# ACADL and ADH1B signify ketone body metabolic reprogramming in osteoarthritic synovium: insights from bioinformatics and animal model studies

## TL;DR

This study identifies ACADL and ADH1B as key genes in synovial ketone body metabolism linked to osteoarthritis, offering potential for early diagnosis and targeted therapies.

## Contribution

The study discovers ACADL and ADH1B as novel OA biomarkers and proposes progesterone and fomepizole as potential targeted therapies.

## Key findings

- ACADL and ADH1B are associated with synovial inflammation and lipid oxidation in OA.
- Progesterone and fomepizole show strong binding affinities to ACADL and ADH1B, respectively.
- Mouse models confirmed reduced protein levels in OA synovium.

## Abstract

Osteoarthritis (OA) is characterized by articular degeneration and chronic joint pain, partly resulting from synovial inflammation. Accumulating evidence suggests that alterations in the synovial ketone body metabolism (KBM) are closely associated with OA pathogenesis. This study aimed to investigate the metabolic changes in synovial tissues to optimize the treatment of clinical OA.

Analysis of OA and normal control synovial transcriptomic datasets extracted from the Gene Expression Omnibus (GEO) identified 808 differentially expressed genes (DEGs). These DEGs were integrated with KBM-related genes from the metabolic databases, yielding 50 candidates related to OA progression. Following enrichment analysis, protein-protein interaction network construction via STRING, and machine learning with expression analysis, two genes were identified as OA biomarkers: ACADL, encoding long-chain acyl-CoA dehydrogenase and ADH1B, alcohol dehydrogenase 1 B.

The nomogram based on these data revealed high accuracy in the training and validation sets. Functional analysis revealed that these genes function in lipid oxidation, a process critical for synovial cell energy metabolism, as well as in the redox balance that prevents oxidative stress from worsening OA inflammation. Immune infiltration analysis revealed that their expression significantly correlated with 21 immune subtypes, including pro-inflammatory M1 macrophages and Th17 cells, which drive synovial inflammation. Molecular docking analysis identified progesterone and fomepizole as potential agents with satisfactory affinities for ACADL and ADH1B, respectively. Assessment of mouse models of OA confirmed a significant reduction in the synovium at the protein level.

ACADL and ADH1B link KBM abnormalities to immune dysregulation in the OA synovium. The nomogram enables the precise early diagnosis of OA, and progesterone and fomepizole are promising targeted therapies. These findings deepen the current understanding of OA pathogenesis and support the advancement of personalized treatments for clinical translation.