Divergent Immunometabolic Regulatory Networks Mediated by FOXO3 During Musculoskeletal Aging: Implications for...

Musculoskeletal aging exhibits prominent tissue heterogeneity. Forkhead box O3 (FOXO3) acts as a master transcription factor orchestrating aging, metabolism and immune homeostasis. Existing mechanistic investigations are largely restricted to single tissues, and a head-to-head comparison of FOXO3-governed immunometabolic regulatory networks between knee osteoarthritis (KOA) synovium and aged skeletal muscle remains absent. A retrospective multi-cohort transcriptomic analysis was performed using datasets retrieved from the Gene Expression Omnibus (GEO) database. Two KOA synovial cohorts (GSE55235 and GSE55457, n = 40) and two aged skeletal muscle cohorts (GSE28422 and GSE25941, n = 146) were enrolled, covering a total of 186 tissue samples. We integrated differential expression analysis, random-effects meta-analysis, receiver operating characteristic (ROC) performance evaluation, single-sample gene set enrichment analysis (ssGSEA), and partial correlation analysis adjusted for disease confounding effects. A bootstrap-scoring system was further established to prioritize candidate therapeutic strategies. FOXO3 exhibited opposing expression patterns: it was downregulated in KOA synovium yet upregulated in aged skeletal muscle. The coupling profiles between FOXO3 and immune or metabolic pathways displayed striking tissue-specific divergence. In KOA synovium, FOXO3 expression was positively correlated with mitochondrial energy metabolism and macrophage infiltration, accompanied by selective inflammatory immune infiltration. By contrast, aged skeletal muscle resided in an immune-quiescent microenvironment, where elevated FOXO3 was strongly negatively coupled to oxidative metabolic pathways. Distinct intervention strategies were derived from these divergent network signatures: combined FOXO3 activation and metabolic modulation was recommended for KOA, whereas supplementation with nicotinamide adenine dinucleotide (NAD⁺) precursors constituted the primary intervention for aged skeletal muscle. Opposite FOXO3 expression levels correspond to fundamentally distinct immunometabolic network landscapes during musculoskeletal aging. The functional output of FOXO3 is dictated by the tissue microenvironment rather than its transcriptional abundance alone. This study supports stratified precision geriatric interventions via tissue-specific modulation of the FOXO3 pathway across divergent musculoskeletal aging contexts.Clinical trial number: Not applicable.