The prior observational research on the impact of polyunsaturated fatty acid (PUFA) supplementation on osteoarthritis (OA) patients had yielded inclusive outcomes. This study utilized the Mendelian randomization (MR) approach to explore potential causal relationships between PUFAs and OA. The MR study was performed using GWAS summary statistics for PUFAs, encompassing omega-3 and omega-6 fatty acids, and for knee OA (KOA) and hip OA (HOA). The primary inverse-variance-weighted (IVW) method and two supplementary MR approaches were used to establish robust causality. Heterogeneity and horizontal pleiotropy were assessed using Cochrane’s Q and MR-Egger intercept tests. Additionally, a range of sensitivity analyses were conducted to strengthen the precision and reliability of the results. The IVW method indicated a potential genetic association between omega-3 fatty acids and KOA risk (odd ratio (OR) = 0.94, 95% confidence interval (CI): 0.89–1.00, p = 0.048). No significant correlation was found between omega-3 levels and HOA. Moreover, genetically predicted higher levels of omega-6 fatty acids were associated with a decreased risk of KOA (OR = 0. 93, 95% CI: 0.86–1.00, p = 0.041) and HOA (OR = 0.89, 95% CI: 0.82–0.96; p = 0.003). The MR-Egger intercept evaluation showed no horizontal pleiotropy affecting the MR analysis (all p > 0.05). Our findings supported the causal relationship between PUFAs and OA susceptibility and offered a novel insight that high omega-6 fatty acids may reduce the risk of KOA and HOA. These results underscore the importance of maintaining optimal levels of PUFAs, particularly omega-6 fatty acids, in individuals with a genetic predisposition to OA. Future research is necessary to validate these findings and elucidate the underlying mechanisms involved.

Background: This exploratory study aimed to characterize amino acid related features in osteoarthritis (OA). Methods: We analyzed independent public synovial transcriptomic datasets and paired fecal metabolomics and 16S ribosomal RNA profiles from 20 patients with knee OA and 14 controls. Metabolite-sensing genes were intersected with nominally differential genes and prioritized using elastic net, support vector machine recursive feature elimination, and extreme gradient boosting. Results:SLC1A5 (solute carrier family 1 member 5) expression was lower in the discovery cohort GSE89408 (log2 fold change = −0.532, p = 0.0159), but did not meet the false discovery rate (FDR) threshold of 0.05 (FDR = 0.0697). GSE55235 showed a concordant decrease (log2 fold change = −0.695, p = 0.00536; area under the receiver operating characteristic curve = 0.830). Single-cell computational predictions from three OA donors suggested endothelial, smooth muscle, and mast-cell contexts. Tissue-level SLC1A5 expression correlated with inferred M2 macrophage proportions after group adjustment (r = −0.575, FDR = 0.002). Six features with Level 3 putative glutamine-, asparagine-, or glutamate-containing tripeptide annotations differed between groups (q = 0.00245 to 0.00948), whereas the corresponding free amino acids did not reach FDR significance. Bacteroides showed a lower centered log-ratio value in OA (q = 0.00273); none of its six tripeptide correlations remained significant after group adjustment. Conclusions: These observations generate a hypothesis about intestinal amino acid-related features and synovial SLC1A5 expression; they do not establish a direct gut-joint relationship, peptide identity, or a metabolic mechanism.