The Phospholipase A2 Activity of Peroxiredoxin 6 Protects Hepatocarcinoma Cells Against Ferroptosis and Mitophagy Impairment

In HepG2 cells, PRDX6 iPLA2 activity loss via the D140A mutation increases lipid peroxidation and iron-linked ferroptosis vulnerability, with mitochondria showing reduced cristae and mitophagy capacity.

• Why it matters: Ferroptosis and impaired mitophagy are linked to cancer cell survival, but how PRDX6’s iPLA2 activity coordinates organelle lipid homeostasis to protect hepatocarcinoma cells is unclear.
• What they did: The study created stable HepG2 lines expressing PRDX6 D140A, compared them with WT and PRDX6-knockout cells, and used integrated proteomic, lipidomic, and enzymatic analyses plus erastin challenge.
• The result: D140A phenocopied PRDX6-KO for ferrous iron accumulation, lipid droplet biogenesis defects, and GPX4 downregulation, implying iPLA2 activity supports lipid release and mitophagy needed to resist erastin-induced ferroptotic death.

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