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The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis
Abstract
Ferroptosis is a unique form of cell death caused by excessive iron-dependent lipid peroxidation. The level of the anabolic reductant NADPH is a biomarker of ferroptosis sensitivity. However, specific regulators that detect cellular NADPH levels, thereby modulating downstream ferroptosis cascades, are largely unknown. We show here that the transmembrane endoplasmic reticulum MARCHF6 E3 ubiquitin ligase recognizes NADPH through its C-terminal regulatory region. This interaction upregulates the E3 ligase activity of MARCHF6, thus downregulating ferroptosis. We also found that MARCHF6 mediates the degradation of the key ferroptosis effectors ACSL4 and p53. Furthermore, inhibiting ferroptosis rescued the growth of MARCHF6-deficient tumours and peri-natal lethality of Marchf6 -/- mice. Together, these findings identify MARCHF6 as a previously unknown NADPH sensor in the ubiquitin system and a crucial regulator of ferroptosis.
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By sensing NADPH, MARCHF6 protects cells from ferroptosis by degrading pro-ferroptotic ASCL4 and P53, as well as SQLE.
“In this context, it is intriguing that Nguyen et al. [29] demonstrated that by sensing NADPH, MARCHF6 protects cells from ferroptosis by degrading pro-ferroptotic ASCL4 and P53, as well as the established target SQLE.”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [29]
MARCHF6 is a direct sensor of cellular NADPH availability, owing to the presence of the C-terminal NADPH-binding MARA domain.
“MARCHF6 was recently implicated as a direct sensor of cellular NADPH availability, owing to the presence of the C-terminal NADPH-binding MARA domain of MARCHF6 [29].”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [29]
High NADPH levels promote MARCHF6 ubiquitylation and ERAD of its targets (e.g., SQLE, PLIN2, and MARCHF6 itself), and low NADPH limits MARCHF6 activity and promotes their stability.
“This study suggested that high NADPH levels promote MARCHF6 ubiquitylation and ERAD of its targets e.g. SQLE, PLIN2, and MARCHF6 itself, and that reciprocally, low NADPH limits MARCHF6 activity and promotes their stability.”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [29]
MARCHF6 is a sensor for cellular NADPH levels owing to residues 870-900 in its C-terminal MARA domain.
“Therefore, it is intriguing that a recent study implicated MARCHF6 as a sensor for cellular NADPH levels owing to residues 870–900 in its C-terminal MARCHF6-regulatory region (MARA) domain [29].”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [29]
Loss of MARCHF6 is associated with a decrease in anti-ferroptotic SLC7A11, GPX4, and NRF2, likely a secondary effect.
“This was also associated with a decrease in the anti-ferroptotic SLC7A11, GPX4, and NRF2, which is likely a secondary effect, as it cannot be directly explained by the loss of E3 ligase activity.”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [29]
Global ablation of Marchf6 in mice results in a marked shift from the expected Mendelian birth distribution.
“In line with it having an important physiological role, global ablation of Marchf6 in mice results in a marked shift from the expected Mendelian birth distribution (this study and [29]).”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [29]
Loss of MARCHF6 increases levels of ASCL4, P53, and SQLE and enhances ferroptosis in an NADPH-dependent manner in vitro.
“Conversely, loss of MARCHF6, increased their level and enhanced ferroptosis in an NADPH-dependent manner in vitro.”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [29]
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Sachdev, V., van Loon, N. M., Kingma, J., Ottenhoff, R., Tan, J. M. E., van den Berg, M., Duijst, S., Jongejan, A., Levels, J. H. M., Rensen, P. C. N., et al. (2026) · Molecular Metabolism · doi:10.1016/j.molmet.2026.102379 · Cited by 1
Metadata
- Authors
- Nguyen, K. T., Mun, S.-H., Yang, J., Lee, J., Seok, O.-H., Kim, E., Kim, D., An, S. Y., Seo, D.-Y., Suh, J.-Y., Lee, Y., & Hwang, C.-S.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2022-08
- Volume
- 24
- Issue
- 8
- Pages
- 1239-1251
- ISSN
- 1465-7392
- 1476-4679
- Cited by
- 92
- References
- 8
- Language
- en
- Funders
- The Korean Government
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