DGAT1 regulates keratinocyte proliferation through the modulation of retinoid homeostasis

The skin barrier is essential for protection against environmental insults, pathogens, and water loss. While acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) has been implicated in lipid and retinoid metabolism, its direct role in keratinocyte biology is not well defined. Here, we show that DGAT1 deficiency in mice drives extensive keratinocyte hyperproliferation and barrier dysfunction under homeostatic conditions. Transcriptomic profiling revealed upregulation of genes associated with proliferation, inflammation, and retinoic acid (RA) signaling, consistent with increased proliferation observed in vitro and in vivo. Unexpectedly, while DGAT1 expression was elevated in human psoriatic lesions and in a murine psoriasis model, DGAT1 loss reduced keratinocyte proliferation. Further analyses identified dysregulated RA signaling as a central mediator of these effects. DGAT1-deficient keratinocytes exhibited elevated RA-target gene expression and increased expression of RA-binding proteins, indicating enhanced RA bioavailability. These alterations were recapitulated by RA treatment of wild-type cells and were attenuated under psoriatic inflammation. Collectively, our findings establish DGAT1 as a context-dependent regulator of keratinocyte proliferation, promoting growth in homeostasis while restraining it in psoriasis. By linking DGAT1 activity with RA signaling, this work uncovers a previously unrecognized pathway contributing to epidermal physiology and pathophysiology of inflammatory skin diseases.