Abstract

Intervertebral disc degeneration (IDD) is a major cause of low back pain, yet the biological effects of commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on disc cells remain poorly understood. Celecoxib is widely prescribed for IDD-related pain, but its direct influence on IDD has not been systematically examined. Here, we identify a concentration-dependent biphasic effect of celecoxib on nucleus pulposus (NP) cells and uncover the mechanism that converts celecoxib from protective to detrimental. Using interleukin-1β-stimulated NP cells and rat IDD models, we show that low-dose celecoxib (≤20 µm) suppresses inflammation and preserves extracellular matrix (ECM). In contrast, high-dose celecoxib (>20 µm) activates a previously unrecognized heat shock protein 90 (HSP90)/RING-box protein 1 (RBX1)/cuproptosis axis, leading to copper accumulation, mitochondrial stress, and ECM degradation. Mechanistically, elevated celecoxib induces HSP90 upregulation, which stabilizes RBX1 by reducing its K48-linked ubiquitination. Accumulated RBX1 promotes ATPase copper transporting beta (ATP7B) and its regulator copper metabolism domain containing 1 (COMMD1) degradation, thereby triggering cuproptosis. Pharmacologic inhibition of HSP90 or cuproptosis effectively reverses the detrimental effects of high-dose celecoxib in vivo. Together, these findings define a strict therapeutic window for celecoxib in IDD and reveal a novel HSP90/RBX1-mediated cuproptosis pathway that mediates its dual effects.