Exploring the Mechanism of Ferroptosis Induction by Sappanone A in Cancer: Insights into the Mitochondrial Dysfunction Mediated by NRF2/xCT/GPX4 Axis

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(13), P. 5145 - 5161

Published: Jan. 1, 2024

Non-small cell lung cancer (NSCLC), a major subtype of cancer, encompasses squamous carcinoma, adenocarcinoma, and large carcinoma. Compared to small NSCLC cells grow divide more slowly, their metastasis occurs at later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) flavonoid compound extracted from plant Caesalpinia sappan, known its antitumor, redox-regulating, anti-inflammatory properties. Recent studies have investigated interaction SA with mitochondrial pathways in regulating death through Nrf-2/GPX-4/xCT axis. This study specifically explores mechanism by which affects morphology structure regulation mitophagy biogenesis tumor cells. The primarily utilizes second-generation transcriptomic sequencing data molecular docking techniques elucidate role programmed omics results indicate that significantly targets genes involved oxidative phosphorylation, mitophagy, dynamics, stress. Further findings confirmed Nrf-2/GPX4/xCT pathway serves as crucial target NSCLC. Knockdown Nrf-2 (si-Nrf-2) overexpression (ad-Nrf-2) were shown modulate therapeutic efficacy varying degrees. Additionally, modifications GPX4/xCT affected regulatory effects on autophagy, biogenesis, energy metabolism. These mechanisms may be mediated caspase ferroptosis-related signaling. Molecular biology experiments demonstrated intervention further inhibits phosphorylation FUNDC1 Tyr18 downregulates TOM20 expression. was found reduce expression PGC1α, Nrf-1, Tfam, resulting decrease respiration Overexpression counteract biogenesis. Confocal microscopy revealed increases fragmentation, subsequently inducing pathway-mediated death. However, genetic modification altered In conclusion, has been identified promising agent apoptosis ferroptosis represent key Targeting axis offers novel approach maintaining homeostasis within cellular microenvironment.

Language: Английский

Connecting the dots: Mitochondrial transfer in immunity, inflammation, and cancer

Immunology Letters, Journal Year: 2025, Volume and Issue: 274, P. 106992 - 106992

Published: March 6, 2025

Language: Английский