ATF4 transcriptionally activates NUPR1 to promote ferroptosis in chondrocytes and osteoarthritis development.

Osteoarthritis (OA) is a common degenerative joint disease characterized by cartilage destruction and inflammation. This study reveals that activating transcription factor 4 (ATF4) is upregulated in IL-1β-treated chondrocytes and promotes ferroptosis, a form of programmed cell death. Knockdown of ATF4 alleviated cartilage damage and reduced ferroptosis in both cell and mouse models. Mechanistically, ATF4 directly binds to the promoter of nuclear protein 1 (NUPR1) and activates its transcription. Overexpression of NUPR1 reversed the protective effects of ATF4 knockdown, confirming the critical role of the ATF4-NUPR1 axis in mediating ferroptosis and OA progression. These findings identify ATF4 as a key driver of OA via ferroptosis regulation and suggest that targeting the ATF4-NUPR1 pathway may offer a promising therapeutic strategy.