What question did this study set out to answer?

This study aims to elucidate how HDAC7 influences PKM2-related endothelial dysfunction during inflammatory lung injury.

May 14, 2026

Epigenetic control of metabolic signaling: HDAC7–PKM2 axis in lung vascular permeability

Key Points

This study aims to elucidate how HDAC7 influences PKM2-related endothelial dysfunction during inflammatory lung injury.
Human lung microvascular endothelial cells were treated with LPS to examine barrier function and metabolic activity.
Endothelial-specific Hdac7 knockout mice were subjected to LPS-induced injury to evaluate lung vascular permeability and PKM2 activity.
HDAC7 and PKM2 interactions were assessed through phosphorylation and metabolic assays.
LPS exposure led to increased HDAC7 export and PKM2 phosphorylation, resulting in endothelial barrier failure as detected by ECIS.
Depletion of HDAC7 restored glycolytic activity and mitigated hyperpermeability due to LPS.
Deleting Hdac7 in vivo significantly reduced lung edema and improved oxygenation after LPS challenge.

Abstract

Acute lung injury is characterized by rapid loss of endothelial barrier integrity, yet the molecular switches that convert inflammatory signaling into vascular leak remain incompletely defined. The objective of this study was to determine how HDAC7 regulates PKM2-dependent endothelial dysfunction during inflammatory lung injury. We hypothesized that lipopolysaccharide (LPS)–induced HDAC7 nuclear export reprograms PKM2 from a glycolytic enzyme into a pro-inflammatory effector, thereby promoting vascular permeability. Human lung microvascular endothelial cells (HLMVECs) were exposed to LPS and assessed for barrier function (ECIS), HDAC7/PKM2 interactions, PKM2 phosphorylation, and metabolic activity (ECAR). Lung vascular permeability and PKM2 activity were evaluated in endothelial-specific Hdac7 knockout mice subjected to LPS-induced injury. LPS increased HDAC7 expression and phosphorylation, driving its export to the cytoplasm, where HDAC7 formed inducible complexes with PKM2. This corresponded with elevated PKM2 phosphorylation, reduced glycolytic flux, and significant ECIS-detected barrier failure. HDAC7 depletion restored glycolytic activity, diminished PKM2 phosphorylation, and reduced LPS-induced hyperpermeability. Stabilization of PKM2’s tetrameric (metabolic) form using TEPP-46 similarly preserved endothelial resistance. In vivo, endothelial-specific Hdac7 deletion significantly reduced lung edema and improved oxygenation following LPS challenge. Our studies also show altered nuclear PKM2 signaling, including reduced engagement of STAT3-linked inflammatory pathways. These findings identify HDAC7 as an upstream regulator that shifts PKM2 away from metabolism and toward pro-inflammatory signaling, directly promoting lung vascular permeability. This HDAC7–PKM2 axis represents a previously unrecognized mechanism of endothelial dysfunction and a potential therapeutic target for acute lung injury. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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