Unraveling the causal web between rheumatoid arthritis and fatigue: from genetic causality to therapeutic targets

Background Fatigue represents a common and disabling extra-articular manifestation of rheumatoid arthritis (RA). However, the extent to which chronic inflammatory diseases share causal genetic links with fatigue remains elusive. This study was therefore designed to identify the causal drivers of fatigue among inflammatory conditions and to elucidate the underlying mechanisms. Methods Fourteen chronic inflammatory diseases (CIDs) were screened using multi-sample and two-sample Mendelian randomization (MR). Key genes were subsequently identified through an integrative pipeline comprising colocalization, transcriptome analysis, single-cell RNA sequencing, in silico knockout, and clinical validation. To quantify mediating pathways, mediation MR analysis was conducted. Finally, drug target prediction was performed using the Comparative Toxicogenomics Database (CTD) and molecular docking. Results The pathogenic effect of RA on fatigue appears to be mediated primarily by anemia rather than direct genetic correlation. ASCC2 interacts with MMP3 and may represents a potential therapeutic target for folic acid and valproic acid. Furthermore, MMP3, IL-1β, and TNF-α were progressively elevated from NC to RA without fatigue (RA group) to RA with fatigue (RF group), whereas ASCC2 was upregulated in the RA group but declined modestly in the RF group. Conclusion RA may represent a unique causal contributor to fatigue, with its effects being potentially mediated primarily by anemia. Furthermore, ASCC2 appears to be a potential therapeutic target for RA-related fatigue.