Trifloxystrobin-triggered Drp1 hyperactivation biases mitophagy and imposes long-lasting SVCV susceptibility in teleost

Environmental pollutants are increasingly recognized as disease modifiers, reshaping host homeostasis and shifting host-pathogen dynamics toward higher infection risk in aquatic ecosystems. Here, we show that the widely used strobilurin fungicide trifloxystrobin (TFS) persistently erodes antiviral competence in fish and increases susceptibility to spring viremia of carp virus (SVCV) by driving dynamin-related protein 1 (Drp1)-mediated excessive mitophagy and sustained mitochondrial dysfunction. Using epithelioma papulosum cyprini (EPC) cells and zebrafish as complementary models, we find that environmentally plausible TFS exposures (2.5–25 μg/L) elevate SVCV permissiveness; notably, this phenotype resolves incompletely after chemical withdrawal. Transcriptomics revealed a dose-concordant shift toward stress/innate immune signaling and mitophagy programs, alongside broad repression of proliferative and DNA-repair pathways. Consistently, TFS induces persistent mitochondrial membrane depolarization, promotes fragmentation and ultrastructural deterioration, and increases mitochondria–lysosome coupling. Mechanistically, TFS elevates Drp1 abundance and Ser616 phosphorylation, promotes Drp1 recruitment to mitochondria, and sustains microtubule-associated protein 1 light chain 3B (LC3B)/lysosomal-associated membrane protein 2 (LAMP2) engagement, accompanied by persistent induction of core autophagy regulators (gabarap, atg5, wipi1, and ambra1) across extended recovery windows. In vivo, prolonged TFS exposure similarly yields durable enhancement of SVCV susceptibility even after long recovery periods, indicating incomplete restoration of host resistance. Together, these findings link a major agricultural fungicide to persistent Drp1-driven mitophagy overactivation and identify long-term antiviral resistance as an ecologically relevant endpoint for pesticide risk assessment and aquatic disease forecasting.