Modulation of Fe3+ homeostasis by African Swine Fever virus facilitates its efficient replication in Ornithodoros lahorensis and pigs.

ASFV replication in porcine PAM cells and Ornithodoros lahorensis is supported by pA151R-driven, NCOA4-FTH1-dependent modulation of labile Fe3+ homeostasis.

• Why it matters: The cellular basis for how ASFV sustains replication in both pig cells and tick vectors is unclear, despite iron being required for metabolism and viral growth.
• What they did: Proteomics in ASFV-infected PAM and OME/CTVM24 cells showed reduced ferritin/FTH1 and dynamic labile Fe3+ changes; deferoxamine mesylate suppressed replication in both cell types. Mechanistically, pA151R interacted with NCOA4 to promote autophagic FTH1 degradation and affected mitochondrial integrity and MDA5-MAVS/VISA signaling.
• The result: Early infection increased NCOA4-associated ferritin turnover, labile Fe3+ release, mitochondria-ER contacts, and ferroptosis-like mitochondrial changes, while later stages restrained iron-associated damage to maintain replication. In pigs and O. lahorensis, ASFV altered serum iron and tissue iron redistribution with transient ferroptosis-like mitochondrial morphology, and A151R deletion impaired Fe3+ modulation and reduced viral replication.

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