Vitamin D Mitigates Klebsiella pneumoniae ‐Induced Pneumonia by Regulating Macrophage Polarization Through miR‐223/ACSL3 Axis‐Mediated Lipid Metabolism Reprogramming

ABSTRACT Background Pneumonia caused by Klebsiella pneumonia ( Kp ) poses a significant risk to global public health. Vitamin D may reduce Kp infection risk and improve prognosis through immunomodulation. This study aimed to validate the treatment effects of Vitamin D and explore its regulatory mechanism in Kp ‐pneumonia. Methods In this study, a murine model of Kp ‐induced pneumonia and the MH‐S alveolar macrophage cell line were used. Experimental assays included RT‐qPCR, Western blot, TUNEL assay, ELISA, flow cytometry, dual‐luciferase reporter assay, and metabolic analyses (FAO activity, Seahorse XF Glycolysis Stress Test). Results The results showed that vitamin D administration mitigated Kp ‐induced lung injury in mice. Mechanically, vitamin D alleviated inflammation by inhibiting macrophage M1 polarization. Vitamin D exerted its effects by upregulating miR‐223, which directly targeted and suppressed ACSL3 expression. In macrophages, miR‐223 overexpression alleviated macrophage apoptosis and M1 polarization by downregulating ACSL3. Knockdown of ACSL3 induced a shift to M2 polarization by enhancing FAO and suppressing glycolysis. In vivo, miR‐223 overexpression alleviated Kp ‐induced lung injury by downregulating ACSL3. Conclusion In conclusion, vitamin D induces macrophage M2 polarization by upregulating miR‐223, which inhibits ACSL3, leading to lipid metabolism reprogramming. This novel axis represents a potential therapeutic strategy for Kp ‐induced pneumonia.