NIPAL4 (NIPA-like domain containing 4) functions primarily as a magnesium (Mg2+) transporter with secondary capacity for other divalent cations 1. The gene is highly expressed in the granular cell layer of human epidermis 2, where it plays a critical role in skin barrier formation and keratinocyte differentiation. Mechanistically, NIPAL4 maintains intracellular Mg2+ homeostasis essential for proper chr5 remodeling during keratinocyte differentiation. Nipal4-knockout mice exhibit neonatal lethality due to severely compromised skin barrier function, characterized by decreased acylceramide lipids, hyperkeratosis, and impaired induction of differentiation-dependent genes (Krt1, Lor, Flg, Elovl1, Dgat2) 1. The low Mg2+ concentration in NIPAL4-deficient keratinocytes disrupts chr5 remodeling necessary for proper barrier lipid synthesis. NIPAL4 mutations cause autosomal recessive congenital ichthyosis (ARCI), a nonsyndromic keratinization disorder 34. NIPAL4-mutated ARCI patients (9.5% of characterized cases) present distinctive phenotypic features including psoriasis-like lesions, trunk reticulate scaling, and striated keratoderma, with relatively lower disease severity compared to TGM1 or ABCA12 mutations 5. Beyond dermatology, NIPAL4 has emerged as a potential prognostic marker in clear cell renal cell carcinoma, where high expression correlates with poor prognosis and associates with immune checkpoint molecules 6.