LCE3C is a structural protein component of the cornified envelope in the stratum corneum that contributes to innate cutaneous host defense. It possesses defensin-like antimicrobial activity against both Gram-positive and Gram-negative bacteria, including aerobic and anaerobic species. Upon skin inflammation, LCE3C may regulate barrier repair by modulating cutaneous microbiota composition and shaping immune responses to bacterial antigens. Genetically, the LCE3C_LCE3B deletion polymorphism is a well-established susceptibility factor for psoriasis across multiple ethnic groups. Meta-analyses confirm significant associations in European (OR 1.21) 1 and Asian populations (OR 1.27-2.08) 1, with the deletion explaining part of psoriasis heritability 2. The LCE3C_LCE3B deletion also associates with psoriatic arthritis 3, rheumatoid arthritis 45, and systemic lupus erythematosus 4, suggesting a shared role for skin barrier defects in autoimmune disease susceptibility. Evolutionarily, this deletion has been maintained under balancing selection since Human-Denisovan divergence, likely reflecting a trade-off between increased autoimmunity risk and pathogen protection 6. Clinically, LCE3C deletion status may help stratify psoriatic disease risk and represents a genetic link between skin barrier integrity and systemic autoimmunity.