EPIGENETIC ALTERATIONS OF AKT1 ORCHESTRATE A METABOLIC REPROGRAMMING IN ADVANCED LIPEDEMA: TRANSLATIONAL INSIGHTS FROM AN INTEGRATED MULTI-OMICS STUDY

BACKGROUND: LIPEDEMA IS A CHRONIC, PROGRESSIVE ADIPOSE DISORDER PREDOMINANTLY AFFECTING WOMEN, CHARACTERIZED BY PAINFUL, SYMMETRICAL SUBCUTANEOUS FAT ACCUMULATION, AND TYPICALLY RESISTANT TO LIFESTYLE INTERVENTIONS. THE PATHOPHYSIOLOGY OF ADVANCED-STAGE LIPEDEMA REMAINS POORLY DEFINED, AND NO VALIDATED BIOMARKERS OR TARGETED THERAPIES ARE CURRENTLY AVAILABLE. METHODS: IN THIS OBSERVATIONAL STUDY, WE APPLIED A COMPREHENSIVE MULTI-OMICS APPROACH TO DISSECT THE MOLECULAR AND METABOLIC ALTERATIONS UNDERLYING LATE-STAGE LIPEDEMA. RESULTS: GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIED OVER 5,000 DIFFERENTIALLY METHYLATED CPG SITES AFFECTING GENES INVOLVED IN RECEPTOR TYROSINE KINASE SIGNALING, PHOSPHO-METABOLISM, AND IMMUNE PATHWAYS. TRANSCRIPTOMIC ANALYSIS REVEALED PROFOUND DOWNREGULATION OF MITOCHONDRIAL FUNCTIONS, INCLUDING OXIDATIVE PHOSPHORYLATION, THE TCA CYCLE, AND FATTY ACID Β-OXIDATION, ALONGSIDE DISRUPTION OF THE SIRTUIN PATHWAY AND EXTRACELLULAR MATRIX REMODELING. INTEGRATIVE ANALYSIS PINPOINTED AKT1 AS A CENTRAL REGULATORY NODE: ITS PROMOTER REGION WAS HYPOMETHYLATED, CORRELATING WITH INCREASED GENE EXPRESSION AND PROTEIN PHOSPHORYLATION. METABOLOMIC PROFILING CONFIRMED AKT1-LINKED METABOLIC DYSREGULATION, INCLUDING ALTERED LEVELS OF L-ARGININE, NADP+, ATP, GUANOSINE, GLYCEROL, AND GLUTAMATE, INDICATING IMPAIRED REDOX BALANCE AND ENERGY METABOLISM. TRANS-OMIC NETWORK ANALYSIS POSITIONED AKT1 AT THE INTERSECTION OF MULTIPLE DYSREGULATED PATHWAYS, SUGGESTING ITS KEY ROLE IN ADVANCED-STAGE LIPEDEMA. CONCLUSIONS: THE CONSISTENT ENHANCING OF AKT PATHWAY SIGNALING ACROSS OMIC LAYERS HIGHLIGHTS ITS POTENTIAL NOT ONLY AS A BIOMARKER FOR DISEASE STRATIFICATION BUT ALSO AS A PUTATIVE DRUGGABLE TARGET FOR THERAPEUTIC INTERVENTION. THESE FINDINGS OFFER NEW MECHANISTIC INSIGHTS INTO LIPEDEMA PATHOPHYSIOLOGY AND PROVIDE A RATIONALE FOR FUTURE PERSONALIZED TREATMENT STRATEGIES GUIDED BY AKT1-CENTRIC MOLECULAR PROFILING.