Bibliogr.

Multiple mechanisms contribute to skin barrier integrity, and emerging evidence suggests that acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) plays a key role in its regulation through both lipid and retinoid metabolism. Although DGAT1 deficiency leads to cutaneous abnormalities, the direct role of DGAT1 in keratinocyte biology remains unclear. Here, we show that DGAT1 deficiency 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 in this inflammatory condition. 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. 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 inflammatory skin disease.