SPRR2D is a small proline-rich protein that functions as a cross-linked envelope protein in keratinocytes [UniProt]. It is synthesized in the cytosol and becomes covalently cross-linked to membrane proteins via transglutaminase, contributing to cornified envelope formation and epidermal barrier integrity [UniProt, GO annotations]. Mechanistically, SPRR2D is an estrogen-responsive gene whose expression is primarily localized to endometrial epithelial cells 1. The protein plays a role in keratinocyte differentiation and skin barrier homeostasis, as demonstrated by its upregulation in response to various skin stressors. Disease relevance: SPRR2D is significantly upregulated in multiple inflammatory and neoplastic conditions. In atopic dermatitis exacerbated by particulate matter exposure, SPRR2D was among the most highly upregulated genes, indicating its involvement in skin barrier dysfunction and inflammation 2. SPRR2D has also been identified as a hub gene in oral squamous cell carcinoma 3, lung adenocarcinoma 4, and breast cancer with lymph node metastasis 5. Additionally, SPRR2D upregulation occurs in chloracne-like skin disease associated with aberrant Nrf2 activation 6 and in eosinophilic esophagitis 7. Clinically, SPRR2D represents a potential biomarker for disease severity and progression in both dermatological and malignant conditions, though further investigation is needed to establish its predictive and therapeutic utility.