Unveiling the role of neurotransmitters in Nrf2 pathway activation in HaCaT cells: toward novel brain-skin redox biomarkers

Oxidative stress is a central feature of both cutaneous biology and neurological disorders; however, the endogenous signals that activate the Nrf2 antioxidant pathway in the skin remain poorly defined. Here, we identified dopamine (DA) as a selective activator of Nrf2-dependent cytoprotective signaling in human keratinocytes and delineated a catecholamine-related mechanism that may connect neuronal stress to peripheral redox responses. Using HaCaT keratinocytes as a model of the brain-skin redox interface, we demonstrated that both DA and norepinephrine (NE) induce Nrf2 nuclear translocation in a dose-dependent manner. However, only DA elicited full pathway activation, characterized by marked transcriptional induction of canonical Nrf2 target genes, including HO-1, NQO1, GCLM, and catalase, followed by elevated NQO1 and HO-1 protein abundance. Despite triggering nuclear translocation, NE fails to activate ARE-dependent gene expression, demonstrating that nuclear accumulation alone is insufficient for functional Nrf2 engagement. Functionally, DA pretreatment conferred robust protection against UVB-induced apoptosis, reducing caspase-3 activation to near baseline levels, whereas NE provided no detectable cytoprotection. Mechanistic analyses revealed that both catecholamines require oxygen and ROS to promote Nrf2 activation and exhibit direct, non-covalent interactions with Keap1. Nonetheless, differences in the oxidative reactivity between DA and NE appear to determine their divergent downstream outcomes. Together, these findings identify DA as an endogenous enhancer of cutaneous Nrf2 antioxidant defenses and establish catecholamine-mediated redox signaling as a previously unrecognized component of the brain-skin axis. This study provides a mechanistic basis for exploring skin-derived biomarkers of neuro-oxidative stress relevant to neurological disorders, such as epilepsy.