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© 2021 American Chemical Society and American Society of Pharmacognosy.Preclinical and clinical studies support cannabidiol (CBD)'s antioxidant and anti–inflammatory effects, which are linked to its skin protective effects, but there have been limited mechanistic studies reported. Herein we evaluated CBD's protective effects against hydrogen peroxide (H2O2)–induced oxidative stress in human keratinocyte HaCaT cells and explored its possible mechanism(s) of action. CBD (10 μM) protected HaCaT cells by alleviating H2O2 (200 μM)–induced cytotoxicity (by 11.3%) and reactive oxygen species (total– and mitochondrial–derived). Several NLRP3 inflammasome–related genes including CASP1 and IL1B were identified as potential molecular targets for CBD's antioxidant effects by multiplexed gene and network pharmacology analyses. CBD treatment down–regulated the mRNA expression levels of CASP1 and IL1B (by 32.9 and 51.0%, respectively) and reduced IL–1β level (by 16.2%) in H2O2–stimulated HaCaT cells. Furthermore, CBD inhibited the activity of caspase–1 enzyme (by 15.7%) via direct binding to caspase–1 protein, which was supported by data from a biophysical binding assay (surface plasmon resonance) and a computational docking experiment. In addition, CBD mitigated H2O2–induced pyroptosis (capase–1–mediated cell death) and apoptosis by 23.6 and 44.0%, respectively. The findings from the current study suggest that CBD exerts protective effects in human keratinocytes via the modulation of the caspase–1–IL–1β axis, supporting its potential skin health applications.
