PAFAH2 is a phospholipase that catalyzes hydrolysis of the acetyl group at the sn-2 position of platelet-activating factor (PAF) and oxidized phospholipids, leading to their inactivation. The enzyme also catalyzes transacetylation reactions, producing plasmalogen analogs and ceramide derivatives. PAFAH2 functions as a metabolic checkpoint in ferroptosis regulation. In acute kidney injury, PAFAH2 suppresses synchronized ferroptosis by detoxifying PAF and PAF-like phospholipids; genetic knockout or pharmacological inhibition exacerbates ischemia/reperfusion injury, while intravenous wild-type PAFAH2 protein prevents tubular cell death 1. Similarly, in KEAP1 mutant lung adenocarcinoma cells, PAFAH2 mediates ferroptosis resistance by selectively detoxifying membrane-bound oxidized phospholipids; PAFAH2 inhibition sensitizes these cells to ferroptosis 2. PAFAH2 also protects against oxidative stress-induced hepatic injury by metabolizing oxidized phospholipids 3, and in pulmonary hypertension, produces omega-3 fatty acid epoxides that suppress vascular remodeling through TGF-β pathway inhibition 4. In clear cell renal cell carcinoma, lower PAFAH2 expression correlates with increased cell proliferation and migration 5. These findings position PAFAH2 inhibition as a potential therapeutic strategy for ferroptosis-resistant cancers, while PAFAH2 enhancement may benefit ischemic and inflammatory diseases.