Abstract
Methotrexate a folic acid antagonist is a widely used drug for many conditions from leukemia to psoriasis and rheumatoid arthritis and other diseases. But, it has significant limitation due to its hepatotoxic effects. While MTX-induced liver damage is known to involve oxidative stress and inflammatory pathways, recent research has identified a more specific mechanism. The cellular stress induced by MTX activates the cGAS-STING signaling pathway, which subsequently triggers a distinct form of regulated cell death known as ferroptosis. Guggulsterone (GS), a natural plant extract, is a promising hepatoprotective candidate known for its potent antioxidant and anti-inflammatory properties. This study aims to investigate the protective effects of Guggulsterone against MTX-induced liver damage in a mice model by exploring its ability to inhibit the STING-ferroptosis axis. Thirty swiss albino mice were used divided into five groups and treated for 10 days, group I (normal control, received vehicle only p.o,), group II (MTX control, received vehicle p.o. and an MTX IP dose 20 mg/kg/day on day 8), group III (guggulsterone, received 25 mg/kg/day p.o.), group IV (received guggulsterone + MTX on day 8), and group V (received guggulsterone +MTX + DMXAA 20 mg/kd/day IP on day 8 and 9 with DMXAA administered 2 hours prior to MTX on day 8). Results show an increase in MDA, AST,ALT, iron, and organ index is observed in group II and V with a decrease in group IV. However the opposite occurs in GSH levels, where we observe a decrease in both group II and V with it being restored to high level in Group IV. As for gene expression, we notice an increase in gene fold in both group II and V in TNF-α, Ifnb1, and Hepcidin with a decrease for ferroportin in these two groups. In conclusion, this study provides evidence of GS hepatoprotective effect through the inhibition of STING-mediated ferroptosis. Our findings demonstrated the extent of MTX injury and its harmful mechanism and most importantly, the administration of GS helped in ameliorating the injury. By suppressing STING pathway, GS successfully suppressed the hallmarks of ferroptosis, lowered lipid peroxidation marker, lowered iron accumulation and replenished GSH stores
| Intend to be published in the IJPS ? | Yes |
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| Has the manuscript been published | not published |
