The abnormal activation of the inflammatory microenvironment is frequently accompanied by metabolic changes that affect the development of various diseases. However, the relationship between metabolic reprogramming and intervertebral disc degeneration (IVDD) remains unclear. This study aims to reveal the metabolic changes in nucleus pulposus (NPCs) during IVDD and investigate the mechanism of glycolysis‐derived lactate on NPCs. Single‐cell RNA sequencing reveals that during IVDD, NPCs are characterized by excessively elevated glycolysis, and the resultant lactate causes the dysfunction of NPCs via ferroptosis activation. Mechanistically, lactate results in the transcription of Acyl‐CoA Synthetase Long Chain Family Member 4 (ACSL4) via promoting Histon H3K18 lactylation. Interestingly, lactate can also increase the lactylation of ACSL4 at K412 site. In addition, lactate‐induced decreased expression of Sirtuin‐3 (SIRT3), and further cause the elevation of ACSL4 lactylation. Finally, animal experiments demonstrate that inhibiting glycolysis through gene silencing with adenoviral‐associated viruses 9 (AAV9)‐si‐Ldha or chemical treatment using 2‐deoxy‐D‐glucose can suppress lactate production and lactylation, thereby ameliorating ferroptosis and NPC dysfunction. The findings of this study indicate that lactate plays a crucial role in IVDD by activating ferroptosis and that interventions aimed at lactate production can offer a potential therapeutical option for patients with IVDD.

Chronic low back pain (CLBP) has been proved to be the dominating cause of disability in patients with lumbar degenerative diseases. Of the various etiological factors, intervertebral disc degeneration (IVDD) has been the dominating cause. In the past few decades, the role and changes of nerve systems, especially the peripheral sensory fibers and their neurotransmitters, in the induction and progression of IVDD have attracted growing concerns. The expression of many neuropeptides, such as SP, NPY, and CGRP, in the nociceptive pathways is increased during the progression of IVDD and responsible for the discogenic pain. Here, the role of CGRP in the progression of IVDD was firstly investigated both in vitro and in vivo. Firstly, we confirmed that human degenerated intervertebral disc tissue exhibited elevated expression of CGRP and its receptor. Secondly, in vitro experiments suggested that CGRP could inhibit the proliferation and induce apoptosis in human nucleus pulposus (NP) cells, as well as promote inflammation and degenerated phenotypes through activating NF‐κB and MAPK signaling pathways. Thirdly, CGRP receptor antagonist, Rimegepant, can ameliorate the adverse effects of CGRP imposed on NP cells, which were confirmed in vitro and in vivo. Our results will bring about a brand‐new insight into the roles of neuromodulation in IVDD and related therapeutic attempts.

Background: Traumatic spinal cord injury (SCI) causes severe motor dysfunction and persistent central neuropathic pain (Nep), which has not yet been effectively cured. Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and contributes to the immune-suppressive in tumor microenvironment. However, the role of PD-L1 in regulating inflammatory response and Nep after SCI remains unclear. A growing amount of researches have begun to investigate the effect of PD-L1 on macrophages and microglia in recent years. Considering the pivotal role of macrophages/microglia in the inflammatory response after SCI, we proposed the hypothesis that PD-L1 improved the recovery of locomotor and sensory functions after SCI through regulating macrophages and microglia. Methods: The mice SCI model was established to determine the changes in expression patterns of PD-L1. Meanwhile, we constructed PD-L1 knockout mice to observe differences in functional recovery and phenotypes of macrophages/microglia post-SCI. Results: In present study, PD-L1 was significantly upregulated after SCI and highly expressed on macrophages/microglia at the injury epicenter. PD-L1 knockout (KO) mice showed worse locomotor recovery and more serious pathological pain compared with wild-type (WT) mice. Furthermore, deletion of PD-L1 significantly increased the polarization of M1-like macrophages/microglia. Mechanistic analysis revealed that PD-L1 may improve functional outcomes following SCI by inhibiting phosphorylation of p38 and ERK1/2. Conclusions: Our observations implicate the involvement of PD-L1 in recovery of SCI and provide a new treatment strategy for the prevention and treatment of this traumatic condition.

