Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

The role of H3K18la in regulating CDKN1B-mediated autophagy in neuropathic pain

Articles in Press

Document Type : Original Article

Authors
Xiao-Jing Ou 1, 2
Feng-Ting Zhu 1, 2
Man-Yan Zhang 1, 2
Lang Li 2
Wei-Cheng Zhao 1, 2
Xian-Jie Wen 1, 2
1 Foshan Second People’s Hospital, Affiliated Hospital of Guangdong Pharmaceutical University, & Postgraduate Joint Training Base of Guangdong Medical University, Foshan, Guangdong 528000, China
2 Department of Pain, Sleep and Psychotherapy, Foshan Second People’s Hospital, Foshan, Guangdong 528000, China
10.22038/ijbms.2026.94596.20411
Abstract
Objective(s): To investigate the role of histone lactylation in chronic constriction injury (CCI)-induced neuropathic pain and elucidate its mechanism.
Materials and Methods: SD rats were assigned to Normal (n=6), CCI (n=24), and CCI+oxamate (n=24) groups; the latter two were subdivided into four time points (days 1, 4, 7, 14; n=6 each). Oxamate (300 mg/kg, IP) was given on days 0, 2, 4, 6, 10, and 12 to inhibit glycolysis. Pain behaviors were assessed. Spinal lactate and histone H3 lysine 18 lactylation (H3K18la) were measured. CUT&Tag on day 14 identified CDKN1B as an H3K18la target. A separate CDKN1B siRNA group received intrathecal siRNA on days 6, 8, 10, and 12 under oxamate treatment. Spinal IL-6, TNF-α, IL-10, Beclin-1, and LC3-II/LC3-I ratio were detected.
Results: CCI elevated spinal lactate, H3K18la, and pain, with increased inflammation compared with Normal. Oxamate reduced lactate, global H3K18la, pain, and inflammation. CUT&Tag showed higher H3K18la enrichment at the CDKN1B promoter in the oxamate group, along with up-regulated CDKN1B, Beclin-1, and the LC3-II/I ratio. CDKN1B knockdown suppressed these autophagy markers and exacerbated pain and inflammation.
Conclusion: CCI causes spinal lactate accumulation and global H3K18la up-regulation, thereby exacerbating pain and inflammation. Oxamate lowers global H3K18la but specifically increases H3K18la enrichment at the CDKN1B promoter, up-regulating CDKN1B to activate autophagy and alleviate neuropathic pain.
Keywords
Beclin-1
Histone lactylation
L-lactate
LC3
Neuroinflammation
Neuropathic pain
Subjects
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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 31 August 2026