Time-resolved transcriptomic responses delineate liver injury, immune-mediated clearance, and regeneration following microcystin-LR exposure in whitefish: implications for an uptake-limiting defense response (autokleisis).

Microcystin-LR (MC-LR), a potent cyanobacterial hepatotoxin, enters hepatocytes via active transport and inhibits protein phosphatases. However, the temporal organization of hepatic injury, immune-mediated clearance, and regenerative repair after MC-LR exposure, as well as the associated transcriptomic signature, remain incompletely understood. Here, we exposed juvenile whitefish (Coregonus lavaretus) to MC-LR (100 μg·kg-1, intraperitoneally) on day 0 and re-exposed them on day 7. Across a 1-14-day time course, we integrated histology and ultrastructure, immunohistochemistry, plasma biochemistry, and bulk RNA-seq with gene set enrichment at selected timepoints. The response to MC-LR exposure consisted of three partially overlapping phases: (i) early hepatocyte injury accompanied by stress-response transcriptional signatures; (ii) an intermediate phase dominated by macrophage-associated clearance, cytoskeletal/trafficking remodeling, and suppressed glucose metabolism; and (iii) a late regenerative phase with proliferative programs, bile-duct-associated epithelial proliferation and re-emergence of immature hepatocytes. Despite re-dosing, hepatic MC-LR immunoreactivity decreased and became confined to discrete degenerating cell clusters, suggesting reduced effective toxin entry and/or retention during regeneration. Together, these findings provide a phase-resolved framework for MC-LR hepatoxicity and recovery in a teleost liver and suggest an uptake-limiting recovery state as a candidate protective component of regeneration.