Osteolytic bone disease is a condition of imbalanced bone homeostasis, characterized mainly by excessive bone-resorptive activity, which could predispose these populations, such as the old and postmenopausal women, to developing high risk of skeletal fragility and fracture. The nature of bone homeostasis is the coordination between the osteoblasts (OBs) and osteoclasts (OCs). Abnormal activation of osteoclasts (OCs) could compromise the bone homeostasis, constantly followed by a clutch of osteolytic diseases, including postmenopausal osteoporosis, osteoarthritis, and rheumatoid arthritis. Thus, it is imperatively urgent to explore effective medical interventions for patients. The traditional Chinese medicine (TCM) gamabufotalin (CS-6) is a newly identified natural product from Chansu and has been utilized for oncologic therapies owing to its good clinical efficacy with less adverse events. Previous study suggested that CS-6 could be a novel anti-osteoporotic agent. Nevertheless, whether CS-6 suppresses RANK-(receptor activator of nuclear factor-κ B ligand)/TRAF6 (TNF receptor-associated factor 6)-mediated downstream signaling activation in OCs, as well as the effects of CS-6 on OC differentiation in vivo, remains elusive. Therefore, in this present study, we aimed to explore the biological effects of CS-6 on osteoclastogenesis and RANKL-induced activation of related signaling pathways, and further to examine the potential therapeutic application in estrogen-deficient bone loss in the mice model. The results of in vitro experiment showed that CS-6 can inhibit RANKL-induced OC formation and the ability of bone resorption in a dose-dependent manner at both the early and late stages of osteoclastogenesis. The gene expression of OC-related key genes such as tartrate-resistant acid phosphatase (TRAP), CTSK, DC-STAMP, MMP9, and β3 integrin was evidently reduced. In addition, CS-6 could mitigate the systemic estrogen-dependent bone loss and pro-inframammary cytokines in mice in vivo. The molecular mechanism analysis suggested that CS-6 can suppress RANKL/TRAF6-induced early activation of NF-κB and ERK/MAPK signaling pathways, which consequently suppressed the transcription activity of c-Fos and NFATc1. Taken together, this present study provided ample evidence that CS-6 has the promise to become a therapeutic candidate in treating osteolytic conditions mediated by elevated OC formation and bone resorption.

Purpose: Multilevel cervical spondylotic myelopathy poses significant challenges in selecting optimal surgical approaches, warranting a comprehensive understanding of their biomechanical impacts. Given the lack of consensus regarding the most effective technique, this study aims to fill this critical knowledge gap by rigorously assessing and comparing the biomechanical properties of three distinct surgical interventions, including anterior controllable antedisplacement and fusion (ACAF), anterior cervical corpectomy decompression and fusion (ACCF), and anterior cervical discectomy and fusion (ACDF). The study offers pivotal insights to enhance treatment precision and patient outcomes.Methods: The construction of the cervical spine model involved a detailed process using CT data, specialized software (Mimics, Geomagic Studio, and Hypermesh) and material properties obtained from prior studies. Surgical instruments were modeled (titanium mesh, anterior cervical plate, interbody cage, and self‐tapping screws) to simulate three surgical approaches: ACAF, ACCF, and ACDF, each with specific procedures replicating clinical protocols. A 75‐N follower load with 2 Nm was applied to simulate biomechanical effects.Results: The range of motion decreased more after surgery for ACAF and ACDF than for ACCF, especially in flexion and lateral bending. ACCF have higher stress peaks in the fixation system than those of ACAF and ACDF, especially in flexion. The maximum von Mises stresses of the bone–screw interfaces at C3 of ACCF were higher than those of ACAF and ACDF. The maximum von Mises stresses of the bone–screw interfaces at C6 of ACDF were much higher than those of ACAF and ACCF. The maximum von Mises stresses of the grafts of ACCF and ACAF were much higher than those of ACDF. The maximum von Mises stresses of the endplate of ACCF were much higher than those of ACAF and ACDF.Conclusion: The ACAF and ACDF models demonstrated superior cervical reconstruction stability over the ACCF model. ACAF exhibited lower risks of internal fixation failure and cage subsidence compared to ACCF, making it a promising approach. However, while ACAF revealed improved stability over ACCF, higher rates of subsidence and internal fixation failure persisted compared to ACDF, suggesting the need for further exploration of ACAF's long‐term efficacy and potential improvements in clinical outcomes.