Gallic acid: A promising anti-non-small cell lung cancer compound targeting early growth response protein-1 for apoptosis and ferroptosis.

BACKGROUND

Regulated cell death (RCD) is a therapeutic strategy for cancer treatment through the clearance of aberrant cells. Given the diversity of malignant tumors, relying on a single mode of RCD may prove difficult in reversing established tumor-supporting ecosystems. Gallic acid (GA), a natural polyphenol, exhibits anti-tumor properties but lacks detailed mechanistic insights in non-small cell lung cancer (NSCLC).

PURPOSE: We demonstrated the dual regulatory mechanism of GA in triggering apoptosis and ferroptosis through early growth response protein-1 (EGR1), and we evaluated its therapeutic potential against NSCLC.

METHODS

Human NSCLC cells (A549, H1299) and BALB/c nude mice models were used. Functional assays were employed for genetic and pharmacological studies. RNA sequencing, systems biology, and network pharmacology-based screening were used to identify the pivotal target. RCD markers were analyzed via terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, flow cytometry, transmission electron microscope, and biochemical assay kits. Safety was validated in BEAS-2B cells and through vivo assessments.

RESULTS

GA suppressed NSCLC cell proliferation, induced cell cycle arrest, and inhibited cell migration and invasion. GA simultaneously facilitated apoptosis and ferroptosis through EGR1 in NSCLC cells. GA treatment induced apoptosis through downregulating thrombospondin-1 via EGR1, inhibiting transforming growth factor beta 1/Smad2/3 signaling pathway. Concurrently, GA modulated the EGR1/ALOX5 axis, leading to ferroptosis-related changes characterized by reduced GPX4 expression, increased reactive oxygen species and malondialdehyde accumulation, altered mitochondria, and iron overload. Liproxstatin-1 or EGR1 knockdown reversed GA-induced cell death.

CONCLUSION

This multimodal mechanism positions GA as a promising therapeutic candidate for NSCLC.