Abstract Body: Background: Truncating variants in FLNC are an established genetic cause of dilated cardiomyopathy (DCM) characterized by arrhythmia and progressive heart failure. While FLNC deficiency is classically linked to cytoskeletal dysfunction, its impact on cardiomyocyte lipid homeostasis remains undefined.
Objective: We investigated whether FLNC insufficiency promotes STAT5A-dependent lipid remodeling in cardiomyocytes and examined its clinical relevance in patients with FLNC loss-of-function variants.
Methods: Human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) with homozygous (FLNC^KO−/−) or heterozygous (FLNC^KO+/−) deletion, as well as patient-derived FLNC truncating variant (FLNCtv) iPSC-CMs, were analyzed. Cardiomyocyte-specific FLNC haploinsufficient mice (Myh6-Cre;Flnc^WT/F) were studied in parallel. Lipid accumulation was quantified by Oil Red O and BODIPY staining. Transcriptomic profiling was performed by bulk RNA sequencing with protein validation by immunoblotting. Cardiac lipidomics was conducted in vivo. Human myocardial samples from five DCM patients harboring FLNC loss-of-function variants were examined for STAT5A activation.
Results: FLNC-insufficient iPSC-CMs induced marked lipid droplet accumulation compared with wild-type controls. RNA sequencing revealed enrichment of STAT5A-associated transcriptional programs, with increased phosphorylated STAT5A confirmed in FLNC^KO−/− and FLNCtv iPSC-CMs as well as in Myh6-Cre;Flnc^WT/F hearts. Lipidomic analysis showed elevated triglyceride and phospholipid species consistent with intracellular lipid droplet expansion. Importantly, myocardial tissue from FLNC loss-of-function DCM patients exhibited increased STAT5A activation. Pharmacologic inhibition of STAT5A attenuated lipid droplet accumulation in both FLNC-deficient iPSC-CMs and murine adult cardiomyocytes.
Conclusions: FLNC insufficiency induces a STAT5A-driven lipid remodeling program in cardiomyocytes that is conserved across cellular, murine, and human FLNC-related DCM. These findings identify a novel mechanistic link between genetic cytoskeletal deficiency and metabolic dysregulation and position STAT5A as a potential therapeutic target.