Zhenhui Luo , Zicen Fang , Xiaomin Cheng , Shuqi Shi , Cao Di , Peikun He , Haiqiang Wu , Chuanming Wang , Wuping Sun
{"title":"Cavidine alleviates paclitaxel-induced peripheral neuropathy by promoting mitochondrial autophagy through inhibiting PKM2-mediated histone lactylation","authors":"Zhenhui Luo , Zicen Fang , Xiaomin Cheng , Shuqi Shi , Cao Di , Peikun He , Haiqiang Wu , Chuanming Wang , Wuping Sun","doi":"10.1016/j.freeradbiomed.2025.09.049","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of chemotherapy, with limited therapeutic options due to unclear mechanisms. Cavidine (CAV), a natural alkaloid, has been shown to possess both anti-inflammatory and neuroprotective properties. However, further research is required to elucidate its role in CIPN and the underlying mechanisms by which it exerts its effects.</div></div><div><h3>Purpose</h3><div>To examine the therapeutic efficacy of CAV in relation to CIPN, with a view to elucidating its underlying mechanism, which is associated with mitophagy and PKM2-mediated histone lactylation.</div></div><div><h3>Methods</h3><div>The post-CAV treatment assessment included the evaluation of mechanical allodynia, thermal hyperalgesia, and footpad immunofluorescence. To identify the regulated pathways of CAV, RNA-seq and lactate metabolomics were performed. The evaluation of mitophagy was conducted through the utilization of immunofluorescence, along with transmission electron microscopy. In addition, the analysis of histone lactylation at H3K18la was undertaken. The use of molecular docking and biolayer interferometry assay confirmed the interactions between CAV-PKM2.</div></div><div><h3>Results</h3><div>CAV significantly alleviated both mechanical and thermal pain, as well as peripheral nerve injury, in mice suffering from CIPN. Mechanistically, CAV suppressed PKM2 activity, reducing lactate accumulation and histone H3K18 lactylation. This inhibition promoted mitochondrial autophagy, evidenced by decreased LC3B-II, upregulated PINK1/Parkin, and reduced p62, and promoted the integration of autophagosomes and lysosomes. Molecular docking and biolayer interferometry assay demonstrated high-affinity binding between CAV and the allosteric site of PKM2.</div></div><div><h3>Conclusion</h3><div>CAV alleviates CIPN by enhancing mitophagy via inhibition of PKM2-driven histone lactylation, thus providing a novel therapeutic strategy for CIPN.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 367-383"},"PeriodicalIF":8.2000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free Radical Biology and Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0891584925010068","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of chemotherapy, with limited therapeutic options due to unclear mechanisms. Cavidine (CAV), a natural alkaloid, has been shown to possess both anti-inflammatory and neuroprotective properties. However, further research is required to elucidate its role in CIPN and the underlying mechanisms by which it exerts its effects.
Purpose
To examine the therapeutic efficacy of CAV in relation to CIPN, with a view to elucidating its underlying mechanism, which is associated with mitophagy and PKM2-mediated histone lactylation.
Methods
The post-CAV treatment assessment included the evaluation of mechanical allodynia, thermal hyperalgesia, and footpad immunofluorescence. To identify the regulated pathways of CAV, RNA-seq and lactate metabolomics were performed. The evaluation of mitophagy was conducted through the utilization of immunofluorescence, along with transmission electron microscopy. In addition, the analysis of histone lactylation at H3K18la was undertaken. The use of molecular docking and biolayer interferometry assay confirmed the interactions between CAV-PKM2.
Results
CAV significantly alleviated both mechanical and thermal pain, as well as peripheral nerve injury, in mice suffering from CIPN. Mechanistically, CAV suppressed PKM2 activity, reducing lactate accumulation and histone H3K18 lactylation. This inhibition promoted mitochondrial autophagy, evidenced by decreased LC3B-II, upregulated PINK1/Parkin, and reduced p62, and promoted the integration of autophagosomes and lysosomes. Molecular docking and biolayer interferometry assay demonstrated high-affinity binding between CAV and the allosteric site of PKM2.
Conclusion
CAV alleviates CIPN by enhancing mitophagy via inhibition of PKM2-driven histone lactylation, thus providing a novel therapeutic strategy for CIPN.
期刊介绍:
Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.