BACKGROUND: Osteoarthritis (OA), a chronic degenerative disease, is characterized by the loss of articular cartilage, impacting more than 500 million individuals worldwide. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA derived from Salvia miltiorrhiza and has anti-inflammatory and anti-oxidative functions. Although STS shows significant pharmacological effects and mechanisms in treating various diseases in vivo and in vitro, its specific treatments and mechanisms for OA remain largely unknown. MATERIALS AND METHODS: Primary chondrocytes were stimulated with interleukin-1β (IL-1β) to establish an in vitro OA model. The optimal concentration of STS for application on chondrocytes was determined to be 100 μM using MTT assays. The effects of STS on catabolic gene expression were assessed through real-time quantitative PCR (RT-qPCR). Western blotting, immunoprecipitation (IP), and mutation techniques were employed to investigate the impact of STS on the deacetylation of nuclear factor kappa B subunit p65 (NF-κB p65) at Lys310 by silent information regulator 1 (SIRT1). Furthermore, RT-qPCR, Enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy, and immunohistochemistry staining were utilized to elucidate the molecular mechanisms underlying NF-κB-driven inflammation and ferroptosis. The destabilization of the medial meniscus (DMM) surgery-induced OA mouse model was employed to evaluate the therapeutic potential of STS in OA treatment. Safranin O-fast green and hematoxylin and eosin (HE) staining analyses were conducted to assess the impact of STS on OA. Additionally, tamoxifen (TM)-inducible Sirt1 cartilage-specific conditional knockout (Sirt1cKO) mice were utilized to further validate the effects of STS on OA. RESULTS: STS suppressed the gene expression levels of collagen type X alpha 1 (COL10A1), matrix metalloproteinase-13 (MMP13), and Caspase3, thereby mitigating matrix degradation and apoptosis in IL-1β-induced primary chondrocytes. Additionally, STS enhanced the expression of SIRT1 in these cells. Furthermore, STS facilitated the deacetylation of NF-κB p65 at Lysine (K) 310 by SIRT1 in primary chondrocytes. STS also inhibited NF-κB p65-mediated inflammation and ferroptosis, contributing to the amelioration of OA. In the DMM surgery-induced OA mice model, STS mitigated OA phenotypes by inhibiting matrix degradation and apoptosis, facilitating SIRT1-mediated deacetylation of NF-κB p65, and subsequently suppressing NF-κB p65-driven inflammation and ferroptosis. Finally, the use of Sirt1cKO transgenic mice further confirmed the effects of STS in attenuating OA progression. CONCLUSION: STS ameliorated OA by activating SIRT1 and inhibiting NF-κB p65-driven inflammation and ferroptosis, indicating its potential therapeutic application in OA patients.