The abstract is read at the publisher; the summary is JClub's.
In hepatocytes, DOT1L acts as a key sensitizer to ferroptosis and subsequent liver injury, and DOT1L inhibition reverses this effect.
- Why it matters: Epigenetic control of lipid metabolism may determine how ferroptosis drives metabolic associated steatohepatitis (MASH) and liver injury, but the responsible epigenetic regulators were unclear.
- What they did: Using pharmacological screening of epigenetics-related compounds and CRISPR-Cas9 screening of epigenetic factors, the study pinpointed DOT1L; DOT1L loss remodeled phospholipids and reduced H3K79me1/H3K79me2 at PLA2G7, ALDH3B1, and PLCXD3 loci.
- The result: DOT1L depletion lowered PUFA-containing phospholipids and increased monounsaturated and lysophospholipid species, suppressing ferroptosis by reducing PL-PUFAs; AMPK phosphorylates DOT1L at Ser786 to weaken AF9 binding and inhibit H3K79 methyltransferase activity.
The findingWhy it mattersWhat they didThe result
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