<p>Psoriasis is a chronic inflammatory dermatosis characterized by the hyperproliferative of keratinocytes. S100A7 plays a pivotal role in the pathogenesis of psoriasis. Lysine crotonylation of proteins is a newly identified modification that impacts diverse biological processes and its dysregulation has been implicated in autoimmune diseases. To investigate the profile of lysine crotonylation and its pathogenic role in psoriasis, we conducted a comparative analysis of crotonylation-modified proteins in psoriatic lesions versus healthy controls. Mutant keratinocytes with crotonylation deficiency of S100A7 were generated to explore its functional effects in psoriasis. Our omic analysis revealed a unique lysine crotonylation profile in psoriatic lesions, with a notable downregulation of crotonylation at lysine 49 (K49) of S100A7. In vitro studies demonstrated that S100A7-K49A crotonylation deficiency exhibited enhanced cell viability, augmented glycolytic metabolism, and upregulated expression of key metabolic enzymes. Furthermore, co-immunoprecipitation assays demonstrated that the K49 crotonylation-deficient form of S100A7 strengthens its interaction with RAGE, leading to enhanced phosphorylation of AKT and mTOR. Our findings suggest that S100A7 K49 crotonylation deficiency plays a pivotal role in promoting keratinocytes proliferation and metabolic reprogramming in psoriasis, and targeting abnormal S100A7 crotonylation as a potential therapeutic strategy for intervention in psoriasis-related pathologies.</p>