The anti-inflammatory role of zDHHC23 through the promotion of macrophage M2 polarization and macrophage necroptosis in large yellow croaker ().

Zinc finger Asp-His-His-Cys motif-containing (zDHHC) proteins, known for their palmitoyltransferase (PAT) activity, play crucial roles in diverse cellular processes, including immune regulation. However, their non-palmitoyltransferase immunomodulatory functions and involvement in teleost immune responses remain underexplored. In this study, we systematically characterized the zDHHC family in the large yellow croaker (), identifying 22 members. Phylogenetic analysis unveiled that each of the 22 zDHHCs formed distinct clusters with their orthologues from other teleost species. Furthermore, all zDHHCs exhibited a highly conserved DHHC domain, as confirmed by tertiary structure prediction. Notably, zDHHC23 exhibited the most pronounced upregulation following () infection of macrophage/monocyte cells (MO/MΦ). Silencing zDHHC23 led to heightened pro-inflammatory cytokine expression and diminished anti-inflammatory cytokine levels in MO/MΦ during infection, indicating its anti-inflammatory role. Functionally, zDHHC23 facilitated M2-type macrophage polarization, as evidenced by a significant skewing of MO/MΦ towards the pro-inflammatory M1 phenotype upon zDHHC23 knockdown, along with the inhibition of MO/MΦ necroptosis induced by infection. These findings highlight the non-PAT immunomodulatory function of zDHHC23 in teleost immune regulation, broadening our understanding of zDHHC proteins in host-pathogen interactions, suggesting zDHHC23 as a potential therapeutic target for immune modulation in aquatic species.