Molecular Hydrogen Attenuates Chronic Inflammation and Delays the Onset of Ultraviolet B-Induced Skin Carcinogenesis in Mice

Molecular hydrogen (H2) exhibits anti-inflammatory and antioxidant properties. However, its role in ultraviolet B (UVB)-induced skin carcinogenesis remains unclear. Male HR-1 hairless mice received continuous H2 (2% hydrogen gas inhalation plus hydrogen-rich water (HRW)) or control treatment (normal air plus dehydrogenated water) during chronic dorsal UVB exposure (270 mJ/cm2, three times per week, 20 weeks), followed by a 10-week observation period. This protocol was replicated independently. H2 exposure consistently delayed the onset of papilloma and reduced cumulative tumor counts in both series, whereas prolonged survival and delayed squamous cell carcinoma (SCC) development each reached statistical significance in only one of the two experimental series. The cyclobutane pyrimidine dimer (CPD) levels remained unchanged, indicating no reduction in DNA photolesions. H2 exposure decreased epidermal T-cell infiltration, dermal IL-6 levels, and nuclear phosphorylated STAT3 levels. ERK and JNK phosphorylation levels were decreased. H2 preserved the GSH/GSSG ratio following acute UVB exposure and reduced nuclear Nrf2 accumulation during chronic exposure. Epidermal thickness and proliferation markers (Ki-67 and PCNA) were decreased. These findings suggest that continuous H2 administration attenuates inflammation-associated early UVB carcinogenesis through modulation of the IL-6/STAT3 and ERK/JNK pathways, supporting its use as a chemopreventive approach.