BIOCHEMICAL DRIVERS OF SKIN DISEASES AND THE PATH FROM MOLECULAR UNDERSTANDING TO EFFECTIVE CURES

Abstract

Skin diseases affect nearly one-third of the global population, yet biochemical drivers remain underappreciated in clinical translation. Despite decades of research focusing on genetics and histopathology, the dynamic molecular currencies lipids, proteases, reactive oxygen species, and cytokines that actually govern disease activity have been largely ignored in routine clinical practice. This review addresses this gap by placing biochemistry at the center of dermatologic diagnosis and therapy. Four biochemical pillars drive inflammatory skin diseases. First, lipid barrier defects, including ceramide deficiency and impaired lipid processing, compromise stratum corneum integrity. Second, protease-antiprotease imbalance, particularly involving KLK5 and KLK7 and their inhibitor LEKTI, leads to premature desquamation and inflammation. Third, redox signaling deregulation, characterized by NADPH oxidase-derived reactive oxygen species and depletion of glutathione and thioredoxin systems, amplifies proinflammatory transcription factors. Fourth, cytokine-mediated inflammation, orchestrated by the IL-23/IL-17 axis in psoriasis and the IL-4/IL-13 axis in atopic dermatitis, represents the final common pathway of disease expression Molecular understanding has already yielded transformative therapies. Biologics targeting IL-17A (secukinumab, ixekizumab), IL-23 (guselkumab, risankizumab), and IL-4Rα (dupilumab) have revolutionized treatment of psoriasis and atopic dermatitis. Small molecule inhibitors including JAK inhibitors (upadacitinib, tofacitinib), TYK2 inhibitors (deucravacitinib), and PDE4 inhibitors (apremilast) offer oral alternatives. Gene-targeted approaches for monogenic skin diseases are advancing through preclinical and early clinical development. Biochemical stratification the systematic measurement of lipid profiles, protease activities, redox status, and cytokine signatures in patient skin represents the missing link between descriptive histopathology and mechanism-based curative therapy. Integrating biochemical endotyping into routine dermatologic practice and clinical trial design will accelerate the development of rational, targeted, and ultimately curative treatments for the full spectrum of inflammatory skin diseases