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

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Purpose The purpose of this study is to investigate the role of aldehyde dehydrogenase‐2 (ALDH2) in septic myocardial injury, focusing on noncanonical pyroptosis. Methods 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). Results 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. Conclusion ALDH2 protects the myocardium from septic injury by inhibiting caspase‐11‐mediated noncanonical pyroptosis, possibly via direct interactions with GSDMD, HMGB1, and RAGE.

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