Giovanni Pellacani, Simone Michelini, Federica Trovato, Alessandra Rallo, Giuseppe Gemma, Camilla Chello, Mauro Pavan, Cristian Guarise, Alberto Giuseppe Passi
Background/Objectives: Sulfated hyaluronic acid (sHA) is a chemically modified derivative of native hyaluronic acid (HA), characterized by enhanced physicochemical stability and increased biological activity. Glycosaminoglycans (GAGs), including HA, are key regulators of skin structure, hydration, and immune homeostasis. This review aims to critically summarize current knowledge on the structural and functional properties of GAGs—particularly HA and its sulfated forms—and to explore their potential dermatological applications in skin aging and inflammatory diseases such as atopic dermatitis, psoriasis, and acne. Methods: A narrative literature review was conducted using PubMed and Scopus databases up to June 2025, including experimental, preclinical, and clinical studies investigating the biological effects, mechanisms of action, and dermatological uses of sHA compared with native HA and other HA derivatives. Results: Compared with HA, sHA demonstrates increased enzymatic resistance, higher charge density, and improved water-binding and antioxidant capacity. These properties contribute to the restoration of skin barrier function, modulation of oxidative stress and inflammation, and promotion of extracellular matrix remodeling. Preclinical evidence supports the efficacy of sHA in reducing dryness, irritation, and inflammatory responses in atopic dermatitis, psoriasis, and acne. Preliminary findings also suggest potential benefits in wound healing and skin barrier repair. Conclusions: sHA represents a promising multifunctional molecule in dermatology and cosmetology, capable of reducing inflammation and supporting tissue regeneration. However, current evidence remains limited to preliminary studies. Future controlled clinical trials are required to confirm efficacy, optimize formulations, and establish standardized treatment protocols.