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

Airn expression was markedly reduced in the hearts of diabetic mice.

• Airn downregulation was observed in a diabetic cardiomyopathy mouse model.
• The reduction in Airn expression was associated with metabolic dysregulation in the diabetic heart.
• This finding motivated investigation of Airn's functional role in cardiac fatty acid metabolism during DbCM.

Cardiomyocyte-specific Airn overexpression improved cardiac structure and function, enhanced fatty acid oxidation, and reduced myocardial lipid accumulation in diabetic mice.

• Overexpression of Airn was achieved in a cardiomyocyte-specific manner.
• Improvements were observed in both cardiac structural remodeling and functional parameters.
• Enhanced fatty acid oxidation (FAO) was accompanied by reduced lipid accumulation in the myocardium.
• These effects occurred in the context of diabetic cardiomyopathy.

Airn knockdown induced cardiac remodeling and dysfunction even under non-diabetic conditions.

• Loss-of-function of Airn was sufficient to cause cardiac pathology in the absence of diabetes.
• This finding suggests Airn plays a necessary role in maintaining normal cardiac metabolic homeostasis.
• Cardiac remodeling phenotypes were observed in non-diabetic mice with Airn knockdown.

Airn directly interacted with the RNA-binding protein quaking (QKI) and increased QKI protein stability.

• A direct physical interaction between Airn lncRNA and QKI protein was demonstrated.
• Airn binding to QKI promoted QKI protein stability rather than altering its transcription.
• The deubiquitinating enzyme PSMD14 was identified as being involved in this stabilization process.
• Loss of Airn led to decreased QKI protein abundance.

QKI bound to QKI response elements (QREs) within the 3'UTR of Ppara mRNA and promoted its stability.

• QKI was shown to bind specific QKI response elements (QREs) located in the 3' untranslated region of Ppara mRNA.
• QKI binding to Ppara mRNA increased its stability, thereby promoting PPARα protein expression.
• Airn preserved this regulatory pathway by maintaining QKI protein abundance.
• This mechanism links Airn to transcriptional regulation of fatty acid oxidation via PPARα.

PSMD14, a deubiquitinating enzyme, was involved in the Airn-mediated stabilization of QKI protein.

• PSMD14 was identified as a deubiquitinating enzyme participating in the regulation of QKI protein stability.
• The data support that Airn modulates QKI protein levels through a mechanism involving PSMD14-mediated deubiquitination.
• This provides a molecular mechanism by which a lncRNA can post-translationally regulate an RNA-binding protein.

Pharmacological activation of PPARα rescued the lipotoxic cardiac phenotype induced by Airn deficiency.

• PPARα activation was used as a functional rescue experiment in Airn-deficient cardiomyocytes or mice.
• Restoration of PPARα activity was sufficient to ameliorate the lipotoxic remodeling caused by Airn loss.
• This finding places PPARα as the downstream effector of the Airn-QKI axis responsible for the metabolic phenotype.
• The rescue confirms that the Airn-QKI-PPARα pathway operates in a linear, epistatic manner.

The Airn-QKI-PPARα signaling axis was identified as a regulatory pathway that preserves cardiac fatty acid oxidation and limits lipotoxic remodeling in diabetic cardiomyopathy.

• The complete axis proceeds from Airn lncRNA → QKI protein stabilization → PPARα mRNA stabilization → enhanced FAO.
• Disruption at any point in this axis (Airn loss, QKI reduction, or PPARα downregulation) contributes to lipotoxic cardiac remodeling.
• The authors highlight Airn as a potential therapeutic target in DbCM based on these mechanistic findings.