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Ferritinophagy-mediated ferroptosis facilitates methotrexate-induced hepatotoxicity by high-mobility group box 1
Chengbo Wang1, Maodong Leng1, Cong Ding1
1Institute of Pediatric Medicine, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou, Henan, China.
Background And Aim:
Hepatotoxicity is a well-defined reaction to methotrexate (MTX), a drug commonly used for the treatment of rheumatoid arthritis and various tumours. We sought to elucidate the mechanism underlying MTX-induced hepatotoxicity and establish a potentially effective intervention strategy.
Methods:
We administered MTX to liver cells and mice and assessed hepatotoxicity by cell viability assay and hepatic pathological changes. We determined ferroptosis and ferritinophagy by detecting ferroptosis-related markers and autophagic degradation of ferritin heavy chain 1 (FTH1).
Results:
We have shown that hepatocytes treated with MTX undergo ferroptosis, and this process can be attenuated by ferroptosis inhibitors. Interestingly, NCOA4-mediated ferritinophagy was found to be involved in MTX-induced ferroptosis, which was demonstrated by the relief of ferroptosis through the inhibition of autophagy or knockdown of Ncoa4. Furthermore, MTX treatment resulted in the elevation of high-mobility group box 1 (HMGB1) expression. The depletion of Hmgb1 in hepatocytes considerably alleviated MTX-induced hepatotoxicity by limiting autophagy and the subsequent autophagy-dependent ferroptosis. It is noteworthy that glycyrrhizic acid (GA), a precise inhibitor of HMGB1, effectively suppressed autophagy, ferroptosis and hepatotoxicity caused by MTX.
Conclusion:
Our study shows the significant roles of autophagy-dependent ferroptosis and HMGB1 in MTX-induced hepatotoxicity. It emphasizes that the inhibition of ferritinophagy and HMGB1 may have potential as a therapeutic approach for preventing and treating MTX-induced liver injury.
Insights
Methotrexate (MTX) causes liver injury through ferroptosis, a process involving ferritinophagy and HMGB1. Inhibiting these pathways, particularly with glycyrrhizic acid, may treat MTX-induced hepatotoxicity.
Area of Science:
- Hepatology
- Toxicology
- Molecular Biology
Background:
- Hepatotoxicity is a known side effect of methotrexate (MTX), a common drug for rheumatoid arthritis and cancer.
- The exact mechanisms of MTX-induced liver injury require further elucidation.
- Identifying effective interventions for MTX hepatotoxicity is crucial.
Purpose of the Study:
- To investigate the molecular mechanisms of methotrexate-induced hepatotoxicity.
- To explore the roles of ferroptosis, ferritinophagy, and HMGB1 in MTX liver injury.
- To evaluate potential therapeutic strategies targeting these pathways.
Main Methods:
- Administered MTX to liver cells and mice.
- Assessed hepatotoxicity using cell viability assays and pathological examination.
- Determined ferroptosis and ferritinophagy markers, including FTH1 degradation.
- Investigated the role of NCOA4 and HMGB1, and tested glycyrrhizic acid (GA) as an intervention.
Main Results:
- MTX-treated hepatocytes underwent ferroptosis, which was reduced by ferroptosis inhibitors.
- NCOA4-mediated ferritinophagy contributed to MTX-induced ferroptosis.
- MTX elevated HMGB1 expression, and its depletion alleviated hepatotoxicity.
- Glycyrrhizic acid (GA) effectively inhibited MTX-induced autophagy, ferroptosis, and hepatotoxicity.
Conclusions:
- Autophagy-dependent ferroptosis and HMGB1 play significant roles in MTX-induced hepatotoxicity.
- Inhibiting ferritinophagy and HMGB1 shows potential for treating MTX-induced liver injury.
- Targeting these pathways offers a promising therapeutic avenue for MTX hepatotoxicity.
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