Divergent in vivo molecular responses to micro-fragmented adipose tissue and hyaluronic acid reveal disease-modifying activity of MFAT in inflammatory knee osteoarthritis

Knee osteoarthritis (KOA) affects an estimated 374 million people worldwide and has no approved disease-modifying treatment. Intra-articular micro-fragmented adipose tissue (MFAT) outperformed hyaluronic acid (HA) on patient-reported outcomes in our recent double-blind randomized trial ( ISRCTN88966184 ). Yet, the molecular basis of this differential efficacy is unknown, and the two interventions have not previously been compared at the level of their in vivo molecular response in human KOA. Here, we provide the first in vivo molecular characterisation of this difference in humans. Using an interpretable AI data-fusion framework based on non-negative matrix tri-factorization, we integrated longitudinal plasma proteomics, N-glycomics, miRNA transcriptomics and patient genetics with prior molecular networks at baseline, one and six months, deriving biologically coherent gene and miRNA pathways significantly enriched in Gene Ontology Biological Process and Reactome Pathway annotations. By six months, the two treatments left clearly distinct molecular signatures: HA remained dominated by canonical OA pathogenic processes, including cartilage-degrading effectors such as MMP13 and LIMK2 and markers of synovial inflammation, whereas MFAT shifted the systemic landscape toward chondroprotection, anti-inflammatory signalling and bone–cartilage homeostasis, with prioritized effectors including SIRT7 and NDUFC1 . These are, to our knowledge, the first molecular data in humans to explain why a regenerative therapy outperforms viscosupplementation in KOA, providing in vivo evidence consistent with MFAT acting as a disease-modifying rather than a purely symptomatic intervention.