LncRNA Airn preserves cardiomyocyte fatty acid oxidation to ameliorate diabetic cardiomyopathy by modulating the QKI-PPARα axis.

Diabetic cardiomyopathy (DbCM) is a major complication of diabetes characterized by metabolic dysregulation in the heart. This study investigated the role of the long non-coding RNA Airn in the regulation of cardiac fatty acid metabolism during DbCM. Airn expression was markedly reduced in the hearts of diabetic mice. Cardiomyocyte-specific Airn overexpression improved cardiac structure and function, enhanced fatty acid oxidation (FAO), and reduced myocardial lipid accumulation, whereas Airn knockdown induced cardiac remodeling and dysfunction even under non-diabetic conditions. Mechanistically, Airn directly interacted with the RNA-binding protein quaking (QKI) and increased QKI protein stability. The present data further support the involvement of PSMD14, a deubiquitinating enzyme, in this process. In turn, QKI bound to QKI response elements (QREs) within the 3'UTR of Pparα mRNA and promoted its stability, while Airn preserved this regulatory pathway by maintaining QKI abundance. Functionally, activation of PPARα rescued the lipotoxic phenotype induced by Airn deficiency. Together, these findings identify an Airn-QKI-PPARα signaling axis that preserves cardiac FAO and limits lipotoxic remodeling, and highlight Airn as a potential therapeutic target in DbCM.