Chronic kidney disease progression in IgA nephropathy
Palmitoylation, a vital post-translational modification of proteins, has remained largely unexplored in immune-associated kidney diseases. This study is the first to reveal that palmitoylation plays a pivotal role in IgA nephropathy (IgAN) by regulating the activity of the transcription factor TEA Domain Transcription Factor 4 (TEAD4), thereby driving Th17 cell recruitment. Moreover, our findings suggest that inhibiting palmitoylation could act as a "braking" mechanism to slow disease progression. By analyzing clinical samples from IgAN patients and mouse models, we observed a significant positive correlation between the extent of Th17 cell infiltration in renal tissues and disease severity. Mechanistic investigations demonstrated that, under an inflammatory microenvironment, damaged renal tubular epithelial cells upregulate the expression of the chemokine CCL20 via TEAD4, thereby promoting Th17 cell recruitment. Notably, we identified that TEAD4 activity is regulated by its palmitoylation status, rather than changes in its protein expression levels. Further analysis identified zinc finger DHHC-type palmitoyltransferase 14 (ZDHHC14) as the critical enzyme mediating TEAD4 palmitoylation. ZDHHC14 was found to be highly expressed in the renal tissues of both IgAN patients and mouse models. Knockdown of ZDHHC14 significantly reduced CCL20 expression and diminished Th17 cell infiltration. In vivo therapeutic experiments confirmed that the ZDHHC inhibitor 2-bromopalmitate (2-BP) effectively alleviated Th17 cell infiltration and renal interstitial fibrosis, substantially delaying disease progression in IgAN mice. This study provides the first comprehensive insight into the regulatory mechanism of TEAD4 palmitoylation in IgAN progression. It further proposes a novel therapeutic approach targeting palmitoylation to modulate Th17 cell recruitment, offering critical theoretical foundations and potential clinical applications for the precise treatment of immune-mediated kidney diseases. Overall design: RNA-seq profiling of fibroblast co-culture with/without Th17 cells