Yin, Guangrong

Abstract The progression of osteoarthritis (OA) is fundamentally characterized by the aberrant transformation of chondrocytes into a fibrotic phenotype, although the precise molecular mechanisms involved remain inadequately understood. In this study, the interplay between epigenetic modifications and metabolic reprogramming during the activation of fibrocartilage cells in osteoarthritis was investigated. The findings demonstrate that FSTL1 markedly upregulates key glycolytic enzymes, including LDHA, HK2, and PKM, in chondrocytes, triggering a “glycolytic burst” that results in elevated intracellular lactate levels. This accumulated lactate acts as a precursor for epigenetic modifications, specifically promoting the lactylation of histone H3 lysine 18 (H3K18la) in fibrocartilage cells, thereby facilitating the transcriptional activation of critical fibrosis‐related genes such as Itga6, Cxcl10, and Parp16. Notably, pharmacological inhibition of the PI3K/mTOR pathway or lactate dehydrogenase significantly diminishes H3K18la levels and markers of chondrocyte fibrosis, while exogenous lactate supplementation can counteract this effect. In summary, this study unveils the core mechanism by which FSTL1 reshapes the epigenetic landscape of chondrocytes and drives the fibrotic process through the activation of the “glycolysis‐lactate‐H3K18la” cascade axis, offering a dual‐target intervention strategy for OA involving metabolic reprogramming and epigenetic modification.

Abstract Senile osteoporosis (SOP) is a systemic bone disease characterized by increased susceptibility to fractures. In this study, it is found that senescent bone marrow mesenchymal stem cells (BMSCs) exhibit increased sensitivity to ferroptosis, a phenomenon associated with Steap4, a nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)‐dependent metalloreductase that reduces Fe 3+ to Fe 2+ . Therefore, it is aimed to innovatively elucidate how Steap4 affects ferroptosis in senescent BMSCs. These findings indicate that Steap4 promotes intracellular Fe 2+ accumulation and elevates reactive oxygen species (ROS) levels, collectively driving the upregulation of CCAAT/enhancer binding protein beta (C/EBPβ) expression. Interestingly, a functional C/EBPβ binding site is identified within the Steap4 promoter region. Mechanistically, knockdown studies demonstrated that C/EBPβ depletion attenuated Steap4 expression, whereas C/EBPβ overexpression conversely upregulated Steap4 levels. These regulatory processes establish a self‐amplifying Steap4/Fe 2+ ‐ROS/C/EBPβ positive feedback loop. Notably, a large number of adipocytes are also observed in the bone marrow of aged mice. Knockdown of Steap4 and C/EBPβ suppressed the differentiation of BMSCs into adipocytes. Knockdown of Steap4 or deferoxamine (DFO) treatment in animal experiments effectively relieves SOP. In conclusion, Steap4 accelerates the onset of ferroptosis in senescent BMSCs and promotes their differentiation to adipocytes through the Steap4/Fe 2+ ‐ROS/C/EBPβ axis, ultimately impairing their osteogenic capacity.

Abstract Background Osteoarthritis (OA) is one of the most common degenerative diseases. Accumulating evidence suggests that ferroptosis may be important in the progression of OA. Angelica Sinensis polysaccharide (ASP), a traditional Chinese medicine, possesses antioxidative, anti-inflammatory and anti-apoptotic properties. However, it is unclear whether ASP can slow down the progression of osteoarthritis by suppressing ferroptosis. Methods Collection of postoperative joint cartilage from patients who underwent total knee arthroplasty (TKA), detection of ferroptosis-related markers including glutathione peroxidase 4 (GPX4) and ferritin heavy polypeptide 1 (FTH1) expression, as well as glutathione (GSH) and malondialdehyde (MDA) levels, and investigation of the correlation between ferroptosis and osteoarthritis. Chondrocytes were isolated and cultured, stimulated separately with IL-1β or erastin, rescued by ASP and ferroptosis inhibitors, and changes in cell viability and ferroptosis were detected. A destabilization of the medial meniscus surgical model (DMM) model was established in mice, and ASP was administered orally at different dosages to evaluate its therapeutic effect and level of ferroptosis. Results First, the expression of GPX4, FTH1 and reduced GSH was lower while the MDA level was up-regulated in cartilage of the OA group as compared to the control group. Moreover, chondrocyte ferroptosis induced by Erastin or IL-1β was rescued by the application of ASP or ferroptosis inhibitors in vitro. Further, the anti-ferroptotic effect of ASP was related to enhanced nuclear transfer of Nrf2 and decreased activation of NF-κB as indicated by down-regulated expression of p-p65. Next, the in vivo experiments showed that ASP alleviated the cartilage damage of mice joints induced by DMM. Conclusions In summary, ASP can attenuate chondrocyte ferroptosis through the Nrf2/NF-κB pathway in the progression of OA, suggesting that ASP may a potential inhibitor of ferroptosis for the treatment of OA.