Drug‐Induced Cuproptosis Defines the Therapeutic Window of Celecoxib in Intervertebral Disc Degeneration via the HSP90‐RBX1 Axis

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 µ m ) suppresses inflammation and preserves extracellular matrix (ECM). In contrast, high‐dose celecoxib (>20 µ m ) 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.