Abstract
ABSTRACT
Osteoarthritis (OA) is a chronic degenerative joint disease and a leading cause of disability worldwide, yet no disease‐modifying therapies are currently available. The role of synovial macrophages in OA pathogenesis remains incompletely understood, and the molecular mechanisms by which they drive cartilage destruction have not been fully elucidated. By integrating human OA microarrays, synovial single‐cell RNA‐seq, and multi‐level validation, we identified lymphocyte‐specific protein 1 (LSP1) as a macrophage‐specific hub gene upregulated in OA. Mechanistically, LSP1 directly binds to and inhibits superoxide dismutase 1 (SOD1), inducing a redox imbalance that concurrently activates the NADPH oxidase (NOX) and mitochondrial reactive oxygen species (mtROS) pathways. This cascade drives the release of macrophage extracellular traps (METs), which directly damage chondrocytes and accelerate OA progression. Virtual screening of the DrugBank database identified the cardiac glycoside digoxin as a compound that competitively binds LSP1, restores SOD1 activity, and suppresses the NOX/mtROS‐METs axis. This study defines a novel LSP1‐SOD1‐METs pathogenic axis in OA and nominates digoxin as a repurposable therapeutic candidate. Unlike its previously reported cartilage‐targeting mechanism, digoxin alleviates OA by suppressing synovial inflammation via LSP1 targeting, highlighting its dual‐target potential for concurrent modulation of synovial and cartilage pathology.