Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated. To identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis. Chondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4^flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested. Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium. Our findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment.

Intervertebral disc degeneration (IVDD) is one of the most prevalent spinal degenerative disorders and imposes places heavy medical and economic burdens on individuals and society. Mechanical overloading applied to the intervertebral disc (IVD) has been widely recognized as an important cause of IVDD. Mechanical overloading-induced chondrocyte ferroptosis was reported, but the potential association between ferroptosis and mechanical overloading remains to be illustrated in nucleus pulposus (NP) cells. In this study, we discovered that excessive mechanical loading induced ferroptosis and endoplasmic reticulum (ER) stress, which were detected by mitochondria and associated markers, by increasing the intracellular free Ca²⁺ level through the Piezo1 ion channel localized on the plasma membrane and ER membrane in NP cells. Besides, we proposed that intracellular free Ca²⁺ level elevation and the activation of ER stress are positive feedback processes that promote each other, consistent with the results that the level of ER stress in coccygeal discs of aged Piezo1-CKO mice were significantly lower than that of aged WT mice. Then, we confirmed that selenium supplementation decreased intracellular free Ca²⁺ level by mitigating ER stress through upregulating Selenoprotein K (SelK) expression. Besides, ferroptosis caused by the impaired production and function of Glutathione peroxidase 4 (GPX4) due to mechanical overloading-induced calcium overload could be improved by selenium supplementation through Se-GPX4 axis and Se-SelK axis in vivo and in vitro, eventually presenting the stabilization of the extracellular matrix (ECM). Our findings reveal the important role of ferroptosis in mechanical overloading-induced IVDD, and selenium supplementation promotes significance to attenuate ferroptosis and thus alleviates IVDD, which might provide insights into potential therapeutic interventions for IVDD.

Prolonged and incurable bacterial infections in soft tissue and bone are currently causing large challenges in the clinic. Two-dimensional (2D) materials have been designed to address these issues, but materials with satisfying therapeutic effects are still needed. Herein, CaO₂-loaded 2D titanium carbide nanosheets (CaO₂-TiO_x@Ti₃C₂, C-T@Ti₃C₂) were developed. Surprisingly, this nanosheet exhibited sonodynamic ability, in which CaO₂caused the in situ oxidation of Ti₃C₂MXene to produce acoustic sensitiser TiO₂on its surface. In addition, this nanosheet displayed chemodynamic features, which promoted a Fenton reaction triggered by self-supplied H₂O₂. We detected that C-T@Ti₃C₂nanosheets increased reactive oxygen species (ROS) production in response to sonodynamic therapy, which displayed an ideal antibacterial effect. Furthermore, these nanoreactors facilitated the deposition of Ca²⁺, which promoted osteogenic transformation and enhanced bone quality in osteomyelitis models. Herein, a wound healing model and prosthetic joint infection (PJI) model were established, and the C-T@Ti₃C₂nanosheets played a protective role in these models. Taken together, the results indicated that the C-T@Ti₃C₂nanosheets function as a multifunctional instrument with sonodynamic features, which might reveal information regarding the treatment of bacterial infections during wound healing.Graphical Abstract

Osteoarthritis (OA) has emerged as a significant health concern among the elderly population, with increasing attention paid to ferroptosis-induced OA in recent years. However, the prolonged use of nonsteroidal anti-inflammatory drugs or corticosteroids can lead to a series of side effects and limited therapeutic efficacy. This study aimed to employ the Mannich condensation reaction between epigallocatechin-3-gallate (EGCG) and selenomethionine (SeMet) to efficiently synthesize polyphenol-based nanodrugs in aqueous media for treating OA. Molecular biology experiments demonstrated that EGCG-based nanodrugs (ES NDs) could effectively reduce glutathione peroxidase 4 (GPX4) inactivation, abnormal Fe²⁺ accumulation, and lipid peroxidation induced by oxidative stress, which ameliorated the metabolic disorder of chondrocytes and other multiple pathological processes triggered by ferroptosis. Moreover, imaging and histopathological analysis of the destabilization of the medial meniscus model in mice confirmed that ES NDs exhibiting significant therapeutic effects in relieving OA. The intra-articular delivery of ES NDs represents a promising approach for treating OA and other joint inflammatory diseases.

Intervertebral disc degeneration (IVDD), one of the most common clinical diseases worldwide, causes disc herniation and sciatica. Recent studies have identified the involvement of mitochondrial dysfunction, inflammatory responses, and extracellular matrix degradation in IVDD. Mangiferin is known to protect against various diseases by inhibiting oxidative stress, suppressing inflammation reaction, and relieving mitochondrial dysfunction. Whether mangiferin can alleviate IVDD remains to be elucidated. In the present study, human nucleus pulposus cells (HNPCs) and mouse intervertebral discs were cultured and stimulated with TNF‐α, with or without treatment of mangiferin. Moreover, we established a rat needle puncture model and injected mangiferin into the intervertebral discs to verify its protective effect on IVDD. Furthermore, the activity of the NF‐κB signaling pathway was tested in vitro. Our results indicated that mangiferin alleviated the inflammatory response and reversed the loss of major intervertebral disc components. Besides, mangiferin reduced reactive oxygen species production, ameliorated mitochondrial damage, and decreased the expression of apoptosis‐related parameters in stimulation of TNF‐α. In addition, mangiferin antagonized the activation of the NF‐κB signaling pathway induced by TNF‐α. Collectively, mangiferin antagonized mitochondrial ROS in NP cells and protected against IVDD by suppressing the activation of the NF‐κB signaling pathway, which might provide a potential therapeutic instrument for IVDD.