Abstract
African swine fever virus (ASFV), the causative agent of African swine fever (ASF), poses a catastrophic threat to global swine industries through its capacity for immune subversion and rapid evolution. Multigene family genes (MGFs)-encoded proteins serve as molecular hubs governing viral evolution, immune evasion, cell tropism, and disease pathogenesis. This review synthesizes structural and functional evidence demonstrating that MGFs-encoded proteins suppress both interferon signaling and inflammasome activation, while their genomic plasticity in variable terminal regions drives strain diversification and adaptation. Translationally, targeted deletion of immunomodulatory MGFs enables the rational design of live attenuated vaccines that improve protective efficacy while minimizing residual virulence. Moreover, hypervariable MGFs provide strain-specific signatures for PCR-based diagnostics and phylogeographic tracking, directly addressing outbreak surveillance challenges. By unifying virology with translational innovation, this review establishes MGFs as priority targets for next-generation ASF countermeasures.