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Malic Enzyme 1 as a Novel Anti-Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury
Xuexian Fang1, Jiawei Zhang1, You Li1
1Department of Nutrition and Toxicology, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines of Zhejiang Province, School of Public Health, Hangzhou Normal University, Hangzhou, 311121, China.
Abstract:
Ferroptosis has been linked to the pathogenesis of hepatic injury induced by ischemia/reperfusion (I/R). However, the mechanistic basis remains unclear. In this study, by using a mouse model of hepatic I/R injury, it is observed that glutathione (GSH) and cysteine depletion are associated with deficiency of the reducing power of nicotinamide adenine dinucleotide phosphate (NADPH). Genes involved in maintaining NADPH homeostasis are screened, and it is identified that I/R-induced hepatic ferroptosis is significantly associated with reduced expression and activity of NADP+ -dependent malic enzyme 1 (Me1). Mice with hepatocyte-specific Me1 gene deletion exhibit aggravated ferroptosis and liver injury under I/R treatment; while supplementation with L-malate, the substrate of ME1, restores NADPH and GSH levels and eventually inhibits I/R-induced hepatic ferroptosis and injury. A mechanistic study further reveals that downregulation of hepatic Me1 expression is largely mediated by the phosphatase and tensin homologue (PTEN)-dependent suppression of the mechanistic target of rapamycin/sterol regulatory element-binding protein 1 (mTOR/SREBP1) signaling pathway in hepatic I/R model. Finally, PTEN inhibitor, mTOR activator, or SREBP1 over-expression all increase hepatic NADPH, block ferroptosis, and protect liver against I/R injury. Taken together, the findings suggest that targeting ME1 may provide new therapeutic opportunities for I/R injury and other ferroptosis-related hepatic conditions.
Insights
Ferroptosis, a cell death type, worsens liver injury after blood flow is restored. Targeting malic enzyme 1 (ME1) can restore protective molecules and prevent ferroptosis in hepatic ischemia/reperfusion injury.
Area of Science:
- Biochemistry
- Cell Biology
- Pathology
Background:
- Ferroptosis is implicated in hepatic ischemia/reperfusion (I/R) injury pathogenesis.
- The precise mechanisms underlying I/R-induced ferroptosis remain incompletely understood.
- Hepatic I/R injury involves complex cellular and molecular events impacting liver function.
Purpose of the Study:
- To elucidate the mechanistic basis of ferroptosis in hepatic I/R injury.
- To identify key molecular players involved in maintaining NADPH homeostasis during I/R.
- To explore potential therapeutic targets for mitigating I/R-induced liver damage.
Main Methods:
- Utilized a mouse model of hepatic I/R injury.
- Screened genes involved in nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis.
- Investigated the role of NADP+-dependent malic enzyme 1 (Me1) and its regulatory pathways.
- Employed genetic deletion, L-malate supplementation, and pharmacological interventions.
Main Results:
- Reduced expression and activity of Me1 were significantly associated with I/R-induced hepatic ferroptosis.
- Hepatocyte-specific Me1 deletion aggravated ferroptosis and liver injury.
- L-malate supplementation restored NADPH and glutathione (GSH) levels, inhibiting ferroptosis.
- Me1 downregulation was mediated by PTEN-dependent suppression of the mTOR/SREBP1 pathway.
- PTEN inhibition, mTOR activation, or SREBP1 overexpression protected the liver against I/R injury.
Conclusions:
- Reduced Me1 expression and activity contribute to ferroptosis in hepatic I/R injury by impairing NADPH homeostasis.
- Targeting ME1, potentially through L-malate supplementation or modulation of the PTEN/mTOR/SREBP1 pathway, offers a promising therapeutic strategy.
- These findings provide new insights into the mechanisms of ferroptosis in liver injury and suggest novel therapeutic avenues.
