Selective modulation of IL-6/JAK/STAT-related signaling under redox-shift conditions by luteolin

Luteolin is a naturally occurring flavone known to modulate cellular redox balance and inflammatory signaling; however, its role in integrated redox-inflammatory responses remains incompletely defined. The present study investigated the effects of luteolin, alone and in combination with the selective JAK1 inhibitor upadacitinib, on oxidative stress parameters, inflammatory mediators, and JAK/STAT-related gene expression in human breast (MCF-7), colorectal (HT-29), and hepatocellular (HepG2) cancer cell lines, with L929 fibroblasts as a non-tumor comparator.

Real-time impedance analysis was used to establish cytotoxicity profiles and define submaximal, non-lethal exposure conditions. Under these conditions, total oxidant status (TOS), total antioxidant status (TAS), lipid peroxidation (MDA), catalase (CAT) activity, and glutathione (GSH) levels were assessed, together with interleukin-6 (IL-6) and interleukin-1β (IL-1β) secretion and transcriptional expression of JAK1, JAK2, JAK3, and STAT3.

Luteolin exposure was associated with a consistent reduction in oxidative burden (decreased TOS and MDA) and enhancement of antioxidant capacity (increased TAS, CAT, and GSH) across cell lines, indicating a shift toward a more reduced intracellular state. These changes were accompanied by selective modulation of inflammatory signaling, characterized by a reduction in IL-6 secretion in a cell line-dependent manner, while IL-1β levels remained largely unchanged. Transcriptional downregulation of JAK/STAT pathway components was observed following luteolin exposure, with additional modulation in combination with upadacitinib.

Importantly, these findings reflect transcriptional and biochemical alterations under basal, non-stimulated conditions and do not constitute direct evidence of functional pathway inhibition. Furthermore, the concentrations required to induce these effects exceed typical physiological levels, indicating that the observed responses should be interpreted within a mechanistic in vitro framework.

Collectively, the results demonstrate that luteolin induces a redox shift associated with selective modulation of IL-6-related signaling without broad cytokine suppression. These findings support the use of luteolin as a context-dependent redox modulator and a tool compound for investigating redox-inflammatory pathway interactions in vitro.