Zoledronic acid induces ferroptosis by upregulating POR in osteosarcoma.

Osteosarcoma, usually originating in the stroma, is the most common primary bone cancer in adolescents, and its prognosis is poor. Surgery, adjuvant and neoadjuvant chemotherapy and radiation therapy are not satisfactory at the present time. Therefore, it is critical to develop novel therapeutic strategies to improve the quality of life and long-term survival rate of osteosarcoma patients. In this study, we discovered that zoledronic acid (ZOL) dramatically increased cell death in osteosarcoma cells, and this cytotoxicity was greatly reversed by liproxstatin-1 (a ferroptosis inhibitor). ZOL also had an obvious effect on lipid peroxidation and reactive oxygen species (ROS), which suggested that ZOL most certainly induces ferroptosis in osteosarcoma cells. In addition, we further found that ZOL increases cytochrome P450 oxidoreductase (POR) expression dose dependently in osteosarcoma cell lines. Knockdown of POR attenuated ZOL-induced cytotoxicity and attenuated the effect of ferroptosis in osteosarcoma cells, which indicated that POR plays an important role in ferroptosis. Moreover, we also found that ZOL inhibits osteosarcoma growth in vivo. Our findings suggest that ZOL induces ferroptosis by upregulating POR expression to increase ROS levels and upregulate lipid peroxidation levels in osteosarcoma cells. POR may be used as a therapeutic target to inhibit osteosarcoma.

Interleukin-23 mediates the reduction of GADD45a expression to attenuate oxidative stress-induced cellular senescence in human fibroblasts.

The interleukin-23 (IL-23) plays a key role in various inflammatory diseases, such as spondyloarthritis, by acting on target cells through the IL-23/IL-17 pathway. Recent studies have suggested that IL-23 can also directly affect fibroblasts. Senescent fibroblasts are implicated in many physiological and pathological processes, including those related to inflammatory diseases. However, it remains unclear whether IL-23 can influence fibroblast senescence and contribute to pathogenesis. In our study, we investigated the effects of IL-23 on oxidative stress-induced senescence in human fibroblasts, using the H2O2-induced senescence model, and found that IL-23 pre-treatment significantly attenuated senescence in these cells. RNA-seq and in vitro experiments indicate that IL-23 may act by regulating GADD45a expression and the p38/MAPK pathway. Furthermore, we confirmed that IL-23 inhibits oxidative stress-induced up-regulation of GADD45a expression and subsequent activation of the p38/MAPK pathway through GADD45a knockdown and overexpression experiments. Our study is the first to demonstrate that IL-23 can effectively suppress the senescence of fibroblasts induced by oxidative stress, by inhibiting the H2O2-triggered induction of GADD45a and subsequent activation of the p38/MAPK pathway. These findings have significant implications for understanding the role of IL-23 in immune-inflammatory diseases and may provide a new avenue for the diagnosis and treatment of these conditions.