zDHHC-Mediated S-Palmitoylation in Skin Health and Its Targeting as a Treatment Perspective.

S-acylation, which includes S-palmitoylation, is the only known reversible lipid-based post-translational protein modification. S-palmitoylation is mediated by palmitoyl acyltransferases (PATs), a family of 23 enzymes commonly referred to as zDHHCs, which catalyze the addition of palmitate to cysteine residues on specific target proteins. Aberrant S-palmitoylation events have been linked to the pathogenesis of multiple human diseases. While there have been advances in elucidating the molecular mechanisms underlying the pathogenesis of various skin conditions, there remain gaps in the knowledge, specifically with respect to the contribution of S-palmitoylation to the maintenance of skin barrier function. Towards this goal, we performed PubMed literature searches relevant to S-palmitoylation in skin to define current knowledge and areas that may benefit from further research studies. Furthermore, to identify alterations in gene products that are S-palmitoylated, we utilized bioinformatic tools such as SwissPalm and analyzed relevant data from publicly available databases such as cBioportal. Since the targeting of S-palmitoylated targets may offer an innovative treatment perspective, we surveyed small molecules inhibiting zDHHCs, including 2-bromopalmitate (2-BP) which is associated with off-target effects, and other targeting strategies. Collectively, our work aims to advance both basic and clinical research on skin barrier function with a focus on zDHHCs and relevant protein targets that may contribute to the pathogenesis of skin conditions such as atopic dermatitis, psoriasis, and skin cancers including melanoma.