outcomes 4. Additionally, PTDSS2 expression is altered in major depressive disorder patients and participates in glycerophospholipid metabolism pathways 5. Epigenetic silencing of PTDSS2 via DNA hypermethylation occurs in response to 27-hydroxycholesterol in breast cancer cells 6. PTDSS2 genetic variants may influence HIV-1 reservoir size in suppressed individuals 7. These findings suggest PTDSS2 as a potential therapeutic target, particularly through combination strategies targeting the ATP11B-PTDSS2 axis in metastatic breast cancer.