# Aldehyde Dehydrogenase‐2 Alleviates Septic Myocardial Injury by Inhibiting Caspase‐11‐Mediated Noncanonical Pyroptosis

## TL;DR

This study shows that ALDH2 reduces heart damage during sepsis by blocking a specific type of cell death called noncanonical pyroptosis.

## Contribution

The study reveals a novel protective mechanism of ALDH2 in septic myocardial injury through its interaction with noncanonical pyroptosis pathways.

## Key findings

- Alda-1 improved cardiac function and reduced histological damage in septic mice.
- ALDH2 overexpression decreased cell death markers in LPS-treated H9C2 cells.
- ALDH2 interacts directly with GSDMD, HMGB1, and RAGE to inhibit pyroptosis.

## Abstract

The purpose of this study is to investigate the role of aldehyde dehydrogenase‐2 (ALDH2) in septic myocardial injury, focusing on noncanonical pyroptosis.

In vivo, C57BL/6J mice were divided into five groups: Sham, cecal ligation and puncture (CLP), CLP + Alda‐1 (ALDH2 agonist), Sham + dimethyl sulfoxide (DMSO, solvent control), and CLP + DMSO. Cardiac function and histological/ultrastructural changes were assessed via echocardiography, hematoxylin–eosin (HE) staining, and transmission electron microscopy (TEM). Tumor necrosis factor‐α (TNF‐α) and noncanonical pyroptosis‐related proteins (caspase‐11, gasdermin‐D [GSDMD], high mobility group box 1 [HMGB1], and receptor for advanced glycation end products [RAGE]) were measured by enzyme‐linked immunosorbent assay (ELISA) and western blotting. Coimmunoprecipitation (CO‐IP) explored molecular mechanisms. In vitro, H9C2 cells were divided into six groups: Control, lipopolysaccharide (LPS)‐treated, ALDH2‐green fluorescent protein (GFP), LPS + ALDH2‐GFP, GFP, and GFP + LPS. Cell viability, lactate dehydrogenase (LDH) release, creatine kinase isoenzymes (CK‐MB), and target protein levels were detected via spectrophotometry, western blotting, and immunofluorescence (IF).

In vivo, Alda‐1 significantly attenuated CLP‐induced cardiac dysfunction and reduced myocardial histological damage and ultrastructural impairment. In vitro, ALDH2 overexpression lowered LPS‐induced H9C2 cell viability, CK‐MB, and LDH release. Upregulating ALDH2 significantly reduced caspase‐11, HMGB1, and RAGE expression. CO‐IP showed ALDH2 interacted with HMGB1, RAGE, and GSDMD.

ALDH2 protects the myocardium from septic injury by inhibiting caspase‐11‐mediated noncanonical pyroptosis, possibly via direct interactions with GSDMD, HMGB1, and RAGE.