FOS-Mediated Mitophagy Suppression Links Stress Signaling to Heart Failure Progression

Heart failure (HF) constitutes the terminal phenotype of cardiovascular disease, defined by profound metabolic disarray and pervasive mitochondrial dysfunction.Contemporary "quadruple therapy" regimens mitigate disease progression primarily through suppression of neuroendocrine activation, yet the fundamental energetic insufficiency that sustains cardiac decline remains unaddressed.Mounting evidence implicates defective mitochondrial autophagy (mitophagy) as a central driver of cardiomyocyte injury.Nonetheless, the upstream transcriptional networks governing the collapse of mitophagy competence remain largely unresolved.To identify molecular determinants of mitophagy impairment in HF, we integrated three independent transcriptomic datasets (GSE95140, GSE133054, GSE141910) using Robust Rank Aggregation with batch correction.Differentially expressed genes (DEGs) were subjected to GO, KEGG, PPI, and GSEA analyses.Hub genes were validated in vivo using a pressure overloadinduced transverse aortic constriction (TAC) mouse model and in vitro in primary mouse cardiomyocytes exposed to angiotensin II (Ang II).Functional assays, including echocardiography, histology, qRT-PCR, western blotting, immunofluorescence, and transmission electron microscopy, were employed to assess cardiac remodeling, mitophagy flux, and mitochondrial integrity.Transcriptomic integration revealed 256 consistent DEGs across datasets, primarily enriched in oxidative phosphorylation and mitochondrial metabolic pathways.Protein-protein interaction analysis identified five hub genes FOS, VWF, TAGLN, B2M, and CCL2 with FOS ranking highest by multiple centrality metrics.Receiver operating characteristic analysis confirmed its superior diagnostic performance (AUC = 0.659).Gene set enrichment and correlation analyses demonstrated a robust negative association between FOS expression and multiple mitophagy-related gene sets, including PINK1/ Parkin-mediated and receptor-mediated pathways.In TAC mice, FOS was markedly upregulated and accompanied by hypertrophic remodeling, impaired cardiac contractility, elevated p62 accumulation, and reduced LC3-II/LC3-I ratios.In Ang II-treated cardiomyocytes, FOS silencing via siRNA restored mitophagy flux, reduced p62 expression, increased LC3-II conversion, and preserved mitochondrial morphology.FOS is identified as a stress-inducible transcriptional repressor of mitophagy that precipitates mitochondrial dysfunction and maladaptive cardiac remodeling under pressure overload.Mechanistically, hyperactivation of FOS disrupts mitochondrial quality control, triggering oxidative stress, energetic collapse, and subsequent cardiomyocyte loss.Pharmacological or genetic inhibition of FOS reinstates mitophagy and restores mitochondrial homeostasis, thereby attenuating both structural and functional deterioration of the heart.These results delineate a FOS-mitophagy regulatory axis as a mechanistic nexus linking stress signaling to metabolic failure in heart failure, and position FOS as a potential therapeutic target for mechanism-driven, disease-modifying interventions in cardiac hypertrophy and heart failure.