Rheumatoid arthritis (RA) is characterized by the aggressive transformation of fibroblast-like synoviocytes (FLS). While dysregulated copper homeostasis (cuproptosis) and aberrant Wnt/β-catenin signaling are implicated in RA, the molecular link connecting metabolic copper handling to synovial hyperplasia remains elusive. We hypothesized that Lipoyltransferase-1 (LiPT1), a key cuproptosis regulator, acts as a metabolic checkpoint driving FLS dysfunction.

We integrated three RA synovial transcriptome datasets using Weighted Gene Co-expression Network Analysis (WGCNA) to identify hub genes associated with cuproptosis. Validation was performed in peripheral blood mononuclear cells (PBMCs) from RA patients. In cultured RA-FLS, the functional role of LiPT1 was assessed via siRNA-mediated knockdown, followed by evaluation of cell viability, migration, and oxidative stress markers. A rescue experiment using the Wnt agonist SKL2001 was conducted to confirm pathway dependency.

LiPT1 and MTF1 were identified as key cuproptosis-related genes upregulated in RA synovial tissues, a finding systematically validated in RA patient PBMCs. Functionally, LiPT1 knockdown in RA-FLS significantly suppressed cell viability and migratory capacity. Notably, LiPT1 silencing disrupted copper handling, leading to intracellular copper accumulation, while paradoxically restoring redox balance (increased SOD/POD activity, decreased MDA levels). Mechanistically, LiPT1 depletion inactivated the Wnt/β-catenin pathway. Crucially, pharmacological re-activation of Wnt signaling with SKL2001 not only reversed the phenotypic inhibition but also restored LiPT1 expression, indicating a positive feedback loop between LiPT1 and the Wnt signaling cascade.

Our study reveals that LiPT1 orchestrates RA-FLS pathogenicity by maintaining metabolic homeostasis and driving a reciprocal LiPT1-Wnt/β-catenin regulatory circuit. Targeting this metabolic-signaling axis may offer a novel therapeutic strategy to disrupt the aggressive phenotype of synovial fibroblasts in RA.

In summary, this study uncovers a novel pathological axis in rheumatoid arthritis (RA), wherein the cuproptosis-related gene LiPT1 acts as a metabolic checkpoint to drive fibroblast-like synoviocyte (FLS) dysfunction. By integrating bioinformatic screening with functional validation, we demonstrate that aberrant LiPT1 upregulation enables RA-FLS to maintain low intracellular copper levels and evade cuproptosis, thereby promoting cell survival and aggressive migration. Mechanistically, this process is reinforced by a reciprocal positive feedback loop between LiPT1 and the Wnt/β-catenin signaling pathway: LiPT1 activates Wnt signaling to sustain its own expression, locking FLS in a hyper-proliferative state. Consequently, targeting the LiPT1-Wnt axis to disrupt this metabolic adaptation represents a promising therapeutic strategy to restore synovial homeostasis and sensitize pathogenic fibroblasts to copper-induced cell death(Fig. 6).