2. Academic Validation
  3. Cavidine alleviates paclitaxel-induced peripheral neuropathy by promoting mitochondrial autophagy through inhibiting PKM2-mediated histone lactylation

Cavidine alleviates paclitaxel-induced peripheral neuropathy by promoting mitochondrial autophagy through inhibiting PKM2-mediated histone lactylation

  • Free Radic Biol Med. 2025 Sep 24:241:367-383. doi: 10.1016/j.freeradbiomed.2025.09.049.
Zhenhui Luo 1,  Zicen Fang 2,  Xiaomin Cheng 3,  Shuqi Shi 4,  Cao Di 5,  Peikun He 6,  Haiqiang Wu 7,  Chuanming Wang 8,  Wuping Sun 9
Affiliations

Affiliations

  • 1 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, National Key Clinic of Pain Medicine, Shenzhen Nanshan People's Hospital, and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518060, China; Guangdong Key Laboratory for Biomedical Measurement and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering Shenzhen University Medical School, Shenzhen, 518060, China.
  • 2 NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 The Research Center of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, 510000, Guangzhou, China.
  • 4 Department of Clinical Laboratory Medicine, The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, 510900, China.
  • 5 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, National Key Clinic of Pain Medicine, Shenzhen Nanshan People's Hospital, and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518060, China.
  • 6 Guangdong Key Laboratory for Biomedical Measurement and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering Shenzhen University Medical School, Shenzhen, 518060, China; Department of Infectious Diseases, Shenzhen Nanshan People's Hospital and Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518052, China.
  • 7 School of Pharmacy, Shenzhen University Medical School, Shenzhen, 518055, China.
  • 8 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, National Key Clinic of Pain Medicine, Shenzhen Nanshan People's Hospital, and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518060, China. Electronic address: wchm1212@163.com.
  • 9 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, National Key Clinic of Pain Medicine, Shenzhen Nanshan People's Hospital, and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518060, China; Department of Clinical Laboratory Medicine, The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, 510900, China. Electronic address: wuping.sun@foxmail.com.
PMID: 41005738 DOI: 10.1016/j.freeradbiomed.2025.09.049
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.

Keywords

CIPN; Cavidine; Histone lactylation; Mitophagy; PKM2; Paclitaxel.

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