<p>Community-acquired pneumonia (CAP), particularly severe CAP (SCAP), poses a significant clinical challenge with high mortality. MicroRNAs, including miR-342-3p, have been implicated in various pulmonary diseases, suggesting a potential role in SCAP. To examine the expression, functional mechanisms, and clinical relevance of miR-342-3p in SCAP. Bioinformatic analysis was performed on two independent GEO datasets (GSE196399 and GSE136390). Serum miR-342-3p levels were measured in a clinical cohort of 109 SCAP patients and 109 healthy controls by RT-qPCR, and its correlation with clinical prognosis was analyzed. An in vitro pneumonia model was established using LPS-stimulated MRC-5 cells. Gain-of-function experiments of miR-342-3p were achieved through mimic transfection. MiR-342-3p’s involvement in inflammation, cytotoxicity, and pyroptosis was assessed via ELISA, western blot, CCK-8, and LDH assays. The interaction between miR-342-3p and EP300 was confirmed by dual-luciferase reporter and RNA pull-down assays, and its functional role was confirmed through rescue experiments. The downregulation of miR-342-3p in SCAP patient serum correlated with increased mortality. In vitro, miR-342-3p overexpression reduced LPS-induced inflammation and pyroptosis. Bioinformatics analysis confirmed that histone acetyltransferase EP300 is a candidate target gene for miR-342-3p. Mechanistically, miR-342-3p directly targeted and negatively regulated EP300. Overexpression of EP300 abolished the anti-inflammatory and anti-pyroptotic effects of miR-342-3p through the activation of NF-κB p65. MiR-342-3p acts as a protective factor in SCAP by targeting EP300 to inhibit inflammation and pyroptosis. These results indicate the potential of miR-342-3p as a biomarker and therapeutic target in SCAP.</p>