Abstract
As aquaculture continues to expand and intensify, infectious diseases are increasingly viewed as a major constraint on sustainable and high‐quality production. In aquatic animals, post‐translational modifications (PTMs) serve as central regulatory layers of innate immunity by tuning immune sensing, signal transduction, downstream defense execution, and tissue homeostasis. This review brings together recent advances in PTM‐related disease‐resistance research across teleosts, crustaceans, mollusks, and echinoderms, with particular attention to viral, bacterial, and parasitic infections. We focus on phosphorylation and ubiquitination as two major regulatory mechanisms that tune the activation threshold, signal intensity, and termination of immune signaling at conserved but unevenly characterized nodes within RLR‐, TLR‐, cGAS–STING‐, and JAK–STAT‐related pathways. Rather than acting through a single shared mechanism, these PTMs regulate aquatic immune responses through pathway‐specific kinase activation, phosphatase‐mediated restraint, ubiquitin‐chain editing, and protein turnover. Beyond phosphorylation and ubiquitination, we also discuss other PTMs, including methylation, acetylation, SUMOylation, ISGylation, glycosylation, and lipidation, which may contribute to immune homeostasis, tissue repair, barrier protection, and host–pathogen adaptation in context‐dependent ways. Pathogens, meanwhile, can exploit PTM‐dependent checkpoints by targeting host kinases, altering ubiquitin‐dependent protein turnover, interfering with transcriptional or cytoskeletal regulation, or using their own surface glycosylation and lipidation patterns to modify host recognition. Finally, we consider emerging directions, including PTM‐focused proteomics, functional validation by gene‐editing approaches, metabolism‐linked modifications, and PTM‐informed biomarkers, to clarify host–pathogen interactions in aquatic animals and inform future strategies for disease control in aquaculture.