ZDHHC17-mediated IKKβ palmitoylation suppresses NF-κB signaling to mitigate the progression of liver fibrosis.

Liver fibrosis (LF) is a common consequence of chronic liver injury and inflammation, driven by the IKK complex-mediated NF-κB signaling pathway. This study investigated the role of macrophage IKKβ palmitoylation in NF-κB signaling and LF progression. Analysis of liver tissues and peripheral blood mononuclear cells (PBMCs) from LF patients and healthy individuals revealed decreased ZDHHC17 expression in LF-associated macrophages. Using mouse models of LF and ZDHHC17 knockout mice, we found that ZDHHC17 deficiency accelerated LF progression. Mechanistically, ZDHHC17 palmitoylated IKKβ at cysteine 299, inhibiting its autophosphorylation and NF-κB pathway activation. This suppression reduced macrophage inflammatory responses and hepatic stellate cell activation, mitigating LF. Additionally, IKKβ palmitoylation weakened its interaction with TAK1, reducing phosphorylation at Ser177 and Ser181, further inhibiting NF-κB signaling. These findings highlight ZDHHC17 as a key regulator of IKKβ palmitoylation, suppressing inflammation, and LF progression. Targeting IKKβ palmitoylation may offer a novel therapeutic approach for LF.