HDACs x HMOX1 x Nrf2

Glioblastoma is a fast-growing, invasive brain tumor with poor prognosis. Polyphyllin I, a saponin from Liliaceae plants, shows anti-tumor, anti-inflammatory effects, and induces ferroptosis, but its impact on glioblastoma and underlying mechanisms are not well understood.

Tumor malignancy was evaluated using assays such as scratch assays, CCK-8, clonogenic analyses, transwell experiments, along with EdU incorporation staining. Quantification for relevant molecules was performed using WB and RT-qPCR experiments. Ferroptosis in cells was quantified using JC-1, Boodipy, and TME assays. Lastly, the in vivo anti-tumor effects and mechanisms of Polyphyllin I were examined using a mouse xenograft model.

This study reveals how PPI significantly inhibits GBM growth and spread while simultaneously improving the efficacy of chemotherapy drugs. In addition, the anti-tumor properties of PPI are linked to ferroptosis, and its effect is significantly diminished when ferroptosis is inhibited. Specifically, PPI binds directly to SIRT1, reducing its levels, which subsequently promotes oxidative cell death via the SIRT1/Nrf2/GPX4/HO-1 signaling pathway, thus suppressing glioblastoma. Furthermore, overexpression of SIRT1 can negate the therapeutic effects of PPI. The mouse xenograft model further supported the anti-tumor efficacy of PPI and provided deeper insights into its underlying mechanism.

Additionally, through regulating the SIRT1/Nrf2/GPX4/HO-1 axis, PPI induces iron-dependent cell death, contributing to its inhibition of glioblastoma. According to this research, PPI could serve as a superior treatment approach for GBM patients and holds promise for its combination with chemotherapy drugs in GBM treatment.

Autism spectrum disorder (ASD) is a diverse collection of neurodevelopmental disorders often accompanied by excessive oxidative stress and chronic inflammatory responses. Selenium (Se), a trace element, has demonstrated anti-inflammatory, antioxidant, and neuroprotective effects. The present study aimed to examine the effects of sodium selenite, a Se supplement, on a rat model of ASD. The valproic acid intervention method was used during pregnancy to construct an ASD rat model. Rats were then treated with sodium selenite. Behavioral tests, morphological assessments, and measurements of antioxidant enzymes, oxidative stress indicators, and inflammatory factors in the hippocampal tissues and serum were conducted. Se supplementation mitigated inflammatory responses and oxidative stress in ASD rats while preserving neuronal morphology and function. In addition to Se supplementation, rats received specific inhibitors targeting the signaling pathway. Protein and mRNA expression levels, as well as the tissue distribution of sirtuin 1 (Sirt1), heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap1), were evaluated. The results demonstrated that Se treatment upregulated the expression levels of Sirt1, Nrf2, and HO-1, while downregulating Keap1 expression. These findings demonstrate that Se attenuates inflammatory damage and oxidative stress in the brain, and this protective effect is associated with the Sirt1/Keap1/Nrf2/HO-1 signaling pathway.

Osteoarthritis (OA) is a prevalent joint disease featured by articular cartilage destruction, causing a huge socio-economic burden worldwide. Repressing endoplasmic reticulum stress (ERS)-mediated ferroptosis can alleviate the progression of OA. Sirtuin 6 (SIRT6) has been shown to suppress OA, but whether SIRT6 can regulate ferroptosis in OA through ERS remains unclear.

In this study, both in vivo and in vitro models of OA were constructed. Micro-CT scans and three-dimensional reconstruction were used to observe the structural injury of knee joint in mice. H&E, TB, SOFG and TUNEL staining were employed to conduct pathological examination of cartilage tissues. The levels of inflammatory factors were analyzed using ELISA. Besides, ERS was assessed by detecting the levels of ERS-related proteins using immunohistochemistry, immunoblotting and immunofluorescence staining. Iron deposition in cartilage tissues was tested by prussian blue staining. Moreover, the contents of intracellular ROS, lipid ROS and Fe²⁺ were evaluated in IL-1β-stimulated C28/I2 cells. Finally, ML385 (an inhibitor of Nrf2) or tunicamycin (an agonist of ERS) was added to C28/I2 cells to elucidate the exact mechanism.

SIRT6 upregulation reduced the structural injury and inflammation in cartilage tissues of OA mice. ERS and ferroptosis were inhibited by SIRT6 overexpression in cartilage tissues of OA mice and C28/I2 cells exposed to IL-1β. Additionally, SIRT6 upregulation activated Nrf2/HO-1 signaling, as evidenced by elevated nuclear Nrf2 and HO-1 expression. Further, ML385 treatment attenuated the impacts of SIRT6 overexpression on inflammation, ERS and ferroptosis in C28/I2 cells under IL-1β conditions. Particularly, tunicamycin intervention blocked the effects of SIRT6 upregulation on ferroptosis in IL-1β-treated C28/I2 cells.

Collectively, SIRT6 inhibits ERS-medicated ferroptosis through activation of Nrf2/HO-1 pathway in chondrocytes to alleviate OA.